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Jak zlepšit odolnost firmy: Řízení rizik vyplývajících z vypršení platnosti certifikátů MDD

veronikav@arete-zoe.com (Veronika Valdova) — Sun, 13 Nov 2022 14:06:42 GMT

Jak řídit rizika vyplývající z vypršení platnosti certifikátů MDD

V současné době je v České republice jediný oznámený subjekt s kompetencí pro MDR, který ovšem stále ještě čeká na akreditaci. Jeden oznámená subjekt, který přijímá podání v češtině, je na Slovensku. Zpoždění v akreditaci způsobilo nahromadění značného počtu podání žádostí o certifáty. Požadavky MDR jsou složitější a přísnější jak pro zpracovatele, tak pro posuzovatele v oznámených subjektech. Tato situace činí proces podání zranitelným z celé řady důvodů, což představuje rizika, která mohou být a měla by být minimalizována!

Potenciální důsledky zpoždění certifikace mohou být pro některé výrobce kritické. Stojí zato riskovat náklady související s prodlením z důvodu nutných revizí nebo zamítnutí, a trvat na zpracování podání svépomocí? Získejte pro svůj tým posouzení od týmu s historií úspěšných MDR podání! Kontaktujte Arete-Zoe pro posouzení vaší situace a zajistěte si včas pomoc s Vaším podáním, která sníží riziko zpoždění pro Vaši firmu! Zůstaňte agilní, konkurenceschopní a ziskoví!

Jaká je současná situace?

Nařízení (EU) 2017/745 o zdravotnických prostředcích (Nařízení o zdravotnických prostředcích, MDR), které bylo přijato v dubnu 2017, vstoupilo v platnost 26. května 2021 po ročním zpoždění kvůli Covidu [1] . Platnost certifikátů vydaných podle stávajících směrnic pro zdravotnické prostředky (Směrnice 93/42/EHS a AIMD, 90/385/EHS) vyprší nejpozději 24. května. Poté budou muset všichni výrobci, kteří chtějí své výrobky udržet na evropském trhu, aktualizovat veškerou dokumentaci na nové standardy. Nové požadavky jsou nesrovnatelně náročnější než standardy původní, což výrazně zatěžuje jak výrobce, tak i posuzovatele v oznámených subjektech. Řada předchozích podání dle MDR byla vrácena na základě nedostatků v dokumentaci v kterékoli z jejích mnoha částí. Vezmeme-li v úvahu nahromaděná podání čekající na certifikaci, jakýkoli aspekt dokumentace, který vyžaduje revizi, zpozdí certifikaci a může ohrozit přístup na trh pro řadu dalších zdravotnických prostředků. Toto vše je třeba provést ve lhůtě, která odpovídá době nezbytné pro přezkoumání dokumentace a před vypršením platnosti současných certifikací. Dalším zásadním problémem je nedostatečná kapacita oznámených subjektů v celé EU z důvodu snížení jejich počtu (viz. databáze NANDO), zvýšenému počtu zdravotnických prostředků, které podléhají posouzení oznámeným subjektem z důvodu reklasifikace, a zvýšené složitosti podání MDR ve srovnání s MDD/AIMD. Česká republika stále nemá svůj oznámený subjekt. Jakmile dojde k akreditaci, bude tento jediný oznámený subjekt zavalen ohromným počtem nevyřízených podání v českém jazyce. V prvních měsících se dá očekávat vysoký počet vrácených podání s žádostí o změny a revize, což dále zpomalí proces certifikace pro všechny. Do května 2024 se mnoho výrobců ocitne v situaci, kdy jejich výrobky již nebudou prodejné v EU kvůli prošlým certifikátům a budou čelit dalším důsledkům vyřazení výrobků z distribučního řetězce.

Diskuse

MDR tu zůstane.

Ministr zdravotnictví České republiky MUDr. Vlastimil Válek [2] ve svém úvodním prohlášení na říjnové konferenci AVDZP 2022 uvedl, že další odložení MDR nepřichází v úvahu. I když není v zájmu Evropské unie, aby byl evropský trh ovládnut výrobci ze zemí mimo EU, především z Asie, je nepravděpodobné, že by ve stávajícím nařízení došlo k podstatným změnám, aby bylo vyhověno požadavkům výrobců. MUDr. Válek také veřejnosti připomněl, že mentalita divokého východu s improvizovanými zdravotnickými prostředky v nemocničním systému, která dominovala českému trhu v 90. letech, je již pryč a už se nevrátí. MDR je zkrátka realita, které se výrobci budou muset přizpůsobit.

Notifikované osoby dostupné českým výrobcům podle MDR

Počet notifikovaných osob v EU, které mají designaci dle MDR, se zvýšil na 34. Z tohoto počtu se polovina nachází v Itálii (9) a Německu (8). Zbývajících 17 je v Belgii (1), Chorvatsku (1), Finsku (2), Francii (1), Maďarsku (1), Irsku (1), Nizozemsku (3), Norsku (1), Polsku (2) , Slovensku (1), Slovinsku (1), Španělsku (1) a Švédsku (1) [3] .

Evropští výrobci mohou podat žádost o certifikaci svých zdravotnických prostředků u jakékoli notifikované osoby v EU, s omezením na typ prostředku a kapacitu a ochotu NB přijímat nové klienty. Pro přístup k co největšímu počtu notifikovaných osob by však podání mělo být v angličtině a nikoliv česky.

Dle Směrnice 93/42/EHS (MDD) byly v ČR dvě české notifikované osoby: Institut pro testování a certifikaci, a.s. (ITC) a Elektrotechnický Zkušební Ústav, s.p. (EZÚ). Pouze jeden z nich, ITC, je nyní v procesu notifikace podle MDR. Konečný rozsah kódů MDR, které bude ITC schopen zpracovávat, však dosud nebyl zveřejněn. O notifikaci dle MDR usiluje ještě jedna instituce, Český metrologický institut (ČMI). ČMI nemá předchozí zkušenost s posuzováním zdravotnických prostředků dle MDD nebo AIMD. Předpokládá se, že jejich notifikace bude trvat další rok.

Institut pro testování a certifikaci, a.s. (ITC), Česká republika

Současná notifikace ITC zahrnuje Nařízení (EU) No 305/2011 – Stavební výrobky, Směrnici 2009/48/ES – Bezpečnost hraček, Nařízení (EU) 2016/425 – Osobní ochranné prostředky, Směrnici 2014/68/EU – Tlaková zařízení a Směrnici 2014/30/EU – Elektromagnetická kompatibilita.

Platnost notifikace podle Směrnice 93/42/EHS zdravotnické prostředky (MDD) a 98/79/ES pro diagnostické zdravotnické prostředky in vitro (AIMD) vypršela v květnu 2021 [4] . ITC bude i nadále provádět audity dle MDD až do konce přechodného období dne 24. května 2024.

ITC podal žádost o notifikaci podle MDR dne 30. prosince 2019. Jmenující orgán (ÚNMZ) ověřil úplnost žádosti a předal ji Evropské komisi v listopadu 2020. Komise jmenovala Tým pro společné posouzení (Joint Assessment Team, JAT) v prosinci 2020, který dokončil vyhodnocení v březnu 2021. Společné posuzování na místě bylo dokončeno v červnu 2021. Oficiální zpráva JAT byla vydána v září 2021. ITC implementoval veškerá nápravná opatření na podzim 2021. V červnu 2022 jmenující orgán ÚNMZ dokončil přezkum nápravných opatření implementovaných ITC a předložil jej společnému hodnotícímu týmu ke schválení. V srpnu 2022 vydal ÚNMZ závěrečnou zprávu. V září 2022 vydal JAT své konečné hodnocení a v říjnu 2022 ITC prošlo revizí MDCG. Nyní již jen čeká na stanovisko MDCG, zda notifikace může být přijata. Očekává se, že ITC by měl být uveden v databázi NANDO pro MDR do ledna 2023 [5] .

Podle Mgr. Jiří Heše, ITC bude sloužit především českým výrobcům, kteří již jsou jejich klienty a mají jimi vystavené certifikáty dle MDD. Mgr. Heš dále uvedl, že nové certifikáty podle MDR nebudou vydány včas a nevyhnutelně vznikne mezera v pokrytí zdravotnických prostředků, které v současné době mají platnou certifikaci dle MDD [6] . Pokud jde o IVDR, ITC teprve začal připravovat žádost o notifikaci. Vzhledem k množství certifikátů MDR, které bude nutno zpracovat souběžně s přípravou na IVDR, lze očekávat, že proces notifikace pro IVDR nebude o nic rychlejší.

ITC v současné době nenabízí žádná školení o MDR pro výrobce ani návod, jak připravit podání. Nejdůležitější věcí, kterou pro sebe může každý výrobce udělat, je zajistit, aby jeho podání bylo co nejpřiměřenější hned napoprvé. V současné době jsou však výrobci, pokud jde o přechod na MDR, odkázáni na vlastní zdroje. Bez konkrétních pokynů od ITC ohledně jejich očekávání existuje značné riziko ohledně přípravy dokumentace dle MDR. Toto riziko lze ovšem snížit díky zkušenostem a zpětné vazbě s MDR podáními jiným notifikovaným osobám, což poskytuje dostatečnou záruku pro úspěšné a včasné vyřízení žádosti.

Elektrotechnický Zkušební Ústav, s.p. (EZÚ), Česká republika

Současné notifikace EZÚ zahrnují nařízení (EU) č. 305/2011 – Stavební výrobky a 2014/30/EU Elektromagnetická kompatibilita. EZÚ nebude usilovat o notifikaci dle MDR. Mezi činnosti EZÚ bude i nadále patřit audit podle MDD v přechodném období u 42 výrobců, jimž vydali MDD certifikáty, a certifikace systémů managementu jakosti a elektrické bezpečnosti. EZÚ taktéž zajišťuje školení o MDR pro výrobce a distributory [7] .

Český Metrologický Institut (ČMI), Česká republika

ČMI podal svou první žádost v prosinci 2020, o rok později než ITC. Hodnocení JAT dle článku 39, odstavce 4 MDR) bylo dokončeno v prosinci 2021. V květnu 2022 předložil ČMI svůj navrhovaný plán nápravných opatření. ČMI se snaží zachovat rozsah posuzovaných zdravotnických prostředků obsažených v jejich žádosti (23 ze 44 základních kódů a 18 z 27 horizontálních kódů). Klíčovým požadavkem je prokázat personální dostupnost pro každý kód. ČMI hodlá primárně obsluhovat české výrobce v českém jazyce. Důvodem je, že pouze třetina jejich posuzovatelů má dostatečnou znalost angličtiny. ČMI neposkytuje žádná školení ani pokyny pro výrobce, jak připravit dokumentaci, aby prošla jejich posouzením.

Certifikace zdravotnických prostředků na českém trhu

V databázi RZPRO je evidováno přes 400 českých výrobců, kteří obchodují téměř 6000 zdravotnických prostředků. Z toho 4323 dříve nevyžadovalo zapojení oznámeného subjektu (třída I). Kvůli reklasifikaci však některé z nich budou vyžadovat posouzení notifikovanou odobou v rámci MDR, což dále zvýší jejich zátěž. Z 1634 současných certifikátů jich 514 vydal EZÚ a 391 ITC. Dalších 133 certifikátů MDD bylo vydáno jinými oznámenými subjekty, které v současné době nemají notifikaci dle MDR. Databáze také obsahuje 2305 zdravotnických prostředků vyšší rizikové třídy než I, u nichž není uveden oznámený subjekt. Celkem ITC vydal 541 aktuálně platných certifikátů, včetně výrobců z jiných zemí. Databáze aktuálně obsahuje 630 platných certifikátů vydaných EZÚ. Všechny výrobky certifikované EZÚ budou muset být recertifikovány jiným oznámeným subjektem [8] . Seznam kódů MDR, na které se moci posuzovat ITC (nebo ČMI, jakmile bude notifikován), není v současné době k dispozici.

Mgr. Irena Storová (Státní Ústav pro Kontrolu Léčiv, SÚKL) zdůraznila kvalitu dokumentace MDR jako nezbytnou podmínku k odvrácení krize. Současná rychlost vydávání certifikátů evropskými notifikovanými osobami je cca 1000 certifikátů ročně. Předpokládaná odhadovaná potřeba v Evropě je ovšem asi 23 000 certifikátů vydaných oznámenými subjekty během 20 měsíců, což činí přechod na MDR extrémně náročným. Klíčovými problémy jsou nedostatečná kapacita oznámených subjektů, zčásti z důvodu nahromadění podání čekajících na vyřízení, zčásti z důvodu zvýšené složitosti MDR ve srovnání se Směrnicemi MDD a AIMD. Dalším důvodem je nedostatečná připravenost výrobců plnit nové komplexní požadavky MDR [9] .

Zkušenosti ostatních evropských oznámených subjektů ukazují exponenciální nárůst žádostí a výrazné zpoždění ve zpracování certifikátů. V únoru 2021 oznámené subjekty přijaly 1840 žádostí a zpracovaly 224 certifikátů. Do října 2022 se počet žádostí zvýšil na 8120, přičemž počet vydaných certifikátů byl 1990 [10] . Tato čísla naznačují spíše další hromadění nevyřízených žádostí než dohánění rostoucí poptávky.

Doba pro získání certifikace dle MDR (Systém řízení kvality a produktová certifikace) se obvykle pohybuje okolo 13 až 18 měsíců [11] . Toto je v souladu s odhadem ITC, že posouzení kompletního podání bude trvat přibližně rok, než bude moci být vystaven certifikát. To znamená, že výrobci, kteří potřebují obnovit své certifikáty před jejich vypršením v květnu 2024, budou muset podat své žádosti do května 2023. Jelikož ITC začne přijímat žádosti až po oficiální notifikaci dle MDR, dá se předpokládat, že velká část žádostí bude podána v období mezi datem notifikace a květnem 2023, čímž vznikne dlouhá fronta nevyřízených žádostí. Aby se situace ještě více zkomplikovala, výrobci, jejichž kódy MDR nebudou na seznamu ITC, budou muset hledat jinou notifikovanou osobu, aby mohli získat své certifikáty.

Česko jako trh s nízkými cenami

Nízká hladina cen zdravotnických prostředků na českém trhu přechod na MDR ještě více komplikuje. Systém definování úhrad zdravotnických prostředků je velmi rigidní. Navíc existuje řada faktorů, které drží ceny na nízké úrovni. Tyto cenové limity jsou v přímém rozporu se zvýšenými náklady spojenými s certifikací a recertifikací zdravotnických prostředků, o to více, pokud jsou uvažovány v kontextu zvýšených nákladů na energii, suroviny, dopravu a práci.

MUDr. Vlastimil Válek na konferenci AVDZP dne 13. října 2022 uvedl, že není v zájmu Evropské unie nechat mimoevropské výrobce ovládnout evropský trh, a že soběstačnost v dobách krize má hodnotu sama o sobě [12] . Výsledky průzkumu o počtu žádostí a vydaných certifikátů, který byl proveden MDCG & Stakeholders mezi notifikovanými osobami (51 dotazovaných, 47 obdržených odpovědí) naznačují, že 60 % klientů notifikovaných osob jsou mimoevropští výrobci (10 913), ve srovnání se 7 143 evropskými [13] .

Přednostní zacházení pro malé podniky není pravděpodobné, protože malá a střední podniky tvoří většinu klientů oznámených subjektů, a to jak v EU, tak lokálně v České republice. Navíc, jak se hrozba nedostatku zdravotnických prostředků stává naléhavější, politici by mohli vyřešit krizi tím, že upřednostní výrobce s vysokou kapacitou, kteří jsou schopni uspokojit požadavky zdravotnických systémů, jak jsme již viděli u příkladu dovozu zdravotnických prostředků a osobních ochranných prostředků a jiných materiálů během Covidové krize.

Jaká obchodní rizika vyplývají ze zpoždění v certifikaci?

Schopnost oznámených subjektů zpracovávat žádosti včas je nezbytnou podmínkou fungování sektoru zdravotnických prostředků. To je přímo ovlivněno kvalitou podání předkládaných výrobci. Výrobci nemohou legálně uvádět výrobky na evropský trh bez platné certifikace. Další náklady vzniknou, pokud bude nutné produkty stáhnout zpět z distribučních řetězců kvůli zpožděním v certifikaci. Toto navíc vytvoří mezery na trhu, které budou moci zaplnit konkurenti. Dlouhá doba nepřítomnosti může ohrozit životaschopnost jinak kvalitních produktů a snížit jejich prodeje i poté, kdy kýžené certifikáty konečně získají. Neschopnost získat certifikaci MDR pro kteroukoli část produktového portfolia představuje existenční hrozbu pro jakýkoli podnik. Následkem může být vynucené snížení počtu zaměstnanců, omezení rozsahu operací, zranitelnost podniku vůči konkurenci nebo ztrátu životaschopnosti a ukončení podnikání.

Absence zpětné vazby ohledně detailů obsahu a formátu podání způsobí další zpoždění a další náklady na přizpůsobení se těmto požadavkům ze strany výrobců. ITC neposkytuje žádné školení MDR a nevydalo žádné pokyny, které by usnadnily přípravu podání a snížily nejastnosti souvisejících s novostí procesu. První MDR certifikát byl vydán v září 2019 BSI [14] . To znamená, že kumulativní zkušenosti v oboru mezi konkurencí jsou díky zpětné vazbě od oznámených subjektů výrazně vyšší a staví české výrobce o 4 roky za ostatními hráči z EU.

V současné době se čeští výrobci mohou opřít o vlastní porozumění nařízení MDR a souvisejících doporučujících pokynů MDCG, školení poskytované jinými oznámenými subjekty a na zkušenosti konzultantů, kteří kromě téhož mají navíc ještě zpětnou vazbu od klientů. Přestože má CzechInvest v plánu zahájit komplexní školicí program pro výrobce, aby jim přechod na MDR usnadnil, kurz ještě nezačal. První studenti by měli promovat v červnu 2024 [15] . Křivka učení a zlepšení se dá očekávat jak u nově jmenovaných notifikovaných osob, tak u výrobců. Toto nevyhnutelně ovlivní rychlost zpracování podání. Dalším následkem budou nutné revize dokumentace a úpravy, kterým by se jinak bylo možné vyhnout. Zajištění poradenství s prokázanou kompetencí v přípravě MDR podání odstraní podstatná rizika ze současné situace.

Doporučení

Jakým rizikům výrobci čelí, a jak Arete-Zoe může vašemu podniku pomoci toto riziko zmírnit?

Klíčem k úspěšné certifikaci MDR je vysoce kvalitní, včasné podání, které vyhovuje požadavkům MDR nebo tyto minimální požadavky dokonce překračuje. Cílem je zajištění včasného zpracování oznámeným subjektem a zamezení vrácení podání, žádostem o další informace či dokonce zamítnutím. Je důležité poznamenat, že proces kontroly a schvalování závisí na pochopení a aplikaci požadavků MDR jednotlivými posuzovateli. Překročení minimálních požadavků se proto stává nutností pro spolehlivé schválení podání. Dopad žádostí o dodatečné informace, i když je z hlediska vícepráce malý, může být významný kvůli zpožděním. Vzhledem k obrovskému nahromadění žádostí se dá předpokládat, že systém bude ještě více přetížen neúspěšnými a vrácenými podáními jiných výrobců. Kvalita prvotního podání je zásadní k hladkému přechodu na MDR, a může být také jediným faktorem, který udrží podnik otevřený.

I výrobci, kteří již mají plně vyškolený interní tým, by měli počítat s problémy při přípravě podání MDR. Čas na rozvoj odborných znalostí v oblasti MDR je velmi omezený, vezmeme-li v úvahu tlak na přípravu úplné dokumentace a její předložení do května 2023. I s dobře obsazeným týmem může být tento úkol jednoduše zdrcující kvůli obrovskému množství požadovaného materiálu ve srovnání s předchozími požadavky Směrnic MDD a AIMD.

Tým Arete-Zoe má značné zkušenosti s přípravou klinické dokumentace pro klienty přecházející z MDD na MDR v českém i anglickém jazyce a jejich podáním několika ozámeným subjektům. Náš výjimečný úspěch s klinickou dokumentací zahrnuje produkty, které byly již dříve zamítnuty a vráceny, ale s naší pomocí prošly. Můžeme tudíž pomoci kontrolovat riziko selhání nebo zpoždění pro naše klienty tím, že jim poskytneme nezbytnou podporu, která je nutná k zabránění zpoždění v certifikaci výrobků, kterým je možno předejít. Tým Arete-Zoe může buď připravit kompletní podání, nebo rozšířit váš stávající tým o dovednosti, které váš tým nemusí mít.

Použitá literatura
[1] https://www.ema.europa.eu/en/news/medical-device-regulation-comes-application

[2] Válek, V (2022). Introduction. AVDZP Conference 13/10/2022, Praha, Czech Republic.

[3] NANDO database https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=34

[4] NANDO database https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=34

[5] Heš, J (2022). Implementace MDR: Kde jsme a kam směřujeme. AVDZP Conference 13/10/2022, Praha, Czech Republic. Institut pro Testování a Certifikaci.

[6] Heš, J (2022). Implementace MDR: Kde jsme a kam směřujeme. AVDZP Conference 13/10/2022, Praha, Czech Republic. Institut pro Testování a Certifikaci.

[7] Vlasák, M (2022). Dozorová činnost dle MDD. AVDZP Conference 13/10/2022, Praha, Czech Republic. Elektrotechnický zkušební ústav.

[8] RZPRO

[9] Storova, I (2022). Problematika ukončení přechodného období MDR z pohledu SÚKL. AVDZP Conference 13/10/2022, Praha, Czech Republic. State Institute for Drug Control.

[10] MDCG & Stakeholders (2022). Notified Bodies Survey on certyifications and applications (MDR/IVDR). 24/10/2022. European Commission.

[11] MDCG & Stakeholders (2022). Notified Bodies Survey on certyifications and applications (MDR/IVDR). 24/10/2022. European Commission.

[12] Válek, V (2022). Introduction. AVDZP Conference 13/10/2022, Praha, Czech Republic.

[13] MDCG & Stakeholders (2022). Notified Bodies Survey on certyifications and applications (MDR/IVDR). 24/10/2022. European Commission.

[14] BSI (2019). BSI certifies first product to the Medical Devices Regulation. 02 September 2019. BSI. https://www.bsigroup.com/en-GB/medical-devices/news-centre/enews/2019-news/bsi-certifies-first-product-to-the-medical-devices-regulation/

[15] Hájek, J (2022). Národní plán obnovy. Komponenta 1. 4. Digitální ekonomika a společnost, inovativní start-upy a nové technologie. Program na podporu specifických systémových a produktových certifikací a souvisejícího vzdělávání. AVDZP Conference 13/10/2022, Praha, Czech Republic.

Business resiliency: How to manage your risk from expiring MDD certificates

Sat, 05 Nov 2022 19:42:57 GMT

The reduction of Czech-based Notified Bodies (NBs) leaves only one still pending accreditation and one in Slovakia that does accept submissions in Czech. The delay in accreditation has produced a significant backlog for submissions pending review and acceptance. The complexity of MDR is more stringent both for the preparers and the reviewers at the NB. This situation introduces many vulnerabilities into the submission process and represents substantial risk that can and should be minimized!

The potential consequences of certification delays may be critical for some manufacturers. Is the cost penalty from delay because of necessary revision or rejection worth the minor economy of an in-house effort? Get your staff an assessment from a team with proven MDR success! Contact Arete-Zoe for a courtesy review of your situation and secure assistance that will reduce your risk! Stay agile, competitive, and profitable!

What is the current situation?

Regulation (EU) 2017/745 on medical devices (the Medical Device Regulation, MDR), which was adopted in April 2017, became applicable in the European Union on 26 May 2021, after a year delay due to Covid [i] . The certificates issued under the existing Directives for medical devices ( 93/42/EEC and 90/385/EEC ) will expire on or before May 24th, 2024. By then, all manufacturers who wish to keep their products on the market as medical devices, will have to upgrade their documents to the new standards. Previous documentation standards fall far short to the new requirements, placing significant burden on both the manufacturers and reviewers at the NB. Many previous submissions under MDR have been rejected based on documentation shortfalls within any of the many sections. When considered with the significant backlog, any aspect of documentation that requires revision only compounds certification delay and may jeopardize market access for many medical devices. All this needs to be done within a period that accounts for the time necessary for review prior to expiration of current certifications.

Additionally, there is a significant bottleneck in submission processing due to the limited capacity of NBs in the EU due to a reduction in the number of designated NBs, increased number of products that are subject to review by NB due to reclassification, and increased complexity of MDR submissions compared to MDD/AIMD.

The Czech Republic still does not have its own designated NB. Once accreditation occurs, the backlog of Czech language submissions will be overwhelming. The high number of returns and requests for amendments and revisions shall be expected in the initial months, slowing the process further for all. By May 2024, many manufacturers will find themselves in a situation when their products will no longer be marketable in the EU due to expired certificates and face additional consequences from having products purged from supply chain.

Discussion

MDR is here to stay.

Czech Minister of Health MUDr. Vlastimil Válek in his introductory statement at the October 2022 AVDZP Conference [ii] stated that another postponement of MDR is out of question. While it is not in the interest of the European Union to be dominated by non-EU manufacturers, primarily from Asia, it is unlikely that the existing Regulation will be substantially changed to accommodate manufacturers’ concerns. Válek also reminded the public that the Wild East mentality with improvised devices throughout the hospital system that dominated the Czech market in the 1990s is gone and will not return. In short, MDR is a reality to which manufacturers will have to adjust.

Notified bodies available to Czech manufacturers under MDR

The number of EU NBs that are designated under MDR has increased to 34, half of which are located in Italy (9) and Germany (8). The remaining 17 are in Belgium (1), Croatia (1), Finland (2), France (1), Hungary (1), Ireland (1), the Netherlands (3), Norway (1), Poland (2), Slovakia (1), Slovenia (1), Spain (1) and Sweden (1) [iii] . European manufacturers can pursue certification of their products with any EU NB, with limitations to the type of product and the capacity and willingness of NBs to take on new clients. However, for access to the greatest number of NBs, the submission should be in English.

Two Czech NBs were designated in Czechia under the 93/42/EEC (MDD): Institut pro testování a certifikaci, a.s. (ITC) and Elektrotechnický Zkušební Ústav, s.p. (EZÚ). Only one of them, ITC, is in the process for designation under MDR. However, the final scope of MDR codes ITC will be able to process has not been released. One additional institution, Czech Metrological Institute (CMI) is pursuing designation under MDR without prior history in medical devices under MDD or AIMD. The anticipated accreditation will take an additional year.

Institut pro testování a certifikaci, a.s. (ITC), Czech Republic

ITC’s current designations include Regulation (EU) 2016/425 Personal protective equipment, 2014/68/EU Pressure equipment, 2009/48/EC Safety of toys, Regulation (EU) No 305/2011 - Construction products and 2014/30/EU Electromagnetic compatibility. Designations under 93/42/EEC Medical devices and 98/79/EC In vitro diagnostic medical devices expired in May 2021 (MDD) and May 2022 (IVDD) [iv] . ITC will continue to perform audits under MDD during the transitional period until May 24, 2024.

ITC submitted their application for designation under MDR on December 30, 2019. The Designating authority (ÚNMZ) verified completeness of the application and forwarded it to the European Commission in November 2020. The Commission designated the Joint Assessment Team in December 2020, which completed the evaluated in March 2021. On-site Joint Assessment was completed in June 2021. The official JAT report was issued in September 2021. ITC implemented CAPAs in fall 2021. In June 2022, designating authority ÚNMZ completed their review of CAPAs implemented by ITC and submitted it to the Joint Assessment Team for approval. In August 2022, ÚNMZ issued the final report. In September 2022, JAT issued its final assessment and a in October 23022, ITC underwent MDCG review and is now awaiting MDCG opinion that the notification can be accepted. The expectation is that ITC should be listed in the NANDO database by January 2023 for MDR [v] .

According to Mgr. Jiří Heš, ITC will primarily serve Czech manufacturers who already are their clients and have certificates issued by them under MDD. New certificates under MDR won’t be issued in time and there will inevitably be a gap in coverage of products with valid MDD certification. [vi] ITC only began preparing application for designation under IVDR. Due to the extensive backlog of MDR certificates, it is reasonable to expect that the process of designation under IVDR will not be any faster.

ITC currently does not offer any training on MDR for manufacturers or guidance on how to prepare submissions. The most significant thing any manufacturer can do for themselves is to ensure their submission is as appropriate as possible the first time. But they are left to their own means to sort out the transition from MDD to MDR. Without specific guidance from ITC on their expectations, there is significant risk from the ambiguity of the MDR Regulation itself. However, this risk can be reduced from experience from submissions under MDR to other NBs which will provide reasonable opportunity for a successful submission.

Elektrotechnický Zkušební Ústav, s.p. (EZÚ), Czech Republic

EZÚ’s current designations include Regulation (EU) No 305/2011 - Construction products and 2014/30/EU Electromagnetic compatibility. EZÚ won’t pursue designation under MDR. The activities EZÚ will continue include audit under MDD during the transitional period for 42 manufacturers whose certificates they serve, certification of quality management systems, and electrical safety. EZÚ also provides training on MDR for manufacturers and distributors [vii] .

Czech Metrological Institute (CMI), Czech Republic

CMI submitted their initial application in December 2020, a year later than ITC. The Joint Assessment Team evaluation (Article 39, paragraph 4 MDR) was completed in December 2021. In May 2022, CMI submitted their proposed CAPA plan. CMI strives to maintain the scope of devices included in their application (23 out of 44 basic codes and 18 out of 27 horizontal codes). The key requirement is to prove personnel availability for each code. CMI primarily intends to serve Czech manufacturers in Czech language, as only about a third of their reviewers have sufficient proficiency in English. CMI does not provide any training or guidance for manufacturers how to prepare documentation to pass their scrutiny.

Certification of products on the Czech market

There are over 400 Czech manufacturers listed in the database RZPRO holding nearly 6000 certificates that are currently valid. Of these, 4323 did not previously require the involvement of a NB (Class I). However, due to reclassification, some of these will require involvement of the NB under MDR, further stressing the throughput of the NB. Of the 1634 remaining certificates, 514 were issued by EZÚ and 391 by ITC. Another 133 MDD certificates were issued by other NBs that do not currently have MDR designation. The database also holds 2305 products other than Class I that do not have a NB listed. In total, ITC issued 541 certificates that are currently valid, including manufacturers from other countries. The database currently holds 630 valid certificates issued by EZÚ. All products certified by EZÚ will have to be recertified by another NB [viii] . The list of MDR codes that will be covered by ITC (or CMI, once designated) is not currently available.

Mgr. Irena Storova (Czech State Institute for Drug Control) emphasized the quality of the MDR documentation as an essential condition required to avert a crisis. The current speed of issuing certificates by EU NBs is about 1.000 certificates a year. However, the anticipated need for medical devices in Europe is about 23.000 certificates issued by NBs over the period of 20 months, making the transition to MDR extremely challenging. The key problems are insufficient capacity of NB, partly due to accumulated backlog, partly due to increased complexity of MDR compared to MDD/AIMD, as well as inadequate preparedness of manufacturers to meet the new complex requirements of MDR [ix] .

Experience of other EU NB shows exponential growth of applications and a serious lag in processing certificates. In February 2021, NBs received 1840 applications and processed 224 certificates. By October 2022, the number of applications grew to 8120, while the number of issued certificates was 1990 [x] . These numbers suggest further accumulation of backlog of unprocessed applications rather than catching up with the growing demand.

The time to reach a Certificate according to MDR (MDR Quality Management System and Product certification) typically ranges from 13 to 18 months [xi] . This is consistent with ITC’s estimate that the review of a complete submission will take a year to issue a certificate. This means that all manufacturers who need their certificates renewed before the May 2024 deadline when they all expire will have to submit their applications before May 2023. Since ITC will only start accepting applications after the official MDR designation, it is safe to assume that all applications will be submitted in the period between the designation date and May 2023, creating a long backlog queue. To complicate the situation even further, manufacturers, whose MDR codes won’t be on ITC’s list, will have to look for a different NB to pursue their certificates.

Czechia as a low price-point market

The low-price level of devices on the Czech market complicates the transition to MDR even further. The system of defining reimbursements for medical devices is very rigid, and there are multiple pressures that keep prices down. These price controls conflict with increased costs associated with certification and recertification of products when considered with increased costs of energy, raw materials, transport, and labor.

MUDr. Vlastimil Válek at the AVDZP Conference on October 13, 2022, stated that it is not in the interest of the European Union to allow non-EU manufacturers to dominate the EU market, and that there is an intrinsic value in self-sufficiency in times of crisis [xii] . The results from Survey on certifications and applications performed by MDCG & Stakeholders among NBs (51 NBs asked, 47 replies received) suggest that 60% of medical device clients are non-EU (10,913), compared to 7,143 EU clients [xiii] .

Priority treatment for small business is not likely since SMEs are the majority of NB clients, both EU-wide and locally in the Czech Republic. In fact, as the threat for shortage of medical equipment becomes more urgent, policymakers might solve the crisis by prioritizing producers with high capacity, capable of meeting the demands of their respective health systems, as we have seen with the imports of medical equipment and protective materials during the Covid crisis.

What is the risk to business due to delays in certification?

The ability of NBs to process applications in a timely manner is an essential condition for the function of the medical device sector. This is directly influenced by the quality of manufacturers’ submission for certification. Manufacturers cannot legally keep their products on the EU market without valid certification. And, additional expenses will be incurred, if products have to be recovered from distribution chains due to delays in certification. Furthermore, this will create gaps in coverage, creating a void that can be filled by competitors. Extended periods of absence can stall otherwise good products and limit marketability once certification is finally obtained. Failure to obtain MDR certification for any portion of a product portfolio is an existential threat to any enterprise, potentially forcing reduction of staff, downsizing, making the enterprise vulnerable to competitors, or simply losing viability and going out of business.

The absence of a feedback loop regarding the minutia of submissions’ content and format will cause additional delays and adjustments by the industry. ITC does not provide any MDR training and did not issue any guidance documents to facilitate successful submissions and reduce ambiguity relating to the novelty of the process. The first MDR certificate was issued in September 2019 by BSI [xiv] . This means that the cumulative experience in the industry among competition is significantly higher, placing Czech manufacturers 4 years behind other EU players.

At present, Czech manufacturers have to rely on training provided by other NBs, industry consultants who rely on the same, in addition to feedback from their clients, and their own understanding of the Regulation and associated MDCG guidelines. Although CzechInvest does have a plan to start a comprehensive training program for manufacturers to facilitate the transition to MDR, the course has not started yet. The first students are expected to graduate in June 2024 [xv] . Learning curve by both newly designated NBs as well as manufacturers will inevitably affect the speed of processing, forcing reworks and amendments that would otherwise be avoidable. Securing consultancy with demonstrated MDR competency will remove substantial risk from the current situation.

Recommendations

What is the risk, and how does Arete-Zoe help your enterprise to mitigate such risk?

The key to a successful MDR certification is a high quality, timely submission that complies with or better, exceeds minimum MDR requirements, ensuring timely processing and avoiding returns, requests for more information and outright rejections. It is important to note that the review and approval process depends on the understanding and application of MDR requirements by individual reviewers. Therefore, exceeding minimum requirements becomes a necessity for confident approval. The impact of additional information requests, although minor in terms of extra work, can be significant due to delays. Additionally, other manufacturers’ failed submissions in a long backlog of applications will continue to burden the system. The quality of the initial submission is essential to avoiding consequences in the transition to MDR and may be the single factor that keeps the business open.

Manufacturers who have a fully trained in-house team already should still expect challenges in preparing MDR submissions themselves. The time to develop MDR expertise is very limited, considering the pressure to prepare the full documentation and submit it before May 2023. Even with a well-staffed team, the task can simply be overwhelming due to the sheer volume of material required in contrast to previous MDD/AIMD submissions.

Arete-Zoe team has significant experience preparing clinical documentation for clients transitioning from MDD to MDR in both Czech and English and submissions through multiple NBs. Our exceptional success record with clinical documentation includes products that were previously rejected but passed with our assistance. We can help control the risk of failure or delay for our clients by providing the essential support you need to avert a avoidable delays in product certification. Arete-Zoe team can either prepare the full submission or augment your existing team with essential skillset your team might not have.

References

[i] https://www.ema.europa.eu/en/news/medical-device-regulation-comes-application

[ii] Válek, V (2022). Introduction. AVDZP Conference 13/10/2022, Praha, Czech Republic.

[iii] NANDO database https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=34

[iv] NANDO database https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=34

[v] Heš, J (2022). Implementace MDR: Kde jsme a kam směřujeme. AVDZP Conference 13/10/2022, Praha, Czech Republic. Institut pro Testování a Certifikaci.

[vi] Heš, J (2022). Implementace MDR: Kde jsme a kam směřujeme. AVDZP Conference 13/10/2022, Praha, Czech Republic. Institut pro Testování a Certifikaci.

[vii] Vlasák, M (2022). Dozorová činnost dle MDD. AVDZP Conference 13/10/2022, Praha, Czech Republic. Elektrotechnický zkušební ústav.

[viii] Czech database of medical devices RZPRO https://eregpublicsecure.ksrzis.cz/Registr/RZPRO/ZdravotnickyProstredek

[ix] Storova, I (2022). Problematika ukončení přechodného období MDR z pohledu SÚKL. AVDZP Conference 13/10/2022, Praha, Czech Republic. State Institute for Drug Control.

[x] MDCG & Stakeholders (2022). Notified Bodies Survey on certyifications and applications (MDR/IVDR). 24/10/2022. European Commission.

[xi] MDCG & Stakeholders (2022). Notified Bodies Survey on certyifications and applications (MDR/IVDR). 24/10/2022. European Commission.

[xii] Válek, V (2022). Introduction. AVDZP Conference 13/10/2022, Praha, Czech Republic.

[xiii] MDCG & Stakeholders (2022). Notified Bodies Survey on certifications and applications (MDR/IVDR). 24/10/2022. European Commission. https://health.ec.europa.eu/latest-updates/notified-bodies-survey-certifications-and-applications-2022-10-26_en?fbclid=IwAR3w3YH7UD2HBccQ6pBKWP3UlpgSnvQj9qFoNUeLIF-6ZWl8IOwP2Wx88Tk

[xiv] BSI (2019). BSI certifies first product to the Medical Devices Regulation. 02 September 2019. BSI. https://www.bsigroup.com/en-GB/medical-devices/news-centre/enews/2019-news/bsi-certifies-first-product-to-the-medical-devices-regulation/

[xv] Hájek, J (2022). Národní plán obnovy. Komponenta 1. 4. Digitální ekonomika a společnost, inovativní start-upy a nové technologie. Program na podporu specifických systémových a produktových certifikací a souvisejícího vzdělávání. AVDZP Conference 13/10/2022, Praha, Czech Republic.

Crash Course on the EU Medical Device Regulation - Part II

veronikav@arete-zoe.com (Veronika Valdova) — Tue, 21 Jun 2022 20:20:49 GMT

History of EU device legislation, definitions, obligations of economic subjects

A brief history of EU medical device legislation

The Council Resolution of 7 May 1985 on a new approach to technical harmonization and standards (OJ85/C136/01) introduced a new system organized by the product sector. General requirements are defined in legislative norms that are supplemented by harmonized standards. It is assumed that conformity with the harmonized standards implies compliance with the relevant legislation.

The Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices (Active-Implantable Medical Device Directive, AIMDD) first implemented this new approach. The Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (Medical Device Directive, MDD) underwent five major legislative updates since it first came into force. The new Medical Device Regulation (EU) 2017/745 merges all requirements described in AIMDD and MDD into one legal norm.

The Council Decision of 22 July 1993 concerning the modules for the various phases of the conformity assessment procedures and the rules for the affixing and use of the CE conformity marking, which are intended to be used in the technical harmonization directives 93/465/EEC described various types of conformity assessment and defined the rules for CE marking of medical devices.

Later, the Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices updated conformity assessment methods based on 93/465/EEC.

In 2008, the Decision No 768/2008/EC of the European Parliament and of the Council of 9 July 2008 on a common framework for the marketing of products and repealing Council Decision 93/465/EEC introduced a common framework for newly adopted legislation, replacing Council Decision 93/465/EEC.

In 2013, Commission Implementing Regulation (EU) No 920/2013 of 24 September 2013 on the designation and the supervision of notified bodies under Council Directive 90/385/EEC on active implantable medical devices and Council Directive 93/42/EEC on medical devices specified requirements on accreditation of notified bodies and their oversight.

Commission Recommendation of 24 September 2013 on the audits and assessments performed by notified bodies in the field of medical devices (2013/473/EU) made it mandatory for notified bodies to conduct unannounced audits at manufacturer's sites. Compared to sector legislation from 2009, the Medical Device Regulation (EU) 2017/745 - MDR and In-Vitro Diagnostic Device Regulation (EU) 2017/746 - IVDR represent a significant diversion from the Decision No 768/2008/EC.

Definitions. The Medical Device Regulation (EU) 2017/745 lists 72 definitions, a significant increase from the Medical Device Directive (MDD). Most are already known from other documents, such as MEDDEV guidelines. Additional definitions were added based on Decision No 768/2008/EC .

New obligations of manufacturers (Article 10)

New obligations of manufacturers include the implementation of the UDI system (Article 10, point 7) and keeping the technical documentation for ten years after the last device covered by the EU declaration of conformity has been placed on the market ( 15 years for implantable devices ) (Article 10, point 8).

Where manufacturers have their devices designed or manufactured by another legal or natural person , the person's identity shall also be submitted to EUDAMED (Article 10, point 15).

Moreover, natural or legal persons may claim compensation for damage caused by a defective device in accordance with applicable Union and national law. Manufacturers shall have measures in place to provide sufficient financial coverage in respect of their potential liability under Directive 85/374/EEC (Article 10, point 16). The manner of such coverage shall be proportionate to the risk class, type of device, and the size of the enterprise (Article 10, point 16).

Manufacturers newly shall have available at least one person responsible for regulatory compliance who possesses the requisite expertise in the field of medical devices (Article 15). Micro and small enterprises (fewer than 50 employees, less than 10 million Euro yearly revenue, defined in Commission Recommendation 2003/361/EC) shall not be required to have the person responsible for regulatory compliance within their organization but shall have such person permanently and continuously at their disposal (MDCG 2019-7).

The obligations of Authorized Representatives (AR) (Article 11 and 12)

Where the manufacturer of a device is not established in a Member State, the manufacturer designates a sole authorized representative for devices it places on the Union market.

The authorized representative (AR) shall perform the tasks specified in the mandate agreed upon with the manufacturer. Minimum requirements of AR's mandate include verification of the EU declaration of conformity and manufacturer's technical documentation and keeping copies of these documents for competent authorities. ARs must comply with the registration obligations (Article 31) and verify the manufacturer's registration (Articles 27 and 29).

In response to a request from a competent authority, ARs must provide all the information and documentation necessary to demonstrate the conformity of a device. This documentation shall be available in an official Union language determined by the Member State concerned. ARs must forward these requests to the manufacturer.

ARs must cooperate on any preventive or corrective action and immediately inform the manufacturer about complaints and incident reports. AR shall terminate the mandate if the manufacturer acts contrary to its obligations. The Regulation also specifies obligations that cannot be delegated to the AR (Article 11, point 4). Where the manufacturer has not complied with its obligations, the AR shall be legally liable for defective devices on the same basis as, jointly and severally with, the manufacturer (Article 11, point 5).

The detailed arrangements for a change of authorized representative shall be clearly defined in an agreement between the manufacturer and the outgoing and incoming authorized representatives (Article 12).

General obligations of importers (Article 13)

In order to place a device on the Union market, importers shall verify CE marking, the EU declaration of conformity, labeling, and instructions for use, identify a manufacturer or its authorized representative, and make sure a UDI has been assigned. An importer must inform the manufacturer and/or the AR about the device not in conformity. Devices that pose a serious risk or falsified devices are subject to notification to competent authorities. Importers ensure proper storage or transport conditions and keep a registry of complaints and incidents.

Other natural or legal persons (Article 16)

A distributor, importer, or another person shall assume the obligations of manufacturers if it makes a device available on the market under its name, if it changes the intended purpose of the device or modifies the device that is already placed on the market or put into service (Article 16).

Next: Crash Course on the EU Medical Device Regulation - Part III

Contact ARETE-ZOE, LLC for support with your European medical device submissions.

Crash Course on the EU Medical Device Regulation - Part I

veronikav@arete-zoe.com (Veronika Valdova) — Tue, 21 Jun 2022 20:03:44 GMT

Introduction & Orientation

On April 5, 2017, the Medical Device Regulation (EU) 2017/745 replaced the two existing directives, the Medical Devices Directive (MDD) and the Active Implantable Medical Devices Directive (AIMDD). The Medical Device Regulation entered into force on May 25, 2021, after a four-year transition period. Existing certificates issued under MDD/AIMDD remain valid until May 2024 or until they expire.

The new European Commission (EC) website divides device-related content into the following categories: Sector , New regulations , Topics of Interest , Dialogue between interested parties , Expert Panels , and EUDAMED . Guidance documents, namely MDCG endorsed documents and other guidance, can be found in section New Regulations - Guidance .

Medical Device Regulation (EU) 2017/745 (MDR) significantly increased in volume compared to the Medical Device Directive (MDD) 93/42/EHS and In-Vitro Device Directive (IVDD) 98/79/ES.

Medical Device Regulation (EU) 2017/745 reinforces the supervision of notified bodies, conformity assessment procedures, clinical investigations, clinical evaluation, vigilance, and market surveillance. New provisions are introduced to ensure transparency and traceability of medical devices.

Exclusions. Medical Device Regulation (EU) 2017/745 does not apply to in vitro diagnostic medical devices (covered by Regulation (EU) 2017/746), medicinal products (Directive 2001/83/EC), advanced therapy medicinal products (Regulation (EC) No 1394/2007), human blood, blood products, plasma or blood cells of human origin (Directive 2001/83/EC, Regulation (EC) No 726/2004), cosmetic products (Regulation (EC) No 1223/2009), transplants, tissues or cells of animal origin, or their derivatives (Directive 2004/23/EC), products containing viable biological material or viable organisms, and food (Regulation (EC) No 178/2002).

New additions. This Regulation also applies to products without an intended medical purpose, such as contact lenses, breast implants, facial fillers, liposuction equipment, high-intensity electromagnetic radiation devices for skin resurfacing, tattoo or hair removal, and equipment intended for brain stimulation. Annex XVI addresses the application of risk management and clinical evaluation regarding safety.

In case of doubt, which products constitute a medical device, refer to the Manual on Borderline product s.

Most definitions are already known from other documents, such as MEDDEV guidelines. Additional definitions were added based on Decision No 768/2008/EC .

The European Commission publishes a summary of harmonized standards that consolidates the references of harmonized standards published by the Commission in the Official Journal of the European Union (OJ).

A range of documents exists to elucidate how the Regulation (EU) 2017/745 on medical devices (MDR) should be applied. The majority of these documents are endorsed by the Medical Device Coordination Group (MDCG) and present a common understanding of how the MDR and IVDR should be applied in practice.

Key changes

The new Medical Device Regulation aimed to address some inherent weaknesses in the old directives and the rapid evolution of science and technology in the field of medical devices. Key changes include:

Stricter ex-ante control for high-risk devices via pre-market scrutiny facilitated by a pool of experts at EU level
Rigorous designation processes for oversight of Notified bodies
Expansion of products covered such as liposuction devices, contact lenses and breast implants
Improved transparency through the establishment of EUDAMED
Introduction of device traceability system based on Unique Device Identification
Introduction of an “implant card” containing information about implanted medical devices for a patient
Increased requirements on clinical evidence for clinical evaluations and investigations
EU-wide coordinated procedure for authorisation of multi-centre clinical investigations
Strengthening of post-market surveillance requirements
Improved coordination between EU countries in vigilance and market surveillance

Next: Crash Course on the EU Medical Device Regulation - Part II

Contact ARETE-ZOE, LLC for support with your European medical device submissions.

What does it take to place your Medical Devices on the European market?

veronikav@arete-zoe.com (Veronika Valdova) — Sat, 28 May 2022 21:58:15 GMT

More than 500,000 medical technologies are available on the European market, from hospitals to community care settings and people's homes. The products range from syringes, pregnancy tests, and wheelchairs to X-Ray machines and body scanners, pacemakers, hip implants, and pharmacogenomic tests.

The medical technology industry is the source of a constant flow of innovations. The sector spends about 8% of its sales on R&D. Typical product lifecycle is about 18 to 24 months when a new, improved version becomes available. In 2020, the European Patent Office (EPO) accepted nearly 14,200 patent applications in the medical technology sector, trumping pharmaceutical patents (8,500 applications) and biotechnology (7,200). European and U.S. entities filed almost 80% of the applications (38% EU and EEA, 39% U.S.) [ 1 ].

The European medical technology sector employs more than 760,000 people, mainly in Germany (210,000), the United Kingdom (102,800), Italy (94,000), France (89,000), Switzerland (63,000), and Ireland (40,000), accounting for 0.3% of total employment. In comparison, the European pharmaceutical industry employs around 795,000 people. These jobs reach a value-added of about €184,000 per employee. More than 33,000 medical technology exist in Europe, of which 95% qualify as small, medium, and micro-sized companies (SMEs). The majority of these enterprises employ less than 50 people [ 1 ].

In 2020, Europe had a positive trade balance in the medical technology sector of € 8.7 billion. Compared to 2019, the European trade balance dropped by 27.5% (€ 12 billion in 2019). The most important trading partners for Europe are the United States, China, Japan, and Mexico. Germany, Ireland, the Netherlands, Belgium, and Switzerland have the highest trade share, both within and outside the EU [ 2 ].

Until May 2021, the medical device sector was regulated by Medical Device and In Vitro Diagnostic Device Directives 93/42/EC and 90/385/EEC (MDD and IVDD), when the new Regulations replaced these: Medical Device Regulation (EU) 2017/745 (MDR) and In Vitro Diagnostic Device Regulation (IVDR) 2017/746 [ 3 ],[ 4 ]. The new regulations introduced numerous changes, including the reclassification of some devices, requiring additional obligations for manufacturers to comply with. About 85% of in-vitro diagnostic devices will now require Notified Body involvement, compared to ~20% under the IVDD. Existing MDD/IVDD certificates remain valid until May 2024. After this date, all devices on the EU market must comply with the new MDR/IVDR regulations [ 5 ].

For some manufacturers, the costs associated with keeping some of their devices on the market under MDR/IVDR may no longer justify the expense considering their profitability. Others may not be able to obtain new CE Mark certification in time due to decreased capacity of notified bodies. These factors combined are already reducing the number of devices on the EU market and limiting the certification of innovative products. The number of notified bodies available to review new certifications and recertifications dropped significantly under the MDR/IVDR. Of 51 notified bodies designated to MDD [ 6 ] and ten to AIMDD [ 7 ], only 29 obtained designation for MDR, of which seven operate in Germany, seven in Italy, and three in the Netherlands [ 8 ].

The situation is even worse with in-vitro diagnostic devices. Of the 19 notified bodies designated to IVDD [ 9 ], only seven obtained their designation under IVDR [ 10 ].

With a combination of growing demand for medical devices in Europe and expiring certificates issued under MDD, IVDD, and AIMDD, there is a concern that the capacity of Notified Bodies won't match the demand, potentially causing shortages of medical equipment in Europe. The COVID-19 pandemic only aggravated the situation when the already stretched Notified Bodies had to meet their surveillance obligations under the current directives while undergoing the designation process for MDR/IVDR at the same time. To address the problem, Team NB proposed allowances to be made for manufacturers with valid MDD/AIMD/IVDD certificates whose applications have been accepted by notified bodies. In addition, Team NB suggested an extension of the IVDR transition beyond May 2024 to accommodate increased demand. Finally, the timeframe required to designate notified bodies to MDR and IVDR needs to decrease to boost the capacity of notified bodies to process the growing number of applications [ 11 ].

Long story short, manufacturers who intend to market their devices in Europe, shall not be discouraged by the regulatory hurdles, and go ahead with their applications as soon as they can.

Next: Crash Course on the EU Medical Device Regulation

Contact ARETE-ZOE, LLC for support with your European medical device submissions.

References

[1] MedTech Europe (2021): The European Medical Technology Industry in figures 2021 https://www.medtecheurope.org/wp-content/uploads/2021/06/medtech-europe-facts-and-figures-2021.pdf

[2] MedTech Europe (2021): The European Medical Technology in Figures. https://www.medtecheurope.org/datahub/trade/

[3] Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC. https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32017R0745&from=EN#d1e1258-1-1

[4] Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU. https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32017R0746&from=EN

[5] European Commission forecasts potential supply disruptions due to MDR, IVDR https://www.emergobyul.com/blog/2019/06/european-commission-forecasts-potential-supply-disruptions-due-mdr-ivdr

[6] Notified bodies designated to 93/42/EEC Medical devices (MDD) https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=13

[7] Notified bodies designated to 90/385/EEC Active implantable medical devices (AIMDD) https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=8

[8] Notified bodies designated to Regulation (EU) 2017/745 on medical devices https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&sort=country&dir_id=34

[9] Notified bodies designated to 98/79/EC In vitro diagnostic medical devices (IVDD) https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=20

[10] Notified bodies designated to Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=35

[11] Team NB (2021): Notified Body position paper on MDR/IVDR Implementation https://www.team-nb.org/wp-content/uploads/2021/12/Team-NB-PositionPaper-on-MDR_IVDR-Implementation-V3.pdf

U.S. MedTech Market: The Ultimate Innovator's Paradise

Sat, 28 May 2022 21:43:20 GMT

The Medical Device industry produces a vast number of products, ranging from bandages and surgical instruments to life function monitors to imaging technology. The technology currently in use varies from devices that have been in use for decades to highly innovative products. Innovations in the medical device field are frequent and typically incremental in response to feedback from physicians.

Mordor Intelligence estimated the global Medical Devices market at USD 532.62 billion in 2021, growing at a CAGR of around 5.5%, to reach USD 734.39 billion in 2027 [1]. Fortune Business Insights projects the global medical devices market growth from $455.34 billion in 2021 to $657.98 billion in 2028 at a CAGR of 5.4%. This development follows a decline from 2020, when CAGR dropped to 3.7% due to the pandemic [2]. The key drivers of market growth include the rising prevalence of chronic diseases, increased disability throughout the population, technological advancements in medical devices, and population aging.

The U.S. medical device market was valued at USD 186.5 billion in 2021 and is anticipated to exhibit a compound annual growth rate (CAGR) of 5.0% over the forecast period to reach USD 262.4 billion in 2028 [4]. The Medical Device sector is even larger than Biopharmaceuticals, that by comparison, employed over 224,000 people, earning $21.2 billion [3]. The rising prevalence of chronic diseases and the increasing geriatric population in the country are the key market drivers.

The Medical Device industry has a significant impact on the U.S. economy and supports hundreds of thousands of jobs. More than 80 percent of U.S. medical device companies have fewer than 100 employees [5]. In 2020, the U.S. Medical Device industry supported over 329,000 jobs, with an annual payroll of $25.8 billion [3].

Employment and payroll for Medical Device Subsectors, 2020 ( SelectUSA ):

A relatively small number of large companies with diverse portfolios dominate the market [6]. Yet, more than 6,500 small companies exist, many of them specializing in developing innovative, niche devices [5]. The primary customer of the U.S. MedTech industry is the U.S. Health System.

The highest share of sales and revenue belonged to Surgical and Medical Instrument Manufacturing ($36.3 billion) ( SelectUSA ):

The U.S. medical device market is highly regulated. Manufacturers and importers of Medical Devices distributed in the U.S. must register their establishments with the FDA ( Establishment Registration - 21 CFR Part 807 ). Manufacturers and other establishments, e.g., sterilizers, repackagers, and U.S. manufacturers of "export only" devices must list their products in Medical Device Listing . Class I, II, and III devices, unless exempt, must submit a 510(k) to FDA to prove the device to be substantially equivalent and only market the device once cleared by the FDA (see The 510(k) Program Guidance ). In addition, Class III devices require Premarket Approval (PMA) process of scientific and regulatory review that evaluates their safety and effectiveness ( Premarket Approval, PMA ). An Investigational Device Exemption ( IDE, 21CFR Part 812 ) allows the investigational device to be used in a clinical study to support a PMA or a 510(k) submission. All devices on the U.S. market must comply with labeling requirements and have a system in place to report adverse events and product problems to the FDA ( Medical Device Reporting ). In February 2022, the FDA published a Proposed Rule: Quality System Regulation Amendment to amend the device cGMP requirements defined in 21 CFR Part 820 to incorporate ISO 13485:2016 .

Medical device regulations tend to become more standardized over time, as international standarsds are adopted throughout the industry. Yet, despite advanced technology and mature quality management systems, U.S. medical device manufacturers can still face significant challenges when placing their products on the European market.

Next: What does it take to place your Medical Devices on the European market?

Contact ARETE-ZOE, LLC for support with your European medical device submissions.

References

[1] Mordor Intelligence (2021): Medical Devices Market - growth, trends, Covid-19 impact, and forecast (2022 - 2027)

[2] Fortune Business Insight (2022): Medical Devices Market .

[3] SelectUSA (2022): An Overview of the U.S. Medical Devices and Biopharmaceutical Industries .

[4] Grand View Research (2021): U.S. Medical Device Manufacturers Market Size, Share & Trends Analysis Report By Type (Diagnostic Imaging, Consumables, Patient Aids, Orthopedics), And Segment Forecasts, 2021 - 2028

[5] AdvaMed (2022): Medical Device Industry Facts

[6] NS Medical Devices (2020): Top 10 American medical device companies in 2020 by market cap .

The Dark Side of Pharma Globalization

Tue, 28 Sep 2021 22:04:26 GMT

U.S. Pharmaceutical Dependency on Foreign Sole-Source Production of Essential Materials Imposes Vulnerable Exposure to Interruption by Both Natural and Man-Made Threats

The Dark Side of Pharma Globalization

U.S. Pharmaceutical Dependency on Foreign Sole-Source Production of Essential Materials Imposes Vulnerable Exposure to Interruption by Both Natural and Man-Made Threats

Authors: Veronika Valdova & Ronald Sheckler

Pharmaceutical supply chains have become increasingly complex due to the shift of manufacturing and critical operations to Asia. U.S. pharmaceutical dependency on foreign sole-source production of essential materials imposes vulnerability affecting the entire industry and national health systems from interruption by exposure to natural events and man-made threats, both accidental and criminal as well as political. Sector vulnerabilities stem from complex regulatory landscape, difficulties for enforcement of quality standards at foreign facilities, single-source supply chain resulting from limited sourcing options, increasing shipping distance exposure to both natural events and complicated by maritime chokepoints. Periodic and chronic shortages of many essential products across therapeutic categories have been significant for more than a decade. The Covid-19 crisis aggravated some of these long-standing issues and made the systemic vulnerabilities publicly evident. The combination of limited capacity to exercise control over essential commodities, the long-term trend of outsourcing, with the politicization of business relationships causes the entire pharmaceutical industrial sector to be internationally dependent, creating numerous potentials for systemic failure.

The business case for more robust pre-clinical research

Thu, 13 Feb 2020 14:02:58 GMT

Published 20 October 2017

In the high consequence environment of pharmaceutical development, any assumption made earlier in the process can prove extremely costly if uncorrected once more information becomes available.

From a business perspective, it is essential to create a safe avenue for communication of concerns regarding the drug candidate’s efficacy, safety, toxicity, or pharmacological function immediately as the researchers become aware of them.

Compliance, IND submissions, and business incentives

The Food and Drug Administration (FDA) requires researchers to provide specific data about new drug candidates before the drug can to proceed to human clinical trials. The IND submission package includes preclinical data on animal pharmacology and toxicology. This data serves as proof that the drug candidate is reasonably safe for human trials, manufacturing information to ensure consistent quality of the product, and clinical protocols and investigator information. The application also includes information on clinical professionals and a commitment to obtain informed consent and a review by the institutional review board (Food and Drug Administration, 2017).

The pharmacology/toxicology package contains pharmacology studies, acute, subchronic and chronic toxicity studies, special toxicity, carcinogenicity, reproduction toxicity, mutagenicity and absorption, distribution, metabolism and excretion (ADME) studies (Food and Drug Administration, 2017). This information generally comes from in vitro tests, computer modeling, and from experiments on laboratory animals. All experiments on animals in the U.S. have to conform to Part 58 of Title 21 of the Code of Federal Regulations Good Clinical Practice for Nonclinical Laboratory Studies (eCFR — Code of Federal Regulations, 2017).

From a business risk perspective, compliance and due diligence are the easy parts. The hard part is the predictive power of this information, whether or not the drug candidate has the potential to show safety and efficacy in clinical trials and obtain approval. There is a universal pressure to conduct these tests in the timeliest manner practicable, to pass the IND submission landmark. This step typically indicates the company’s willingness to undertake a considerable investment in clinical trials, without any guarantees of success. The impact of IND submission on stock price is typically neutral (Picardo, 2017). The dropout rate is exceptionally high for new molecular entities with the potential of becoming first-in-class. The dropout rate in phase III is especially worrying.

Publication bias in preclinical research

The majority of preclinical research never reaches the publication stage. For commercial research, the reasons mainly include the need to protect intellectual property. Groundbreaking research in the biotech field helps to make a business case for investors. On the other hand, academic research often has no such ambitions, the publication of the results is often part of the contract or grant award, and the main obstacles to publication are negative or inconclusive results and the lack of statistical validity. Verification of claims made in pre-clinical research based on published research is difficult, if not impossible. While all human clinical trials available in databases and registries (World Health Organization, 2017) and (US. National Institute of Health, 2017), no such registry exists for animal studies. According to Matosin et al. (2014), the primary motivation for publication in academic circles is to have their own research cited, hence the reluctance to invest time into attempts to publish negative or inconclusive results (Matosin et al., 2014).

Ter Riet et al. (2012) explored what are the main factors whether preclinical research is published or not, what is the extent of non-publication, and what are the consequences of the lack of publication. Academic research is more likely to be published (50%) than commercial research (10%). The main causes of non-publication were the lack of statistical significance and the inability to pass peer review (ter Riet et al., 2012).

Reproducibility of pre-clinical research

The low reproducibility of pre-clinical research is an essential source of assumptions made in the early stages of preclinical research. Freedman et al. (2015) argue that 50% of all preclinical research is irreproducible. Research that produces no useful results exceeds US$28 billion in the United States only. The reasons include study design, methodology, materials, reference standards and reagents used, laboratory protocols, and analysis and reporting (Freedman, Cockburn and Simcoe, 2015).

The predictive power of animal research data

The predictive power of data from preclinical research is apparent from the attrition rate in clinical trials. The Tufts Center for the Study of Drug Development estimates the cost of a newly approved drug to be at about US$2.6 billion. On average, about 60% drop out in Phase I of clinical research, and only 8% percent of drug candidates from the discovery phase reach the market. The attrition rate in the preclinical stage is approximately 70%. Unsurprisingly, the highest attrition rate is among first-in-class drugs (Booth, 2017).

Early failures

The lack of reliability and predictive power of data from preclinical research costs human lives as well. While these events are sporadic, their consequences are potentially profound. In 1993, a hepatitis B drug fialuridine had to be dropped from a Phase II trial because of severe liver toxicity. Of seven patients, five died, and another two only survived due to a liver transplant. The accident prompted the development of more sensitive tests for the detection of liver toxicity. The cause of the deaths was a rare type of long-term toxicity undetected in preclinical trials (Manning and Swartz, 1995).

The TGN-1412 First-In-Man failure became one of the most studied clinical research disasters due to the unanticipated toxicity of the drug. Not only the accident led to an overhaul of the rules for Phase I trials, but it also caused serious concerns about the predictive power of animal studies. The life-threatening symptoms of a cytokine storm were the result of assumptions made about the biology of the drug in preclinical studies. Research conducted on cynomolgus monkeys did not translate into the human biology of an immune response (Attarwala, 2010).

The most recent instance of unanticipated toxicity occurred in 2016. Healthy volunteers suffered severe neurotoxicity following a new experimental drug BIA 10-2474. The experimental drug is a reversible inhibitor of fatty acid amine hydrolase (FAAH). Its function is to increase the levels of endocannabinoids. Cumulative toxicity that was to blame was not detected in preclinical studies (Kerbrat et al., 2016). In response to the disaster, the European Medicines Agency (EMA) published a concept paper with suggestions on how to improve the safety of First-in-Man trials (European Medicines Agency, 2017).

Phase III failures

The reasons why drugs fail in phase III boil down to a flawed basic science, inappropriate animal disease models, the use of and incomplete understanding of the disease biology and targets, or uncorrected assumptions made earlier in the process of drug discovery and development. The clinical study design is an essential factor because of the use of surrogate endpoints. Additional factors to consider are changes in exclusion and inclusion criteria and patient population, inappropriate dose selection in the transition from Phase II to Phase III, and operational execution. Overly optimistic presentation of findings, leading to “go ahead” decisions for projects that should have been stopped (Shanley, 2017).

Less discussed causes of phase III failures are of organizational origin. It is human nature to protect their work and own projects to ensure continuing participation in projects that receive the organization’s approval and funding. Halting a project is an event every project manager prefers to avoid. The reasons are evident and understandable – from a career perspective, it is always better to participate in a single long project than in multiple projects that all failed in a short time. Bringing up concerns regarding the viability of a project will always represent a career risk to the messenger.

Presentation of unwelcome news, especially if this happens later in the process, is likely to produce controversy. In the high consequence environment of pharmaceutical development, any assumption made earlier in the process can prove extremely costly if uncorrected once more information becomes available. From a business perspective, it is essential to create a safe avenue for communication of concerns regarding the drug candidate’s efficacy, safety, toxicity, or pharmacological function immediately as the researchers become aware of them.

Any plan must proceed on assumptions. An information collection plan needs to exist to facilitate the timely replacement of assumptions with facts as the situation develops. Indicators of risks and potential adverse consequences, specifically potential safety concerns and lack of efficacy, have to be recorded in the original research plan and tracked throughout the drug development process. These Priority Information Requirements (PIR) and Critical Information Requirements (CIR) need to correlate with decision-making to be meaningful as a protective mechanism against the risk of an extremely costly late-stage failure (Sheckler, 2017).

In the drug development industry, a pro-active feedback loop between pre-clinical and clinical stages of development needs to exist to facilitate continuous verification of assumptions and consequent adjustment of plans.

Emerging technologies

New technologies such as human organs-on-a-chip (Wyss Institute, 2017) have the ability to transform preclinical research fundamentally. The technology involves a dynamic 3D model of human tissue on a computerized model that allows a detailed understanding of the disease biology and the effect of drug candidates on disease targets. The number of repetitions is near endless, giving the results the necessary statistical power. It is safe to assume that technology will become more affordable as it matures. Metabolism of xenobiotics, including pharmaceuticals, is a complicated affair that is difficult to observe directly in living creatures, animals, and humans alike. Our understanding of absorption, distribution, metabolism, and excretion, and lack thereof, directly depends on the tools we have. At a theoretical level, we all know that the metabolism of xenobiotics depends on the genetic makeup of the cell, qualitative characteristics, and capacity of cytochromes CYP450 to process the compound, one way or another. Yet in clinical trials, we still heavily rely on chance. New technologies allow in-vitro and in-silico modeling of scenarios that will inevitably occur when the drug reaches real patients such as hypoxic state, raised levels of inflammatory markers, and decreased liver capacity due to NAFLD / NASH or perfusion changes. Abaci and Shuler (2015) argue that their technology can be used for preclinical modeling in drug development.They explored methods on how to achieve scaling up of the organ models to replicate organ-organ interactions. μOrgans-on-a-chip (μOOC) can be used in preclinical research to mimic a physiological system using human cells to predict behavior or validate assumptions made in earlier stages of research.

Once the PK/PD is known, μHuman-on-a-chip (μHOC) can be used to model inter-organ interactions and to model and predict drug partitioning, metabolism rate, permeability rate, and so on (Abaci and Shuler, 2015). Oleaga et al. (2016) successfully utilized the system for modeling organ toxicity of new drugs under development. The model was tested on drugs with known toxicity on functional models of cardiac, muscle, liver, and neuronal tissue. The results showed promising results in regards to the predictive value of the models for in-vitro toxicity screening (Oleaga et al., 2016).

Better times ahead?

Facilitation of appropriate organizational response to new information reduces uncertainty for the organization even if the information is not favorable. Timely termination of a potentially costly project should is a good outcome that is good for business and should not result in adverse consequences for the affected individuals and teams.

References

eCFR — Code of Federal Regulations (2017). eCFR — Code of Federal Regulations: Title 21, Chapter I, Subchapter A, Part 58: Good Laboratory Practice for non-clinical laboratory studies. [online] Ecfr.gov. Available at: https://www.ecfr.gov/cgi-bin/text-idx?SID=57e31d5c0911f0938111f968430b4fd5&mc=true&tpl=/ecfrbrowse/Title21/21cfr58_main_02.tpl [Accessed 1 Jun. 2017].

Food and Drug Administration (2017). Investigational New Drug (IND) Application. [online] Fda.gov. Available at: https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/default.htm [Accessed 2 Jun. 2017].

Food and Drug Administration (2017). Drugs: Guidance, Compliance & Regulatory Information – Guidances (Drugs) – Pharmacology / Toxicology. [online] Food and Drug Administration. Available at: https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm065014.htm [Accessed 2 Jun. 2017].

Shanley, A. (2017). Preventing Phase III Failures. [online] Pharmtech.com. Available at: http://www.pharmtech.com/preventing-phase-iii-failures [Accessed 2 Jun. 2017].

World Health Organization (2017). ICTRP Search Portal. [online] Apps.who.int. Available at: http://apps.who.int/trialsearch/ [Accessed 1 Jun. 2017].

US. National Institute of Health (2017). Home – ClinicalTrials.gov. [online] Clinicaltrials.gov. Available at: https://clinicaltrials.gov/ [Accessed 1 Jun. 2017].

Sheckler, R. (2017). All organizational dysfunctions track directly to leadership failings. (Part 2). [online] Arete-Zoe. Available at: https://www.aretezoe.com/single-post/2017/02/19/All-organizational-dysfunctions-track-directly-to-leadership-failings-Part-2 [Accessed 2 Jun. 2017].

Wyss Institute (2017). Human Organs-on-Chips. [online] Wyss Institute. Available at: https://wyss.harvard.edu/technology/human-organs-on-chips/ [Accessed 2 Jun. 2017].

ter Riet, G., Korevaar, D., Leenaars, M., Sterk, P., Van Noorden, C., Bouter, L., Lutter, R., Elferink, R. and Hooft, L. (2012). Publication Bias in Laboratory Animal Research: A Survey on Magnitude, Drivers, Consequences and Potential Solutions. PLoS ONE, 7(9), p.e43404.

Matosin, N., Frank, E., Engel, M., Lum, J. and Newell, K. (2014). Negativity towards negative results: a discussion of the disconnect between scientific worth and scientific culture. Disease Models & Mechanisms, 7(2), pp.171-173.

Freedman, L., Cockburn, I. and Simcoe, T. (2015). The Economics of Reproducibility in Preclinical Research. PLOS Biology, 13(6), p.e1002165.

Booth, B. (2017). A Billion Here, A Billion There: The Cost Of Making A Drug Revisited | LifeSciVC. [online] LifeSciVC. Available at: https://lifescivc.com/2014/11/a-billion-here-a-billion-there-the-cost-of-making-a-drug-revisited/ [Accessed 1 Jun. 2017].

Manning, F. and Swartz, M. (1995). Review of the Fialuridine (FIAU) clinical trials. 1st ed. Washington, DC: National Academy Press.

Attarwala, H. (2010). TGN1412: From Discovery to Disaster. Journal of Young Pharmacists, 2(3), pp.332-336.

Kerbrat, A., Ferré, J., Fillatre, P., Ronzière, T., Vannier, S., Carsin-Nicol, B., Lavoué, S., Vérin, M., Gauvrit, J., Le Tulzo, Y. and Edan, G. (2016). Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase. New England Journal of Medicine, 375(18), pp.1717-1725.

European Medicines Agency (2017). European Medicines Agency – News and Events – Proposals to revise guidance on first-in-human clinical trials. [online] Ema.europa.eu. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/07/news_detail_002572.jsp&mid=WC0b01ac058004d5c1 [Accessed 1 Jun. 2017].

Abaci, H. and Shuler, M. (2015). Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling. Integr. Biol., 7(4), pp.383-391.

Oleaga, C., Bernabini, C., Smith, A., Srinivasan, B., Jackson, M., McLamb, W., Platt, V., Bridges, R., Cai, Y., Santhanam, N., Berry, B., Najjar, S., Akanda, N., Guo, X., Martin, C., Ekman, G., Esch, M., Langer, J., Ouedraogo, G., Cotovio, J., Breton, L., Shuler, M. and

Hickman, J. (2016). Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs. Scientific Reports, 6(1).

Occam's Razor

Thu, 13 Feb 2020 13:02:02 GMT

Published December 14, 2016

Occam's (or Ockham's) razor is a principle attributed to early medieval logician William of Ockham (1287–1347). He used the principle to justify many of his conclusions including his statement "God's existence" that "cannot be deduced by reason alone". The original principle as formulated by Ockham says:

"Pluralitas non est ponenda sine neccesitate"

(Entities should not be multiplied unnecessarily)

Ockham's razor

Many scientists have adopted Occam's Razor. German rationalist philosopher, Gottfried Wilhelm Leibniz (1646-1716) reinvented the same principle in his Identity of Indiscernibles . Natural philosopher Isaac Newton (1642-1727) in his Principia: the mathematical principles of natural philosophy stated the rule:

"We are to admit no more causes of natural things than such as are both true and sufficient to explain their appearances." (Isaac Newton, Newton's Principia )

"Whenever possible, substitute constructions out of known entities for inferences to unknown entities." (Bertrand Russell)

"Scientists must use the simplest means of arriving at their results and exclude everything not perceived by the senses." (Ernst Mach, Principle of Economy)

"We could still imagine that there is a set of laws that determines events completely for some supernatural being, who could observe the present state of the universe without disturbing it. However, such models of the universe are not of much interest to us mortals. It seems better to employ the principle known as Occam’s razor and cut out all the features of the theory that cannot be observed." (Stephen Hawking, A Brief History of Time)

Did we forget these principles in clinical research?

A recent analysis by PAREXEL evaluated data on 38 Phase III trials from the period between 2012 and 2015 that failed to meet primary or secondary efficacy endpoints. These 38 trials summarily enrolled nearly 150,000 patients. ( Phase III Trial failures: Costly, but preventable )

Darapladib (SB480848): Phase I (12 studies, enrollment 283); Phase II (3 studies, enrollment 264); phase III (3 studies, enrollment 28,918); observational (1 study, 28855 subjects). GSK blockbuster hopeful darapladib had little effect on strokes, one of the key measures on that endpoint, and the drug failed to demonstrate greater efficacy than placebo [FierceBiotech, 2014].

Evacetrapib (LY2484595): Phase I (20 studies, enrollment 953); Phase II (2 studies, enrollment 580); Phase III (4 studies, enrollment 12,604). According to the American College of Cardiology, evacetrapib is a third late failure in a class of cholesteryl ester transfer protein (CETP) inhibitors. These drugs are designed to disrupt the conversion of HDL cholesterol into LDL cholesterol. Another CETP inhibitor, torcetrapib, was abandoned after a phase 3 clinical trial because of increased risk of cardiovascular events and death. Dalcetrapib was stopped when a phase 2 clinical trial which failed to meet efficacy goals [AAC, 2016].

Losmapimod (GW856553): Phase I (3 studies, enrollment 92); Phase II (5 studies, enrollment 908); Phase III (1 study, enrollment 3,503). GSK’s decision to terminate losmapimod development for COPD came in January 2016, following a long and hard look at Phase II data. Termination of the losmapimod heart attack program came after the drug failed to demonstrate efficacy in a Phase III trial. Losmapimod is a selective inhibitor of p38 mitogen-activated protein kinases, which are mediators of acute inflammation. According to CT.gov, the drug was tested for glomerulosclerosis, COPD, acute coronary syndrome, and major depression. [Biospace, 2016]

Otamixaban (XRP0673): Phase I (2 studies, enrollment 73); Phase II (2 studies, enrollment 4,188); Phase III (1 study, enrollment 13,220). In Phase I, otamixaban was studied on patients with renal and hepatic impairment, respectively. The Phase III study failed to show the superiority of otamixaban over a combination of heparin and eptifibatide (standard of care) in moderate- to high-risk patients. Moreover, otamixaban doubled the risk of major or minor bleeding and thrombotic procedural complications. [PharmaTimes, 2013].

Serelaxin (RLX030): Phase I (1 study, 36 patients); Phase II (11 studies, enrollment 810); Phase III (3 studies, enrollment 10,788). The FDA granted breakthrough status to serelaxin in June 2013. A year later, the drug was rejected by both EMA and the FDA. The project continues, however, and the latest study RELAX-REPEAT, is now again recruiting patients with chronic heart failure. [Medscape, 2016]

Aclerastide (DSC127): Phase I (0/0); Phase II (1 study, enrollment 78); Phase III (3 studies, enrollment 1,255). In November 2015, an assessment of aclerastide found the drug did not meet its efficacy endpoints of healing diabetic foot ulcers. Consequently, Derma Sciences halted the clinical trial and is terminated the aclerastide program, and its CEO Edward Quilty resigned. [BusinessWire, 2015]

Aleglitazar: Phase I (8 studies, enrollment 267); Phase II (6 studies, enrollment 899); Phase III (8 studies, enrollment 9,838). Roche has announced the halting of a phase 3 trial of aleglitazar due to failure to meet efficacy endpoints and safety concerns, specifically PPAR class-related toxicity such as bone fractures, heart failure, and gastrointestinal bleeding. Aleglitazar turns on peroxisome proliferator-activated receptor (PPARs), receptors that are known to be problematic. Dr. Bernard Charbonnel in a piece on PPARs noted that more than 50 such drugs had failed clinical trials due to safety concerns. After the Phase III failure of another three PPARs, aleglitazar, muraglitazar and tesaglitazar the whole class of drugs appears to be doomed. [FierceBiotech, Medscape, 2013]

Basal insulin Peglispro (LY2605541): Phase I (14 studies, enrollment 480); Phase II (2 studies, enrollment 269); Phase III (10 studies, enrollment 6087). In December 2015, Eli Lilly announced that it will cease development of basal insulin peglispro, a potential treatment for type 1 and type 2 diabetes [Lilly press release, 2015]

"While we are encouraged by the efficacy data we observed for BIL, we know that moving forward would have required a significant amount of time and investment with no assurance that we would find conclusive answers," said Enrique Conterno, president, Lilly Diabetes.

Saxagliptin: Phase I (18 studies, enrollment 641); Phase II (5 studies, enrollment 784); Phase II/III (1 study, enrollment 450), Phase III (38 studies, enrollment 18,216) Phase IV (37 studies, enrollment 26229). SAVOR was a large randomized, double-blind, placebo-controlled Phase 4 study in patients with T2DM at high risk of CV disease. The primary objective of the study was to evaluate the CV safety of saxagliptin. SAVOR, showed an association between saxagliptin treatment and an increased risk for hHF; however, a mechanism to account for the hHF finding has yet to be determined [AstraZeneca Advisory Committee Briefing Document, 2015]. FDA safety warning followed in February 2014.

Alisertib (MLN8237): Phase I (32 studies, enrollment 1234); Phase I-II (7 studies, enrollment 605); Phase II (17 studies, enrollment 1440); Phase III (1 studies, enrollment 271). Japanese drug-maker Takeda tested Alisertib for the treatment of a variety of cancers, including peripheral T-cell lymphoma, acute myeloid leukemia, small-cell lung carcinoma, solid tumors, and others. The program for lymphoma was halted after the drug failed to show any benefit in progression-free survival. Takeda acquired the program through the acquisition of Milennium Pharmaceuticals in 2008. [PharmaTimes, 2015]

Cabozantinib: Phase I (19 studies, enrollment 950); Phase I/II (3 studies, enrollment 184); Phase II (37 studies, enrollment 2840); Phase III (5 studies, enrollment 2887), Phase IV (2 studies, enrollment 1188); Phase not stated (5 studies, enrollment 121); Observational (1 studies, enrollment 50). In 2014, following phase III failure of its drug against advanced prostate cancer, Exelixis had to ax about 70% of its workforce. In March 2016, French drug-maker Ipsen bought the drug with a hope that it may treat kidney and liver cancers. The drug is already approved for severe thyroid cancer (FierceBiotech).

Dacomitinib (PF00299804): Phase I (18 studies, enrollment 591); Phase I/II (4 studies, enrollment 593); Phase II (16 studies, enrollment 992); Phase III (3 studies, enrollment 2,037); Phase not stated (1 studies, enrollment 6). In January 2014, Pfizer announced that dacomitinib failed in two Phase III studies. Dacomitinib irreversibly inhibits enzyme pan-HER kinase in patients with advanced non-small cell lung cancer. Dacomitinib did not improve progression-free survival when compared with Roche's Tarceva (erlotinib) and placebo, respectively. Research for the treatment of non-small cell lung cancer with specific mutations continues. [PharmaTimes, 2014, Cancer Therapy Advisor, 2016]

Enzastaurin (DB102, formerly LY317615 HCl): Phase I (9 studies, enrollment 280); Phase I/II (2 studies, enrollment 137); Phase II (35 studies, enrollment 2,595); Phase III (2 studies, enrollment 1,106). In 2013 Eli Lilly stopped on development of enzastaurin, which failed to improve disease-free survival in patients with diffuse large B-cell lymphoma. Enzastaurin is a serine/threonine kinase inhibitor of the PKC beta and AKT pathways and has been studied for a range of solid tumors and hematological cancers. [Fierce Biotech, 2016]

Etirinotecan pegol (NKTR-102): Phase I (2 studies, enrollment 57); Phase II (9 studies, enrollment 377); Phase III (2 studies, enrollment 1,202). The results of the BEACON trial failed to demonstrate improvement in survival and progressio-free survival when compared to active control in patients with advanced breast cancer. [PMLive, 2015]

Ganetespib + docetaxel (STA-9090): Phase I (13 studies, enrollment 337); Phase I/II (6 studies, enrollment 434); Phase II (15 studies, enrollment 2,353); Phase II/III (1 studies, enrollment 385); Phase III (3 studies, enrollment 2,296). In October 2015, Synta Announced Termination of Ganetespib Phase 3 GALAXY-2 Trial in Lung Cancer because of futility. [Business Wire, 2015]

Lapatinib + Trastuzumab: Phase 0 (1 study, enrollment 40); Phase I (19 studies, enrollment 1,564); Phase I/II (11 studies, enrollment 468); Phase II (51 studies, enrollment 3,888); Phase II/III (1 study, enrollment 697); Phase III (15 studies, enrollment 13,919); Observational (7 studies, enrollment 715). The results from the phase III ALTTO trial show no additional benefit for adding lapatinib (Tykerb) to trastuzumab (Herceptin) in the adjuvant treatment of HER2-positive breast cancer in terms of progression-free survival and overall survival. [The ASCO Post, 2014]

MAGE-A3: Phase 0 (1 studies, enrollment 25); Phase I (11 studies, enrollment 353); Phase I/II (9 studies, enrollment 400); Phase II (10 studies, enrollment 664); Phase II/III (1 studies, enrollment 4); Phase III (2 studies, enrollment 3,629); Observational (1 studies, enrollment 983). GlaxoSmithKline invested high hopes and lot of fortune in the cancer vaccine MAGE-A3. The vaccine failed to meet efficacy endpoints for non-small cell lung cancer and then again for melanoma. GSK continues to search for a possible sub-population of cancer patients who might benefit from the therapy. [FierceBiotech, 2014]

Motesanib (AMG 706): Phase I (19 studies, enrollment 781); Phase I/II (2 studies, enrollment 51); Phase II (17 studies, enrollment 1,617); Phase III (3 studies, enrollment 1,650); Observational (1 study, enrollment 50). Japanese pharmaceutical giant Takeda acquired the drug from AMGEN and tested in a series of trials for non-small cell carcinoma. Motesanib failed to meet efficacy endpoints and the trial was terminated in 2011. [In the Pipeline, 2015]

Onartuzumab (MetMab): Phase I (4 studies, enrollment 59); Phase I/II (1 studies, enrollment 0); Phase II (7 studies, enrollment 1,141); Phase III (5 studies, enrollment 1,610). In March 2014, Roche oncology R&D arm at Genentech halted a Phase III study comparing MetMab with Tarceva. The drug failed to block metastasis in non-small cell lung cancer and the trial was halted for futility. [Fierce Biotech, 2014]

Ramucirumab: Phase I (20 studies, enrollment 1,292); Phase I/II (2 studies, enrollment 204); Phase II (34 studies, enrollment 3,406); Phase II/III (1 study, enrollment 908); Phase III (12 studies, enrollment 7,785); Phase IV (1 study, enrollment 1,000); Expanded Access (2 studies, enrollment 0). In September 2013, Eli Lilly announced that its Phase III study for ramucirumab failed to meet its efficacy endpoints on progression-free survival in patients with metastatic breast cancer. Phase III study for ramucirumab in gastric cancer hit its primary and secondary endpoints. The announcement was followed by immediate drop in shares by more than 5%. [FierceBiotech, 2013]

Selumetinib + Dacarbazine: Phase I (1 studies, enrollment 211); Phase II (3 studies, enrollment 783); Phase III (1 studies, enrollment 152). AstraZeneca acknowledged that its non-small-cell lung cancer (NSCLC) candidate selumetinib missed its primary endpoint in a Phase III trial assessing the drug with docetaxel. The combination failed to improve progression-free survival and overall survival compared with placebo. [GEN, 2016]

Trebananib + paclitaxel (AMG 386): Phase I (11 studies, enrollment 453); Phase I/II (2 studies, enrollment 122); Phase II (15 studies, enrollment 3,208); Phase III (3 studies, enrollment 2,157); Expanded Access (1 study, enrollment 20). Following disappointing results, trebananib was terminated for ovarian cancer. This is a comment by Sean E. Harper, M.D., executive vice president of R&D at Amgen: [Amgen, 2014]

"While the overall survival results of the TRINOVA-1 study are disappointing, this study is the first of three Phase 3 trials designed to evaluate the safety and efficacy of trebananib in patients with ovarian cancer. We continue to explore the potential of trebananib's novel anti-tumor mechanism of action in other cancer settings"

Xilonix: Phase III (2 studies, enrollment 1,076). The Phase III trial for oncology drug Xilonix had to be halted not because of safety or efficacy issues but because of a series of embarrassing errors and mishaps that made the study impossible to evaluate. The drug was tested for colorectal cancer. [FierceBiotech, 2015]

Vintafolide : Phase I (3 studies, enrollment 72); Phase II (6 studies, enrollment 458); Phase III (1 studies, enrollment 640). Merck & Co. and Endocyte announced that the Data Safety Monitoring Board for the PROCEED trial has recommended that the Phase III study be halted as vintafolide did not meet efficacy endpoints and failed to improve progression-free survival in patients with platinum-resistant ovarian cancer. [FirstWord Pharma, 2014]

Vosaroxin +cytarabine (Qinprezo): Phase I/II (1 studies, enrollment 115); Phase II (1 studies, enrollment 61); Phase III (1 studies, enrollment 675); Expanded Access (1 studies, enrollment 17). Sunesis Pharmaceuticals announced disappointing results from its Phase III trial VALOR trial. The drug failed to improve overall survival in patients with acute myeloid leukemia. [Clinical Trials Arena, 2015]

Fluticasone furoate + vilanterol (Breo/Relvar): Phase I (8 studies, enrollment 258); Phase II (7 studies, enrollment 877); Phase III (36 studies, enrollment 29,361); Phase IV (4 studies, enrollment 332). GlaxoSmithKline tested their new drug Breo to demonstrate improved survival compared to placebo. The SUMMIT trial missed efficacy endpoints and the program was halted. [PharmaForum, 2016]

Bitopertin (RG1678): Phase I (2 studies, enrollment 71); Phase II (2 studies, enrollment 400); Phase III (4 studies, enrollment 2,450). Roche's Phase III failed to meet its primary endpoint, and the company was forced to halt the trial for futility. Bitopertin is a glycine transporter-1 inhibitor designed for the treatment of schizophrenia. Adding bitopertin to antipsychotics failed to improve persistent negative symptoms of schizophrenia as measured by PANSS (Positive and Negative Symptoms Scale) scores when compared to placebo. [PsychCentral, 2015]

Edivoxetine (LY2216684): Phase I (16 studies, enrollment 362); Phase II (2 studies, enrollment 697); Phase II/III (3 studies, enrollment 1,101); Phase III (6 studies, enrollment 6,197). Eli Lilly's antidepressant candidate edivoxetine used as an add-on to a SSRI failed to meet its primary endpoint in three Phase III trials when compared to a SSRI combined with placebo. [GEN, 2013]

Pomaglumetad methionil: Phase I (2 studies, enrollment 160); Phase III (2 studies, enrollment 432); Expanded Access (1 study, enrollment 16). In summer 2012, Eli Lilly wrote of another schizophrenia drug, pomaglumetad methionil. In the first two pivotal Phase III studie the drug did not show superiority to placebo. [GEN, 2013]

Lessons Learned and Potentials for Improvement in CNS Drug Development: ISCTM Section on Designing the Right Series of Experiments (2015)

Solanezumab: Phase I (1 studies, enrollment 130); Phase II (3 studies, enrollment 113); Phase II/III (1 studies, enrollment 210); Phase III (6 studies, enrollment 3,190). Drug designed to treat Alzheimer's disease, through targeting the amyloid plaque, failed a huge Phase 3 clinical trial. The announcement caused Eli Lilly's shares to drop 10.5 percent. [Bloomberg Gadfly, 2016]

Apremilast: Phase I (8 studies, enrollment 398); Phase I/II (2 studies, enrollment 13); Phase II (25 studies, enrollment 2,047); Phase II/III (1 study, enrollment 15); Phase III (10 studies, enrollment 4,446); Phase IV (6 studies, enrollment 418); Observational (8 studies, enrollment 6875); not stated (3 studies, enrollment 45). In summer 2014, Celgene announced that apremilast failed a Phase 3 study in improving symptoms of patients with ankylosing spondylitis. [Xconomy, 2014]

Tabalumab: Phase I (4 studies, enrollment 122); Phase II (8 studies, enrollment 866); Phase III (9 studies, enrollment 7,858). Lilly's two Phase III trials for tabalumab - ILLUMINATE I and II- did not meet primary endpoint and failed to measure up compared to existing therapies. The drug was designed to treat autoimmune diseases such as rheumatoid arthritis and lupus erythematosus. [FierceBiotech, 2014]

Vercirnon (Traficet-EN): Phase I (2 studies, enrollment 54); Phase II (3 studies, enrollment 596); Phase III (4 studies, enrollment 1,492). Data from the SHEILD-1 study failed to meet the primary and secondary endpoints for the secondary treatment of patients with Crohn's Disease. [BioWorld]

Innovation always involves the risk of failure. It is an art to see what the data show, and what they don't, and which projections are the result of our wishful thinking or unsubstantiated assumptions. It may be just my impression that 14th-century logician William of Ockham whispers in my ear that entities shall not be multiplied unnecessarily.

Training improves organizational resilience, even in pharma.

Thu, 13 Feb 2020 11:46:30 GMT

The current operational environment in the pharmaceutical industry

Companies are growing in size due to acquisitions and mergers. Operations routinely span across geographical, jurisdictional, and cultural boundaries. The trend of industry consolidation continues in 2015 and 2016: the total number of deals flattened and remained even at around 600 mergers a year. Geographically, mergers, and acquisitions have been shifting from the U.S. to Western Europe. This shift is the result of transactions driven by the need to add complementary products to the core business areas and tax inversions.

Pharmaceutical industry outsourcing in manufacturing, specialized services, clinical research, and even pharmacovigilance has grown during the past ten years, and this trend is likely to continue. Outsourcing includes a full range of corporate activities—from screening and lead identification to toxicology and other pre-clinical studies, clinical trials, marketing, and manufacturing at all scales. The main outsourcing areas include product characterization testing, validation services, toxicity testing, analytical testing, and fill-finish operations. Much of the growth in outsourcing in the past decade has taken place in China and India.

The result of industry trends is increasing the risk of disruptions due to reorganizations, complex vendor relationships, cultural and legal differences, single-source supply chain, high-impact accidents, natural disasters, and other factors.

The pharmaceutical industry is global, complex, international, and highly regulated. Training is one of the most important ways, how to decrease internal vulnerabilities and improve organizational resilience.

Organizations need to be able to train their existing and newly coming workforce in a much more systematic and flexible manner to accommodate continually changing needs, to adapt to changing operational environments, and to achieve greater resiliency and agility.

The regulatory environment in pharmaceuticals is continuously changing. Often conflicting national and international requirements and policies have to be translated into organizational SOPs and working instructions in a way that ensures unambiguous interpretation. This process requires coordinated inter-departmental effort to ensure consistency in implementation, to reduce liability stemming from non-compliance caused by lack of competence, need for improvisation, differences in interpretation, and human error.

The complexity of the organization affects the number of entities involved in handling material and information. It increases the complexity of operations concerning its internal and external relations, roles and responsibilities and tasks assigned to functions, access rights management, and ultimately training requirements.

Globalization affects all functions of any enterprise, from financial and legal to security situation in regions of interest. Increasing distance and time zone differences make the system slower to respond in case of disruptions. Training improves individual and collective ability to solve operational challenges aggravated by cultural diversity, differing communication styles, language barriers, and other factors in standard situations, as well as during crises.

The increasing complexity of operations is the result of the changing nature of products traded. The consolidating industry increases the complexity of organizations and their internal and external relationships and limits sourcing options. The shift from blockbuster medicines to orphan medicines, individualized treatments, and niche products increases the costs of operations. High volume products with predictable demand are managed differently and often follow different supply and distributions models than products with low and unpredictable market demand.

Information management systems become more sophisticated and complex in response to these trends. New technologies, although valuable, create new vulnerabilities for the enterprise. Human ability to recognize and deter new threats is essential to counter social engineering efforts, hacking, and data breaches.

After all, highly trained and qualified people are the most valuable assets of every learning organization.

Shall we worry about Coronavirus disrupting the pharmaceutical supply chain?

Wed, 12 Feb 2020 23:08:14 GMT

The adventurous journey of pharmaceutical cargo around the globe

Once upon a time, medicines with a patent of Royal favor counted as precious high-value cargo, along with tea, spices, and rum, shipped from Old England to Amerikay and all over the world. The great advantage of medicinal nostrums compared to rum was that the crew typically could not drink the cargo on the way there.

" I've a fine, strong crew and I tell them what to do

I'm the captain of the ship The Bonnie Lady

She's my joy and my pride, and she's twenty meters wide

And they call her the ship The Bonnie Lady."

" We've a vast haul of rum a cargo we will run

From along the far off shores of Haiti

With the brisk salt air just blowin' through my hair

At the wheel of the ship, The Bonnie Lady."

Times have changed. Pharmaceutical companies grew bigger and stronger and moved their manufacturing operations to India and China. Big markets in the U.S. and Europe import vast amounts of medicines from exotic places in South-East Asia. Many active pharmaceutical ingredients, including essential drugs, are manufactured exclusively in China. One thing that has not changed over the centuries: straits and choke-points cargo ships have to pass on their way from Asia to Europe remained the same. Well, except for the Suez Canal, that significantly shortened journey from the Far East to Europe and the Panama Canal that connected the U.S. East and West Coast.

New Paragraph

ICC: Live piracy map

Routes from India to U.S. West Coast

On the way from India to the U.S. West Coast, cargo has to pass the Strait of Malacca and sail through the South China Sea. The total travel time is about 30 days.

Routes from China to Europe

On the way from major pharmaceutical manufacturing centers in China to Western Europe, cargo has to sail through the South China Sea and pass the Strait of Malacca, Bab el-Mandab, Suez Canal, and the Strait of Gibraltar.

The English Channel, the busiest shipping route in the world

Daily Mail: Watch the world's ships sail Earth's oceans in REAL TIME: Interactive map reveals crowded routes taken by planet's vessels.

China's maritime choke points ( Geopolitical Futures )

"Man's natural habitat is land, and land dominates his conscious endeavor--social, economic, political, and military. Yet, almost three quarters of his world is ocean. It is the original source of life for all earth's species; it is the essential means of global transport for man's produce, commerce, and military strength. While the world ocean is beyond sight of much of mankind, its influence is ubiquitous.“ Parameters, US Army War College Quarterly - Summer 1997 Peele, RB: The importance of maritime chokepoints (SSI, 1997)

18 maps that explain maritime security in Asia: Spratly Islands ( Business Insider )

So what? Why does it matter?

The National Bureau of Economic Research documented the geography of manufacturing among off-patent generic prescription drugs. More than 90% of dispensed drugs in the U.S. are generics. The generic drugs sold on the U.S. market are increasingly produced abroad, specifically in China and India. The current industry geography is the result of past decisions by private corporations and policymakers based on incentives, public safety regulations, tax provisions, cost of labor, trade policy, tariffs, and the availability of skilled workforce. As of 2019, there are about 7000 manufacturers of active pharmaceutical ingredients. The authors of the report identified a significant gap in knowledge concerning specific locations of facilities where drugs (active pharmaceutical ingredients and finished drug forms) are being produced and how the trends are developing in time. Similarly, it would be useful to map the geographical dependency of the European Union in terms of the production of generic prescription drugs ( The National Bureau of Economic Research, 2019 )

Root causes of drug shortages

Recently, the inter-agency Drug Shortage Task Force, led by FDA, published a report Drug Shortages: Root Causes and Potential Solutions on the underlying causes of drug shortages. The Taskforce stated that the root causes of drug shortages are the lack of incentives for manufacturers to produce less profitable drugs;

lack of recognition and reward for mature quality systems, and logistical and regulatory challenges that make it difficult for the market to recover from a disruption ( FDA, 2019 ).

Shall we worry about Coronavirus disrupting pharmaceutical supply chain?

Yes indeed. The reason is that critically important products such as active pharmaceutical ingredients and medical devices are manufactured in regions that are being shut down. Just-in-time supply chain and very few alternative suppliers for many off-patent generics make significant, long-term disruption much more likely.

Drugmakers braced for coronavirus disruption to China supplies ( Financial Times, 2020 )

Coronavirus outbreak in China sparks fears of disruption for global drug supplies ( BioWorld, 2020 )

The silent threat of the coronavirus: America’s dependence on Chinese pharmaceuticals ( The Conversation, 2020 )

Coronavirus will impact supply chains around the world within days to week: Infectious disease expert ( CNBC, 2020 )

Can patients' interests prevail?

Wed, 12 Feb 2020 16:29:03 GMT

Data breaches in healthcare: Can patients' interests prevail?

Everybody knows what personally identifiable information (PII) is and how important it is to ALWAYS de-identify case reports before sharing them with any third parties. These legal obligations, however, are not always enough to prevent subsequent data linkage by a determined and motivated researcher. Imagine a hypothetical example: how much effort it would take to find out the unfortunate fellow's true identity, knowing his occupation and employer, his sister's name, and nature of his injuries?

The total number of patient records lost to hackers, other types of IT incidents, and theft, is staggering. In 2015, personally identifiable information of 113,267,174 individuals was affected in a total number of 268 data breach incidents. The compliance-driven industry did not stop these incidents from occurring and did little to increase overall resilience against malicious intrusions and tampering. The most devastating incidents to date involved Health Plans and resulted in the breach of more than 99,800,000 medical records: Anthem Inc. (78,800,000; 2015), Premera Blue Cross (11,000,000; 2015) and Excellus Health Plan Inc. (10,000,000; 2015) (HIPAA Journal, 2020).

Ransomware: the state-of-the-art cash machine

Resulting disruption puts people's health and lives at risk. Healthcare staff lost access to medical records, in some instances, permanently. Emergency patients could not be treated because of malfunctioning electronic equipment and had to be transferred elsewhere. Non-urgent patients had their surgical procedures cancelled or postponed. Dispatch centers and 911 call services defaulted to paper maps and paper logs to support their operations. Movement of staff around buildings was hindered because of badge scanners that ceased to work ( EmsiSoft, 2020 ).

"Do not disturb my circles!"

The most famous case of a medical device purposefully altered to prevent targeted cyberattacks by terrorists is Dick Cheney's pacemaker. But there are many other examples of medical devices that are potentially life-threatening, from insulin pumps to patient life functions monitors ( ScienceMag, 2015 ). The security of medical devices software in hospital environments is often insufficient. The software in the healthcare sector tends to be older and usually poorly maintained, making it more vulnerable than consumer tech because updating the software might risk running afoul of their Food and Drug Administration approval ( The Washington Post)

"Sit down and relax while I go there and wet the tea."

Patient records are private for a reason. It is not always the best idea to share medical records, wittingly or not, with representatives of different cultures. Their understanding of the patient's welfare may be entirely different.

"That is not my baby!"

The Rise of Medical Identity Theft ( Consumer Reports, 2016 )

20,000 pregnant Men in Britain

( MailOnline, 2012 )

NHS is not immune to creative use of patient identity credentials ...even more worrying consequence, especially for unsuspecting gentlemen

IoT enormously expand cyberattacks hospitals suffer " ...and this is how it happens" ( Verizon Report )

The biggest problem with patient data leaks is that the party most affected by inappropriate handling of medical data is the patient, rather than the owner of the data. So while consequences of internal security failure may be financial, as a result of failure to comply, for affected patients, such incidents can be life-threatening.

How long will it take to start taking patient records and hospital data seriously?

Sexually transmitted diseases in the elderly in South Florida

Mon, 20 Jan 2020 17:25:15 GMT

Florida is attractive for retired Americans, and their population continues to grow. In primary care, sexual health is often overlooked in elderly patients, since they rarely open the topic themselves, and physicians often assume their patients are no longer sexually active. Drugs for erectile dysfunction, as well as attractions of life on the beach, create opportunities that may no longer be out of reach. Mature adults do indeed have girlfriends and friends with benefits, along with their regular partners and spouses.

Improving the resilience of vulnerable populations

Mon, 20 Jan 2020 16:42:46 GMT

Improving the resilience of vulnerable populations

July 2017

Vulnerable populations

Vulnerable populations in terms of health care disparities include the economically disadvantaged and uninsured, the elderly, and people with chronic health conditions. Low-education status compounds the problem and leads to poorer outcomes than in people with the same disease but higher educational status. Significant disparities include namely risk factors relating to morbidity and mortality and access to healthcare. In the domain of physical health, the worst affected are people with chronic health conditions such as respiratory diseases and metabolic syndrome, including hyperlipidemia and diabetes, and resulting in heart diseases and hypertension. Vulnerable populations often experience accumulation of problems that are multiplied by poor health, yet the medical and non-medical needs of these populations are still underestimated. A significant number of vulnerable people with at least one chronic condition skip purchasing prescription drugs because of the costs involved. The most relevant risk factors that result in poor access to health care include low income and uninsured status, in combination with a lack of regular care. Chronic conditions such as dyslipidemia may not be particularly apparent now, yet represent a high risk of future disability (“Vulnerable Populations: Who Are They?”, 2006).

How the principles of vulnerability apply to the chronically ill population

Chronic conditions require regular physician visits and a holistic approach to one’s health, including optimal nutrition and physical activity. Low economic status makes all aspects of a healthy lifestyle particularly challenging, often due to long hours spent commuting to work, isolation in areas with limited access to amenities, and budgetary constraints that limit the patients’ ability to optimize their lifestyle. Reliance on processed foods with a long shelf life is often the consequence of efforts to save costs on food and fuel and limit the number of store visits. This behavior, in turn, leads to a higher intake of saturated fats, sugars, and sodium, and high-calorie consumption combined with a low intake of essential nutrients. This compensatory behavior exacerbates the vicious circle of obesity and metabolic syndrome, including dyslipidemia, insulin resistance, and hypertension. Expenses for health care and medication of chronic illnesses that do not provide immediate symptomatic relief are a low priority compared to survival needs that include housing, food, and the ability to maintain employment. Regular doctor visits add additional time and cost demands on the already overstretched budgets. Chronic conditions such may remain unaddressed not only due to the costs of care but also because of frustrations the patients often encounter due to their inability to change their circumstances. Treatment efforts may then be perceived as futile, adding to frustrations from doctor’s feedback and lack of progress.

What disparities in health care apply to vulnerable populations?

The most relevant disparities that affect vulnerable populations include access to care and its utilization and the quality of care received. Non-adherence to treatment regime and long gaps in care, in addition to moving between providers, often lead to overlooking deterioration or lack of improvement. Physician’s frustrations with patients’ non-adherence to treatment and irregular visits often lead to lowering expectations and readjustment of the treatment regimen. Virtual medical environments may offer a solution that is low cost and ensures regular contact without placing an additional burden on the patient.

Nurses Roles and functions in the community

The decision to remain at home in the face of a life-limiting illness or to relocate to a care home or a hospice is a complex one. Boland et al. (2017) analyzed data from 19 systematic reviews that studied more than 270.000 participants and compared the health outcomes from a variety of care settings, such as independent living at home and institutional care. The results show that the health outcomes are generally comparable between different environments, with mixed results for various attributes. The authors are supportive of the positive impact of home care providing the elders to remain within their communities where they receive appropriate support (Boland et al., 2017).

Enrollment in hospice care does not determine the type of patient’s medical care indefinitely. The real-world care paths differ, and there currently is little evidence about the length of stay and transfers between hospitals, hospices, and home care. Hospitalization of terminally ill patients with a high burden of disease and their prolonged treatment in intensive care units raises a series of ethical and pragmatic questions. Studies using patient-centered data should be used to evaluate the data objectively (Pathak, Wieten & Djulbegovic, 2014).

Hospices rely on the help of volunteers to provide support to end-of-life patients and patients with a life-limiting illness. For nurses, the differences in care provided to institutionalized patients represent different kinds of challenges than care offered to patients in their homes. In hospices, nurses rarely have to provide care that is outside the domain of nursing care, and their ability to escalate and delegate responsibility may be better than when the patient is at home. The roles of caretakers within the community are less clearly defined. In communities, nurses can provide training that would facilitate correct escalation of patients’ care needs without overburdening nurses with tasks they can efficiently complete themselves to ensure the appropriate use of resources.

What is the framework that houses the tenets?

The objective of public health nursing is to promote the health of populations in their communities utilizing the knowledge and understanding of public health to improve the health status of the community and reduce the burden of disease and disability. The tenets of public health nursing have to be based on a comprehensive assessment of the population, development of appropriate policy, and quality assurance processes. The capacity of the community needs to be considered to improve the population’s lifestyle practices and optimize environmental factors that may limit their choices.

What is the value of the tenets from a population health standpoint?

A community where people find it easy and convenient to maintain a healthy lifestyle is less prone to common civilization ailments such as obesity, metabolic syndrome, and hypertension. People whose physical mobility is not reduced by chronic illness are more likely to maintain their independence until advanced age. A safe environment that enables physical exercise, both outdoors and indoors, is the prerequisite to maintaining population health. A quality assurance mechanism needs to be implemented to evaluate and improve any measures undertaken. The assessment of the economic value of any investments in the public health domain has to be measurable and quantifiable.

References

Vulnerable Populations: Who Are They?. (2006). The American Journal Of Managed Care, 12(13), S348-S352. Retrieved from http://www.ajmc.com/journals/supplement/2006/2006-11-vol12-n13suppl/nov06-2390ps348-s352/P-1

Boland, L., Légaré, F., Perez, M., Menear, M., Garvelink, M., & McIsaac, D. et al. (2017). Impact of home care versus alternative locations of care on elder health outcomes: an overview of systematic reviews. BMC Geriatrics, 17(1). http://dx.doi.org/10.1186/s12877-016-0395-y

Pathak, E., Wieten, S., & Djulbegovic, B. (2014). From hospice to hospital: short-term follow-up study of hospice patient outcomes in a US acute care hospital surveillance system. BMJ Open, 4(7), e005196-e005196. http://dx.doi.org/10.1136/bmjopen-2014-005196

Prostate cancer, a lifestyle disease?

Mon, 20 Jan 2020 16:17:48 GMT

Prostate cancer, a lifestyle disease?

May 2017

Prostate carcinoma is one of the leading causes of male cancers. Major risk factors include advancing age and family history and lifestyle, and a Western diet rich in saturated fat and low in fiber and obesity with related disorders such as insulin resistance and metabolic syndrome. Healthy weight and diet rich in soy isoflavonoids are the most relevant protective factors. Screening for genetic risks is useful for the detection of high-risk patients who would benefit from a biopsy. The underlying mechanisms that link prostate cancer to obesity include high levels of and insulin-like growth factor I (IGF-I) and sex steroids due to their anabolic properties. Additional theories include chronic inflammation, oxidative stress, hypoxia, and immune system changes. Prostate-Specific Antigen (PSA) is still a useful tool; however, its results need to be interpreted in the context of other risks and clinical presentation. Biopsy shall be performed where clinically justified. Androgen metabolism is essential for the understanding of the pathophysiology of the disease and the development of appropriate drug targets. Blocking the intra-tumor synthesis of androgens is critical to the success of advanced prostate cancers.

Prostate cancer

Prostate carcinoma is the second most common of all cancers and the sixth leading cause of male cancer deaths. The highest prevalence of prostate cancer is among men, Europe, North America, Australia, and New Zealand, whilst men in Southeast Asia are affected the least. The risk of prostate cancer increases with age. Other risk factors include family history, genetics, obesity, diet, medications, infections, and sexual habits. Clinical presentation includes frequent urination, hematuria and dysuria, lower limb lymphedema, and bone tenderness. Prostate carcinoma is locally invasive and spreads into the bone, especially the pelvis and the spine. Treatment involves the combination of surgery, radiation therapy, hormonal treatment, and chemotherapy. Many men who die of other causes have prostate cancer detected at autopsy that was undetected during their lifetime (Mustafa et al., 2016).

Pathophysiology: Risk factors

Advancing age is the most important risk factor for the development of prostate cancer. Approximately 60% of all cases of prostate cancer are diagnosed in men over65 years of age. The disease is associated with a Western lifestyle, fat-rich diet, and obesity. African-Americans are at higher risk of developing prostate cancer and are also 2.4 times more likely to die from the disease (Bashir, 2015). Prostate cancer is one of the most heritable cancers, with about 42% of the risk attributable to genetics. However, family cancer history is not always known to the patient and the clinician. Alternative methods of calculation of genetic risk score (GRS) include single-nucleotide polymorphisms carried by the individual (Helfand, 2016).

Obesity is a significant contributor to cancer deaths, second only to smoking. It is estimated that obesity increases the risk of cancer by up to 20%. Endometrial and postmenopausal breast cancer show the highest association between obesity and malignancy. Other cancers strongly linked to obesity are esophageal adenocarcinoma, colorectal and renal carcinomas, and prostate cancer.

The underlying mechanisms that link cancer to obesity include insulin, insulin-like growth factor I (IGF-I), and sex steroids. Additional theories include chronic inflammation, oxidative stress, migrating adipose stromal cells, obesity-induced hypoxia, and a functional defect of immune function (De Pergola, & Silvestris, 2013).

The lifestyle that leads to cardiovascular disease also increases the risk of prostate cancer. Various dietary supplements such as selenium and vitamin E were tested for their ability to prevent prostate cancer. These supplements were not effective in lowering the risk of cardiovascular disease or cancers. Drugs that promote cardiovascular health, such as statins, metformin, and aspirin, are also effective in the prevention of prostate cancer. These medications are beneficial as auxiliary agents in the management of aggressive prostate cancer. In two large trials, Prostate Cancer Prevention Trial (PCPT) with finasteride and REduction by DUtasteride of Prostate Cancer Events (REDUCE) failed to show any benefit of these medications on the reduction of the incidence of prostate cancer. However, the trials clearly showed how the risk of prostate cancer relates to the risk of death from cardiovascular disease: of the 18.000 men who participated in the PCPT trial, five men on finasteride, and five on placebo died of prostate cancer. In contrast, 1,123 died from other causes, mostly cardiovascular (Moyad, & Vogelzang, 2014). Fibrates, a commonly used medication used as a cholesterol-lowering agent, showed no effect on the prevention of prostate cancer (Bonovas, Nikolopoulos, & Bagos, 2012).

Isoflavones such as genistein, daidzein, and biochanin were investigated for their role in the prevention of prostate cancer. The results are conflicting, showing both harmful and positive effects. Soy foods that are rich in genistein are the main component of the Asian diet. The difference in dietary uptake of genistein can likely account for the difference in the prevalence of prostate cancers in Western and Asian populations (Ahmad et al., 2013).

Increased incidence of prostate cancer is associated with prostate inflammation resulting from prostatitis caused by sexually transmitted infections. Chronic inflammation increases the risk of development of many cancers through cell and genome damage, altered cell signaling functions, and promotion of cell replication and angiogenesis. Detection and recall of prostatitis, especially if asymptomatic, are significant limitations of epidemiological studies. In the absence of androgen stimulation, prostate tissue responds by diffuse atrophy. If androgen stimulation is present, however, the tissue responds to inflammation by focal atrophy that is associated with prostate cancer. Epithelial cells within these lesions proliferate extensively and show indications of the high level of oxidative stress. Accumulated genome damage then leads to transformation into cancer cells. Practical experience suggests the contributing role of colonization by Chlamydia trachomatis, Ureaplasma urealyticum, Trichomonas vaginalis, Neisseria gonorrheae, cytomegalovirus infection, and herpes simplex. Both symptomatic and asymptomatic prostatitis increases PSA levels. However, not all types of prostate inflammation increase the risk of prostate cancer in the same manner (Nakai, & Nonomura, 2012).

Sexual activity affects the probability of developing prostate cancer in both protective and deleterious manner. The main mechanisms studied are high androgen status, the risk of sexually transmitted infections, and the retention of carcinogens within prostatic cells. While frequent ejaculation seems to be protective due to the drainage of carcinogenic substances from prostatic acini, high androgen status, and the risk of contracting sexually transmitted diseases, increase the risk. There is an association between a higher number of female sexual partners and the risk of prostate cancer due to the increased risk of sexually transmitted diseases. The protective effect of phosphodiesterase inhibitors for erectile dysfunction is explained by a higher frequency of ejaculation and the ability to retain sexual functions. Homosexuality increases the risk of developing prostate cancer due to a higher risk of HIV infection. Trauma to the prostate during receptive anal intercourse increases the level of prostate-specific antigen (PSA), artificially increasing the diagnosis rates. Physical injury may also lead to a higher risk of prostate cancer (Kotb, Beltagy, Ismail, & Hashad, 2015).

Androgen metabolism is essential for the understanding of the pathophysiology of the disease and the development of therapeutic targets. Adrenal androgens (i.e., dehydroepiandrosterone) are a source for the intratumoral dihydrotestosterone. This production of hormones by the tumor makes certain types of prostate cancer resistant to castration. Prostate cancer changes the expression of steroidogenic enzymes and affects androgen metabolism. Androgen deprivation therapy through surgical or medical castration is the mainstay therapy for advanced prostate cancer. Overexpression of the androgen receptor in tumor tissue contributes to the progression into castration-resistant prostate cancer. Similarly, mutations in the androgen receptor and the synthesis of dihydrotestosterone (DHT) have the same effect. Blocking the intra-tumor synthesis of androgens can be achieved by inhibiting CYP17A1 activity, resulting in suppression of tumor growth. Abiraterone acetate and enzalutamide halt the progression only temporarily. The reason is that the tumor eventually develops resistance to these agents (Chang, Ercole, & Sharifi, 2014).

The extent of contribution of gender to prostate cancer etiology

Dehydroepiandrosterone (DHEA), available in the bloodstream, is converted first to androstenedione and then to DHT. The first step of adrenal androgen metabolism is catalyzed by 3b-hydroxysteroid dehydrogenase and D5 -D4 isomerase. The conversion to DHT requires 17bHSD and steroid-5a-reductase. Alternatively, adrenal androstenedione is converted to 5a-androstanedione and then to DHT (the ‘5a-dione pathway’). The majority of castration-resistant prostate cancers use the alternative pathway, thus avoiding the need for testosterone. Metabolism of androgens in tumorous tissue and gene expression has been studied extensively as part of screening for new potential drug targets. In clinical oncology, the treatment of individual patients depends on tumor biology and underlying genetic defect (Chang, Ercole, & Sharifi, 2014).

Androgens, however, only become the key factor in prostate cancer pathogenesis in the very last stage. The relevant risk factors are advancing age, obesity, insulin resistance, metabolic syndrome, and chronic inflammation. These factors are gender-neutral and can be influenced by lifestyle.

Prevention

Treatment of prostatitis with antibiotics can reduce the likelihood of the development of prostate cancer by reducing chronic inflammation. Treating prostate infection and targeting dietary habits may be the most important way of prostate cancer prevention (Nakai, & Nonomura, 2012). Antidiabetic therapy is essential to the prevention of prostate cancer. The pathophysiologic effect of insulin and insulin resistance have a critical influence on its development. Insulin and drugs that promote the secretion of insulin, such as sulfonylureas, increase the risk of cancer-related mortality. On the other hand, metformin and thiazolidinediones reduce this risk (Hitron, Adams, Talbert, & Steinke, 2012). A healthy lifestyle, including a diet rich in soy products and low in saturated fat and maintaining a healthy weight, is the most important part of prostate cancer prevention. Diet low in animal fat is also essential to limit the source of prostate inflammation and oxidative stress.

Detection of risk factors

Tests for the early detection of prostate cancer such as the Prostate-Specific Antigen (PSA) and biopsy significantly increased the incidence of prostate cancer. Due to the long latency stage, a positive test does not equal the need for immediate intervention. PSA, although not very specific, is still a valid biomarker useful for monitoring patients under active surveillance, with repeat biopsies as a follow—up (Romero-Otero et al., 2015).

The decision when and how frequently to take bioptic samples depends on various individual risk factors. Indicators relating to obesity currently investigated for cancer risk include body mass index (BMI), waist-to-hip ratio, and waist circumference. Visceral adiposity is associated with a higher risk of cancer than general adiposity. Obesity is the cause of approximately 20% of cancer deaths in women and 14% in men. Some mechanisms are universal; other are more tumor and location-specific. Excess dietary energy and overindulgence in animal fats and alcohol are linked to cancer incidence and tumor progression. The protective effect of energy balance is likely related to the levels of insulin due to its anabolic and antiapoptotic effects, resulting in insulin resistance, increased levels of IGF-I that promote cell growth, and inflammatory biomarkers. Insulin receptors are overexpressed in prostate cancer cells. Obesity leads to oversecretion of proinflammatory molecules. Examples are interleukin-6 (IL-6), tumor necrosis factor-alpha, leptin, resistin, and others. The secretion of beneficial adipokines is lower. An additional effect of obesity includes oxidative stress and immune system alterations (De Pergola, & Silvestris, 2013).

Some of the important gene markers located on chromosome 1 include HPC1, PCAP, and CAPB. Association was found between mutations in the breast cancer predisposition genes (BRCA1 and BRCA2) and increased risk of prostate cancer. Additional regions associated with increased risk of prostate cancer include 1q23, 5q11, 5q35, 6p21, 8q12, 11q13, and 20p11–q11 and the prostate cancer susceptibility gene HOXB13. GCS is a measurement of inherited risk for prostate cancer and is calculated from the cumulative effect of single-gene mutations. GCS is essential information in a clinical decision relating to the timing and frequency of biopsies in addition to family history and other screening tests (Helfand, 2016).

Conclusion

The incidence of prostate cancer increases in the developed world, partially due to advanced screening programs designed to detect prostate cancer in its early stages, and partially due to a strong correlation between cancer and metabolic syndrome. The most relevant risk factors for the development of prostate cancer include advancing age, family history, obesity, insulin resistance, chronic inflammation, including sexually transmitted infections and colonization of prostate by specific pathogens and low sexual activity. In advanced stages, the most relevant mechanism of cancer growth and the spread becomes its acceleration by androgens. Prevention strategies include lifestyle changes and active surveillance of high-risk groups. The timing of biopsies and their frequency remains a challenge. Indicators of high-risk include BMI, waist-to-hip ratio, genetic risk score, and inflammation markers.

References

Mustafa, M., Salih, A., Illzam, E., Sharifa, A., Suleiman, M., & Hussain, S. (2016). Prostate Cancer: Pathophysiology, Diagnosis, and Prognosis. IOSR Journal Of Dental And Medical Sciences (IOSR-JDMS), 15(6), 4-11. http://dx.doi.org/10.9790/0853-1506020411

De Pergola, G., & Silvestris, F. (2013). Obesity as a Major Risk Factor for Cancer. Journal Of Obesity, Epub 2013 Aug 29, 1-11. http://dx.doi.org/10.1155/2013/291546

Helfand, B. (2016). A comparison of genetic risk score with family history for estimating prostate cancer risk. Asian Journal Of Andrology, 18(4), 515. http://dx.doi.org/10.4103/1008-682x.177122

Bashir, M. (2015). Epidemiology of Prostate Cancer. Asian Pacific Journal Of Cancer Prevention, 16(13), 5137-5141. Retrieved from http://journal.waocp.org/?sid=Entrez:PubMed&id=pmid:26225642&key=2015.16.13.5137

Moyad, M., & Vogelzang, N. (2014). Heart healthy equals prostate healthy and statins, aspirin, and/or metformin are the ideal recommendations for prostate cancer prevention. Asian Journal Of Andrology, 0(0), 0. http://dx.doi.org/10.4103/1008-682x.148070

Ahmad, A., Biersack, B., Li, Y., Bao, B., Kong, D., & Ali, S. et al. (2013). Perspectives on the Role of Isoflavones in Prostate Cancer. The AAPS Journal, 15(4), 991-1000. http://dx.doi.org/10.1208/s12248-013-9507-1

Bonovas, S., Nikolopoulos, G., & Bagos, P. (2012). Use of Fibrates and Cancer Risk: A Systematic Review and Meta-Analysis of 17 Long-Term Randomized Placebo-Controlled Trials. Plos ONE, 7(9), e45259.

http://dx.doi.org/10.1371/journal.pone.0045259

Hitron, A., Adams, V., Talbert, J., & Steinke, D. (2012). The influence of antidiabetic medications on the development and progression of prostate cancer. Cancer Epidemiology, 36(4), e243-e250. http://dx.doi.org/10.1016/j.canep.2012.02.005

Kotb, A., Beltagy, A., Ismail, A., & Hashad, M. (2015). Sexual activity and the risk of prostate cancer: Review article. Archivio Italiano Di Urologia E Andrologia, 87(3), 214. http://dx.doi.org/10.4081/aiua.2015.3.214

Nakai, Y., & Nonomura, N. (2012). Inflammation and prostate carcinogenesis. International Journal Of Urology, 20(2), 150-160. http://dx.doi.org/10.1111/j.1442-2042.2012.03101.x

Chang, K., Ercole, C., & Sharifi, N. (2014). Androgen metabolism in prostate cancer: from molecular mechanisms to clinical consequences. British Journal Of Cancer, 111(7), 1249-1254. http://dx.doi.org/10.1038/bjc.2014.268

Romero-Otero, J., García-Gómez, B., Duarte-Ojeda, J., Rodríguez-Antolín, A., Vilaseca, A., Carlsson, S., & Touijer, K. (2015). Active surveillance for prostate cancer. International Journal Of Urology, 23(3), 211-218. http://dx.doi.org/10.1111/iju.13016

Pricing transparency at point of care

Mon, 20 Jan 2020 14:38:06 GMT

Pricing transparency at point of care

July 2017

Medical innovation, increasing the complexity of care, and the relationships between stakeholders gradually lead to the increase in prices of healthcare for consumers. Lack of transparency affects the cost of premiums as well as out-of-pocket expenses. Policymakers in their considerations need to include more indicators than just insurance coverage that, without other measures, will not curb soaring healthcare expenses. Delayed care is a public health concern because of the risk of disability and under-treatment of otherwise treatable conditions. The presentation of data to non-technical audiences, including decision-makers, has to be understandable to convey the information reliably. Systems modeling techniques should be considered to estimate stakeholder behavior in a dynamic system accurately. Currently, many instances of abuse exist within the system. As an example, chargemaster fees apply to uninsured or out-of-network patients. Hospital fees are, however, tackled by state laws rather than at the federal level. Consumers in health care tend to behave differently than in other industries and often think less about the costs involved. Physicians’ education should include the delivery of cost-conscious care to prevent financial harm to their patients. Transparency of cost is one of the most effective mechanisms that enable patients and providers to make informed choices.

Pricing transparency

Medical innovation improves patient outcomes but also considerably increases healthcare costs. Patients were directly responsible for payments to physicians until the end of the 19th century. With the gradual adoption of aseptic techniques, many procedures moved from home settings to the controlled environment in hospitals. Increased complexity of care and the introduction of third-party payers led to decreased transparency of the cost of care for patients. Financial toxicity as a byproduct of otherwise effective treatment first emerged as an important topic in connection with modern cancer therapies. Economic harms inflicted by care are becoming an increasingly important topic in healthcare. The escalating costs of care cannot be tolerated indefinitely (Gupta, Tsay & Fogerty, 2015).

The introduction of the Affordable Care Act was met with high expectations in regards to access to quality healthcare care covered by an insurance policy. In reality, health insurance coverage did not reduce the total medical debt; some individuals and families suffered. The problem got worse due to the high cost of premiums for the most vulnerable groups, high copay, and lack of transparency of the cost of care.

Defining the policy issue

The cost of care and its affordability has long been a hot topic exploited for political purposes. While the Affordable Care Act sought to decrease the number of uninsured, who were among the most affected by excessive medical bills, insurance alone is not going to solve the problem of soaring costs in U.S. healthcare. Confusion over coverage, convoluted insurance coverage plans, out-of-network fees, and other traps are among the causes of exorbitant costs of healthcare in the U.S.

Delayed care as a public health concern

Galbraith et al. (2013) argue that high copay and the complexity of insurance plans lead to underuse and delays in the use of needed care. The inability of providers to foresee these issues compounds the problem. The example of the Massachusetts health insurance exchange showed that the majority of enrollees who did not qualify for subsidies chose bronze or silver plans with high deductibles. Unsurprisingly, the financial burden affected most families with more children and lower incomes and those with more complex health needs. Transparency of pricing and the ability to estimate the cost of care accurately turned out to be a significant problem. The authors concluded that policymakers should focus their attention on the development of cost calculators and price transparency tools (Galbraith et al., 2013).

Insurance does not solve the problem of cost

The reluctance of lower-income population to enroll in mandatory insurance is not driven by the lack of desire for healthcare. The reasons are more complex and depend on the amount of copay, the ability of people to make informed choices about the care they receive, and their ability to navigate the complex U.S. healthcare system. The fact that a drug is new and FDA-approved is not a guarantee that it is always better than therapies that are much less costly. A thorough understanding of treatment cost-effectiveness is a challenge even for seasoned professionals. Policymakers at all levels would need the information to be presented to them in a form that is accessible and understandable.

Presentation of data

The presentation of complex economic evaluations to non-technical audiences can be a challenge in itself. Many guidelines on economic evaluations include standard reporting templates and formats, mostly in the form of tables and graphs. Sullivan et al. (2015) analyzed thirty-one guidelines for instructions on how to present economic analyses to non-technical audiences. In healthcare, common elements include clinical outcomes and quality-adjusted life years (QALY) and disability-adjusted-life-years (DALY), and the effect of delayed or inappropriate care on these attributes. Communication of cost-effectiveness to non-technical audiences such as policymakers and patients may be a tough thing to do. Conveying uncertainties and limitations of science to stakeholders within healthcare is essential to maintain credibility and consistency (Sullivan, Wells & Coyle, 2015).

Modeling of complex systems requires an understanding of the system as a whole. While systems modeling software is available and routinely utilized in many other industries, it seems that healthcare is still more dependent on decisions made by people whose main qualification is an opinion driven by ideology. The use of modeling of stakeholder behavior and cost-effectiveness analyses for individual protocols and procedures needs to become a norm rather than an exception.

Considering the context

In 1933, the Committee on the Costs of Medical Care argued that increased need for healthcare leads to costs that are becoming burdensome for individual families that suddenly had to pay for childbirth and other medical care. In 1954, expectant mothers would have received the cost of their care and board upfront. This transparency vanished with the increasing complexity of care and the introduction of provider-payer-patient relationships (Gupta, Tsay & Fogerty, 2015).

Social and health implications

Patients’ decision to delay or forgo needed care because of the cost may not be evident to providers who rarely discuss the cost of care with their patients. Such avoidance of financial issues leads to non-adherence to prescribed treatment and improper management of otherwise treatable conditions (Galbraith et al., 2013). Under-treatment of chronic diseases such as high blood pressure and diabetes leads to earlier onset of complications, disability, and premature death.

Chargemaster

Price transparency is the key to preventing billing disputes for out-of-network care. A variety of approaches is used to remediate out-of-network billing disputes over overcharged care. Richman et al. (2017), in their review of potential legal remedies, concluded that contract law, if appropriately applied, including price lists, should prevent many if not most of the current billing disputes, and should also provide sufficient incentives for transparent pricing. Inflated charges for out of network care are the primary driver of increasing financial burden to patients, especially those who have to seek urgent unavoidable care. The abuse of vulnerable patients by providers who unilaterally set prices and charge exorbitant amounts for out-of-network care is well documented in the current media. Although federal laws do not safeguard patients against the use of inflated chargemaster prices, some states have enacted consumer protection legislation “balanced billing laws” that limit the practice. Contract law, however, offers a solution that is based on existing market forces and mutual assent (Richman, Kitzman, Milstein & Schulman, 2017).

Stakeholders

Healthcare organization in the U.S. is a complex affair with many direct and indirect relationships between stakeholders. In addition to healthcare providers, patients and insurers, the key participants include the pharmaceutical and medical devices industry, municipal and state administration, regulators, investors, and a variety of private service providers in related industries. The relationships between facility owners, management, healthcare personnel, vendors, suppliers, and government and private payers can be very complex and dynamic due to ongoing organizational changes. The continuum of care needs to function often in spite of these complicated and often conflicting and clashing structures.

Women as critical stakeholders

Women are often responsible for making healthcare-related decisions and choices. In Massachusetts, the cost-containment law intends to improve transparency and curb costs of care utilizing a variety of innovative approaches. The bill, however, had some unintended consequences for women’s care that later had to be corrected in several amendments. Women are more likely to be affected by unmanageable healthcare costs because of a combination of lower-income and higher needs due to longer life span, reproduction-related care, and increased risk of multiple chronic diseases. Women are critical stakeholders among consumers when it comes to healthcare (Glynn, MacKenzie & Fitzgerald, 2016).

Considerations within nursing

Healthcare shopping is not necessarily something patients want to contemplate on, especially when there is a perceived more or less urgent need. The consideration of cost is a shared responsibility between the patient and the physician.

Consumer behavior

Consumer behavior in healthcare differs from the behavior of the same people in any other industry. Commonly, people enroll in plans without overthinking the options and visit providers they know without any consideration of the quality of care or costs involved: confusion and lack of communication compound the problem. First, patients who seek care often do not know where they can find the answers to questions that only occur to them once they are in contact with the provider. Second, the answers they receive may inflict even more confusion, primarily when a provider in their network refers them to out-of-network specialist care.

Most importantly, their personal needs do not always conform to the hospital's internal processes. Consumer behavior in healthcare and patient attitudes depends on their trust in the healthcare system in general and on their understanding and knowledge of the system. Improving institutional culture and communication with customers at their own pace is essential to improve satisfaction and outcomes. Consumers shall be able to make informed choices — rational decision-making by consumers shall be at the heart of curbing health care costs (Roberts, 2016).

Are physicians aware of the costs of care they provide?

Jonas et al (2016) argue that value for patient and cost-consciousness needs to become part of physicians’ training. The study was driven by results of post-intervention surveys in a children’s’ hospital to develop a new curriculum about value-based care. Increased transparency and physician education are essential to provide cost-conscious care and limit the care that does not improve clinical outcomes. Project Striving for Value in Pediatrics includes topics that enable physicians to make treatment decisions that are value-based and cost-effective (Jonas, Ronan, Petrie & Fieldston, 2016).

Options and solutions

The four currently prevailing strategies to counter chargemaster abuses include increased transparency of pricing, enacting state laws that prohibit balance billing, transferring the obligation to pay for out-of-network care from consumers to insurers, and providing mediation. The most promising strategy, however, relies on the current bedrock of contract law (Richman, Kitzman, Milstein & Schulman, 2017).

The quality of care

Patients should be able to decide for themselves what type of care and where they should seek based on data that are available and accessible. The differences between hospitals are substantial in terms of quality, cost, and value. There are no tools in the public domain that would allow comparison of quality and cost of care. Weeks et al. (2016) created a tool that utilizes publicly available data derived from Hospital Compare and Medicare care expenditures. Although imperfect, the measures as presented still offered reasonably accurate information on the cost and quality of care (Weeks, Kotzbauer & Weinstein, 2016).

Transparency tools

By 2014 – 2015, health plans implemented a variety of tools that should assist members in their efforts to estimate the cost of care and their contributions in advance. These tools primarily cover commonly used procedures, including surgery and radiology. Price estimates facilitate informed choices and increase the probability that members will facilities that offer the best value for their money. The majority of the estimator tools allowed the comparison of providers and services and the cost of prescription drugs based on data from paid claims (Higgins, Brainard & Veselovskiy, 2016).

Cost-transparency tools are often not apparent to physicians who should be able to advise their patients on how to access cost-effective care. Out-of-pocket expenses are a significant burden to patients, and unnecessary care that burdens insurers is reflected in the cost of premiums. The Institute of Medicine, in its study of healthcare costs, concluded that in 2009, approximately a third of all healthcare spending, totaling $750 million, was spent on unnecessary services (Kirkner, 2014).

It is also unclear whether transparency tools decrease the cost of care. Studies from some developing countries suggest that this is not always the case. Comparisons of price levels work best when performed against multiple countries to account for a variety of methodologies and variations (Hinsch, Kaddar & Schmitt, 2014).

State laws on transparency

The problem of transparency of healthcare pricing initiated numerous discussions on the topic, such as the Healthcare Incentives Improvement Institute (HCI3) or Catalyst for Payment Reform (CPR). The results of these initiatives highlighted the grim state of affairs: in October 2013, 36 out of 50 states got a D or an F for their price transparency efforts or lack thereof, respectively. A new law passed in North Carolina in 2013, the Health Care Cost Reduction and Transparency Act, gives hospitals numerous obligations, including publishing prices they charge uninsured patients (Carroll, 2013).

State laws to curb costs

The cost of novel prescription drugs and their widespread use is one of the crucial drivers of increasing costs of care. In the absence of federal legislation, some states have been tackling the cost of healthcare on their own. Some states limit access to costly drugs or imposed restrictions for those whose care is covered by public funds. Some legislative proposals challenge the industry claim that the high cost of new drugs reflects the cost of research and approval and require disclosure of research and development costs as well as a value proposition and clinical benefit of the new drug. Verification of the data provided by the industry and the ability to include research expenses for failed projects remains a significant challenge (Sarpatwari, Avorn & Kesselheim, 2016).

Model Act

In November 2015, the National Association of Insurance Commissioners amended the Model Act to include more protections for consumers. The Model Act intends to improve pricing transparency and encourage mediation between payers and providers. Among other obligations, the providers would be required to create accurate network directories that would inform patients what care is out-of-network. The Model Act has not been enacted in any state yet but can serve as an example of growing efforts to curb the problem (Richman, Kitzman, Milstein & Schulman, 2017).

What’s next – options to consider

Because of the legal and political ambiguities in regards to access to care, and the complex system of medical insurance in America, it is advisable to start at the hospital level with a pilot project of cost-conscious care optimization for underinsured and uninsured populations. The pilot could encompass prioritization of cost when providing care to patients and the provision of cost-calculation when offering treatment options to patients. Evaluation of such a project can be conducted in cooperation with local and municipal authorities and academic institutions to develop an evidence-based solution that enhances public health in the community.

Conclusion

Active dissemination of information on relative risks, benefits, and treatment alternatives, including cost comparison and cost-effectiveness to enable consumers to make better choices, seems to be a more viable solution. Physician education of cost-conscious care significantly improves the awareness of the cost-effectiveness of individual therapies. For policymakers, systems modeling, in addition to a more accessible presentation of cost-effectiveness, would facilitate the development of rational, evidence-based solutions.

References

Richman, B., Kitzman, N., Milstein, A., & Schulman, K. (2017). Battling the chargemaster: a simple remedy to balance billing for unavoidable out-of-network care. Am J Manag Care, 23(4), e100-e105. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28554214

Sarpatwari, A., Avorn, J., & Kesselheim, A. (2016). State Initiatives to Control Medication Costs — Can Transparency Legislation Help?. New England Journal Of Medicine, 374(24), 2301-2304. http://dx.doi.org/10.1056/nejmp1605100

Weeks, W., Kotzbauer, G., & Weinstein, J. (2016). Using Publicly Available Data to Construct a Transparent Measure of Health Care Value: A Method and Initial Results. The Milbank Quarterly, 94(2), 314-333. http://dx.doi.org/10.1111/1468-0009.12194

Roberts, K. (2016). Four steps for improving the consumer healthcare experience across the continuum of care. Am J Manag Care, 22(4), e122-4. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27143347

Jonas, J., Ronan, J., Petrie, I., & Fieldston, E. (2016). Description and Evaluation of an Educational Intervention on Health Care Costs and Value. Hospital Pediatrics, 6(2), 72-79. http://dx.doi.org/10.1542/hpeds.2015-0138

Gupta, R., Tsay, C., & Fogerty, R. (2015). Promoting Cost Transparency to Reduce Financial Harm to Patients. The AMA Journal Of Ethic, 17(11), 1073-1078. http://dx.doi.org/10.1001/journalofethics.2015.17.11.mhst1-1511

Glynn, A., MacKenzie, R., & Fitzgerald, T. (2016). Taming Healthcare Costs: Promise and Pitfalls for Women's Health. Journal Of Women's Health, 25(2), 110-116. http://dx.doi.org/10.1089/jwh.2015.5295b

Kirkner, R. (2014). Doctors aren't grasping for cost transparency tools. Manag Care, 23(7), 23-27.

Hinsch, M., Kaddar, M., & Schmitt, S. (2014). Enhancing medicine price transparency through price information mechanisms. Globalization And Health, 10(1), 34. http://dx.doi.org/10.1186/1744-8603-10-34

Carroll, J. (2013). No informed consumers without price transparency. Manag Care, 22(10), 17-8. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24350382

Galbraith, A., Sinaiko, A., Soumerai, S., Ross-Degnan, D., Dutta-Linn, M., & Lieu, T. (2013). Some Families Who Purchased Health Coverage Through The Massachusetts Connector Wound Up With High Financial Burdens. Health Affairs, 32(5), 974-983. http://dx.doi.org/10.1377/hlthaff.2012.0864

Higgins, A., Brainard, N., & Veselovskiy, G. (2016). Characterizing health plan price estimator tools: findings from a national survey. Am J Manag Care, 22(2), 126-31. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26885672

Sullivan, S., Wells, G., & Coyle, D. (2015). What Guidance are Economists Given on How to Present Economic Evaluations for Policymakers? A Systematic Review. Value In Health, 18(6), 915-924. http://dx.doi.org/10.1016/j.jval.2015.06.007

Quality of Care Measures: PTSD

Mon, 20 Jan 2020 13:35:30 GMT

Quality of Care measures: PTSD

April 2017

Hospital quality management series (monitoring outcomes)

Overview

The intent is to compare the effectiveness of most used treatment approaches for the treatment of post-traumatic stress disorder (PTSD): cognitive behavioral therapy (CBT) and antidepressants, especially atypical antidepressants in the population of males over 65 years of age. Measuring quality of care and assessment of the effectiveness of treatment programs is also a compliance obligation. According to Executive Order 13625, of August 31, 2012, program resources shall be reassigned to the highest-ranking programs across all of the military services by 2014 (The White House, 2012). Although this does not apply for a non-military establishment, evidence of treatment effectiveness may be required when providing treatment to military veterans.

The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) redefined criteria for post-traumatic stress disorder (PTSD): A stressor, such as direct or indirect exposure to actual or threatened death or serious injury; intrusion symptoms such as feelings, memories, and nightmares; persistent effort to avoid trauma-related stimuli; negative alterations in cognition and mood; and changes in arousal and reactivity. Alterations in cognition and mood include dissociative amnesia, persistent negative beliefs about oneself, persistent distorted blame for the event or its consequences, persistent negative trauma-related emotions, diminished interest in significant activities, alienation, and persistent inability to experience positive emotions (DSM-5 Criteria for PTSD | BrainLine Military, 2017). Treatment guidelines cited in this work are based on the previous version, DSM-4.

To date, the U.S. National Institute of Health Database identified 236 clinical trials for PTSD, where CBT was used as the studied intervention (Search of: ptsd | cognitive behavioral therapy - List Results - ClinicalTrials.gov, 2017). An additional 76 studies used antidepressants were used (Search of: ptsd | antidepressants - List Results - ClinicalTrials.gov, 2017). Study designs and outcome measures vary from one study to another. Most relevant studies compared two different behavioral techniques. A comparison of behavioral intervention and pharmacotherapy was used in 17 trials. In general, the highest quality evidence comes from randomized controlled trials. The assessment of the quality of evidence coming from clinical trials can be time-consuming and complex, and typically requires the involvement of multiple specialists who review the evidence and make recommendations. The FDA approved only two pharmacotherapies for the treatment of PTSD: SSRIs paroxetine and sertraline. All other medications, such as other SSRIs, different classes of antidepressants, anticonvulsants, benzodiazepines and atypical antipsychotics are used off-label (Jeffreys, 2017).

The U.S. Department of Veterans Affairs (VA) treatment guideline describes the critical decision points and provides evidence-based recommendations for practice. PTSD treatment approaches include evidence-based psychotherapies and pharmacotherapy. Evidence-based pharmacotherapies (particularly SSRIs and SNRIs) are often combined with psychotherapies and adjunctive treatments. The initial discussion about treatment options should include general advantages and disadvantages of each option, side effects, and time commitment. Patient preference and therapist’s specific training often drives the initial selection. A-level evidence is available for trauma-focused psychotherapy that includes components of exposure and/or cognitive restructuring, and stress inoculation training. Both techniques are strongly recommended as beneficial. Cognitive Therapy (CT) techniques were developed to improve mood and behavior through modification of dysfunctional beliefs, thoughts, and expectations. While there is good evidence that these techniques are effective in reducing PTSD symptoms, they are not considered superior to exposure therapies due to conflicting outcomes in available studies (The Management of Post-Traumatic Stress Working Group, 2010, p. 114-122).

The VA treatment guideline strongly recommends antidepressants such as SSRI, namely fluoxetine, paroxetine, or sertraline. Suggested alternatives include and SNRIs, specifically venlafaxine. Mirtazapine, prazosin, nefazodone, and phenelzine showed some benefit. However, the latter two shall be used with caution. The existing evidence does not support the use of bupropion, buspirone, trazodone, and gabapentin. Lamotrigine and atypical antipsychotics in monotherapy are not recommended, either (The Management of Post-Traumatic Stress Working Group, 2010, p. 149-155).

In 2010, the National Defense Authorization Act authorized funding for the Institute of Medicine to conduct a major review of PTSD programs and evaluate their effectiveness. A final report from this comprehensive review and analysis was published in 2014. The working group analyzed available evidence from clinical trials for both pharmacotherapies and psychotherapies and expressed the strength of recommendation for each of them based on the quality of evidence from available clinical trials (Institute of Medicine (U.S.), 2014).

Clinical Outcome Measures

Evidence-based practice is a problem-solving approach to clinical practice that incorporates evidence available from clinical trials, individual needs and preferences of patients, and the expertise of the healthcare provider. The main barriers to implementation as identified by the survey were lack of time, knowledge, support and mentorship, and access to resources (Melnyk et al., 2004).

Tracking outcome measures is essential in ensuring the quality of care. This is especially true for any therapies that are used off-label, or for which there is weak or insufficient evidence of effectiveness. Most PTSD programs did not collect and analyze outcome data, and results were not available for evaluation. Follow-up assessments of former program participants were rarely conducted. The most commonly used tools are the Primary Care PTSD screen and the PTSD Checklist (PCL), the Clinician-Administered PTSD Scale, the Mississippi Scale, the Connor-Davidson Resilience Scale, and the Global Assessment of Function (Institute of Medicine (U.S.)., 2014, p. 79-88).

Standard PTSD checklist (PCL), version PCL-5 is a reasonable choice for data collection efforts. The checklist is a self-report measure that is based on DSM-5 and intended for initial screening and for monitoring symptoms before and after treatment. The data shall be evaluated and interpreted by a clinician. The checklist can be used as a part of care delivery to monitor patient’s progress or as research. The previous version, PCL-4, that was based on DSM-4 considered 5-10 point change to be a reliable change and 10-20 points to be a statistically significant change. The final range for PCL-5 has not been determined yet (PTSD Checklist for DSM-5 (PCL-5) - PTSD: National Center for PTSD, 2017). The checklist can be implemented as part of care to monitor the effectiveness of the tools used rather than research. The initial pilot project is planned for three months.

Satisfaction Outcome Measures

Patient-reported outcome (PRO) is an integral part of a treatment program that enables the evaluation of acceptance of the treatment by the patient and comparison of different programs and treatment options. Besides, PRO tools identify treatment programs that may require change and are instrumental in the screening of patients who may become non-adherent to the prescribed treatment. Treatment Satisfaction Questionnaire for Medication version II is a reliable tool that produces valid results for patient experience with medication, specifically effectiveness, side effects, and convenience of use (Atkinson, Kumar, Cappelleri, & Hass, 2005).

A global satisfaction survey cannot be used on its own but always in combination with TSQM evaluation of effectiveness, side effects, and convenience. Dissatisfaction with treatment is the strongest predictor of non-adherence with treatment (Global Satisfaction scale of the Treatment Satisfaction Questionnaire for Medication (TSQM): the mean scale score for the Global Satisfaction items on the TSQM (version II). | National Quality Measures Clearinghouse, 2017).

Patients who are not on medication but receive a behavioral intervention instead, as well as patients who are receiving both, shall be asked to complete the Experience of Care and Health Outcomes (ECHO) Survey (ECHO Survey Measures, AHRQ 2017). The ECHO Survey can be used to satisfy external standards and to monitor and improve the quality of behavioral health services they received (National Quality Measures Clearinghouse, 2017).

Cost Outcome

Implementation of a measurement program for the tracking of outcomes becomes critical for reimbursement of care provided to military veterans. PTSD severely impacts patients’ quality of life and ability to work, and frequently leads to long-term disability. Quality-adjusted life-years (QALYs) is a measurement tool used to calculate the cost-effectiveness of treatment interventions in terms of gained years of quality life. Disability-adjusted life years (DALYs) account for treatment that prevents disability (Sassi, 2006).

References

Atkinson, M., Kumar, R., Cappelleri, J., & Hass, S. (2005). Hierarchical Construct Validity of the Treatment Satisfaction Questionnaire for Medication (TSQM Version II) among Outpatient Pharmacy Consumers. Value In Health, 8, S9-S24. http://dx.doi.org/10.1111/j.1524-4733.2005.00066.x

Behavioral health care patients' experiences: percentage of adult patients who reported how much of a problem they had getting treatment and information from their health plan or managed behavior health organization. | National Quality Measures Clearinghouse. (2017). Qualitymeasures.ahrq.gov. Retrieved 16 April 2017, from https://www.qualitymeasures.ahrq.gov/summaries/summary/26648/behavioral-health-care-patients-experiences-percentage-of-adult-patients-who-reported-how-much-of-a-problem-they-had-getting-treatment-and-information-from-their-health-plan-or-managed-behavior-health-organization

Blevins, C., Weathers, F., Davis, M., Witte, T., & Domino, J. (2015). The Posttraumatic Stress Disorder Checklist forDSM-5(PCL-5): Development and Initial Psychometric Evaluation. Journal Of Traumatic Stress, 28(6), 489-498. http://dx.doi.org/10.1002/jts.22059

DSM-5 Criteria for PTSD | BrainLine Military. (2017). Brainlinemilitary.org. Retrieved 14 April 2017, from http://www.brainlinemilitary.org/content/2014/06/dsm-v-tr-criteria-for-ptsd.html

ECHO Survey Measures | Agency for Healthcare Research & Quality. (2017). Ahrq.gov. Retrieved 16 April 2017, from https://www.ahrq.gov/cahps/surveys-guidance/echo/about/survey-measures.html

"Global Satisfaction" scale of the Treatment Satisfaction Questionnaire for Medication (TSQM): the mean scale score for the "Global Satisfaction" items on the TSQM (version II). | National Quality Measures Clearinghouse. (2017). Qualitymeasures.ahrq.gov. Retrieved 15 April 2017, from https://www.qualitymeasures.ahrq.gov/summaries/summary/26831/Global-Satisfaction-scale-of-the-Treatment-Satisfaction-Questionnaire-for-Medication-TSQM-the-mean-scale-score-for-the-Global-Satisfaction-items-on-the-TSQM-version-II

Institute of Medicine (U.S.). (2014). Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Final Assessment (1st ed.). Washington, D.C.: National Academies Press.

Jeffreys, M. (2017). Clinician's Guide to Medications for PTSD - PTSD: National Center for PTSD. Ptsd.va.gov. Retrieved 10 April 2017, from https://www.ptsd.va.gov/professional/treatment/overview/clinicians-guide-to-medications-for-ptsd.asp

Melnyk, B., Fineout-Overholt, E., Fischbeck Feinstein, N., Li, H., Small, L., Wilcox, L., & Kraus, R. (2004). Nurses' Perceived Knowledge, Beliefs, Skills, and Needs Regarding Evidence-Based Practice: Implications for Accelerating the Paradigm Shift. Worldviews On Evidence-Based Nursing, 1(3), 185-193. http://dx.doi.org/10.1111/j.1524-475x.2004.04024.x

PTSD Checklist for DSM-5 (PCL-5) - PTSD: National Center for PTSD. (2017). Ptsd.va.gov. Retrieved 15 April 2017, from https://www.ptsd.va.gov/professional/assessment/adult-sr/ptsd-checklist.asp

Sassi, F. (2006). Calculating QALYs, comparing QALY and DALY calculations. Health Policy And Planning, 21(5), 402-408. http://dx.doi.org/10.1093/heapol/czl018

Search of: ptsd | antidepressants - List Results - ClinicalTrials.gov. (2017). Clinicaltrials.gov. Retrieved 14 April 2017, from https://clinicaltrials.gov/ct2/results?cond=ptsd&intr=antidepressants&show_down=Y

Search of: ptsd | cognitive behavioral therapy - List Results - ClinicalTrials.gov. (2017). Clinicaltrials.gov. Retrieved 14 April 2017, from https://clinicaltrials.gov/ct2/results?cond=ptsd&intr=cognitive+behavioral+therapy&show_down=Y

The Management of Post-Traumatic Stress Working Group,. (2010). VA/DoD Clinical practice guideline for management of Post-Traumatic Stress (1st ed.). Washington, DC: Department of Veterans Affairs, Department of Defense. Retrieved from https://www.healthquality.va.gov/guidelines/MH/ptsd/cpgPTSDFULL201011612c.pdf

Weathers, F. W., Litz, B. T., Keane, T. M., Palmieri, P. A., Marx, B. P., & Schnurr, P. P. (2013). The PTSD Checklist for DSM-5 (PCL-5) – Standard [Measurement instrument]. Available from http://www.ptsd.va.gov/

Childhood obesity

Mon, 20 Jan 2020 12:41:43 GMT

Childhood obesity

August 2017

Obesity in adults is defined as having a body mass index (BMI) of 30 or more, while overweight stands for BMI between 25 and 30 (Baker, 2017). BMI, adjusted for age and gender, is used to measure obesity in children, taking into account different growth patterns among boys and girls for each age group. The British 1990 growth reference (UK90) serves as the growth standard. The threshold is 85th percentile for overweight and 95th percentile for obese. The increase in BMI was observed in both genders (The Health and Social Care Information Centre, 2013). At present, nearly a third of UK children are either overweight or obese. Children with excess weight are more likely to become overweight adults and suffer from a range of related ailments such as type-2 diabetes, heart disease, and depression. Excess weight is linked to academic underachievement and economic deprivation, as well as increased costs on the public social and welfare systems (Department of Health, 2017).

Epidemiology

The current prevalence of adult obesity in England is 27%, and another 36% of people are overweight. The number of overweight people has been steadily growing over the past decade. Men suffer from higher obesity rates than women; however, the percentage of overweight people is equal for both genders. The worst affected regions include Northern England, Yorkshire and Midlands. The highest obesity rates are in the age group between 55 and 64 years of age. About 9% of children in England become obese by the age of 4-5. Of every hundred children aged 4 and 5 years, 77 are of normal weight, 13 are overweight, and nine are obese. By the age of 10-11, the number of children with healthy weight falls to 65, and the number s of overweight and obese children increases to 14 and 20, respectively. In the age group of 10-11-year-olds, the highest rate of obesity can be found in the most deprived regions in England, where the obesity rates reach 26% compared to 15% in the least deprived areas. In Scotland, 71% of children 12-15 years of age are of healthy weight, while 14% are overweight, and 15% are obese. Obesity drug prescriptions have fallen in all UK countries since 2008. With 26.6% of the population obese, the UK follows the USA (38.2%) and Australia (27.9%) but ahead of Germany (23.6%) and France (16.9%) (Baker, 2017).

The examination of trends shows a worrying development. In 2015, about one in five first-graders and one in three 10-year-olds were overweight or obese, and it is estimated that if the current trend continues, the number of children with excess weight will increase to 50% by 2020. The numbers of overweight and obese children are higher in urban areas and lower in rural areas where people, including children, tend to spend more time outdoors. Children born after 1980 are three times more likely to have excess weight by the age of 10 than generations born before them, partly because half of them do not meet the target of at least 60 minutes of physical activity a day (RCPCH, 2015).

Ethnic background also affects the risk of becoming overweight or obese. The highest prevalence of childhood obesity at school reception is among those who self-identify as Black or Black British (>30%). By school grade six (10-11 years of age), the prevalence of excess weight, overweight and obesity combined, reaches 30% and more for ethnic groups except for Chinese, Black British being the worst affected (>40%) (Hanson, 2015).

Obese and overweight children are more likely to live in low-income households, especially boys, while girls from the highest income backgrounds were least likely to be obese. Childhood obesity was found to be most prevalent in households where the parents were overweight or obese as well. There was also a positive correlation between a sedentary lifestyle and BMI for both boys and girls (The Health and Social Care Information Centre, 2013).

Health Impact

The health impact on child development starts in the womb. Although two-thirds of pregnancies in the UK are planned to some degree, only a small minority of women change their lifestyle prior to conception, including the efforts to lose weight. In 2013, over one-third of British women aged 16-24 years and 50% of women aged 25-34 years were overweight or obese. Multiple risk factors in early childhood increase the probability of being overweight or obese later in life 4-fold. The most relevant risk factors are maternal obesity and pre-pregnant BMI >30, excess gestational weight gain, smoking during pregnancy, low maternal vitamin D status, and short duration of breastfeeding (Hanson, 2015).

Obesity is a significant public health problem that is associated with cardiovascular disease. Hyperlipidemia, type 2 diabetes, and hypertension further increased the risk of developing cardiovascular complications, such as peripheral artery disease and coronary artery disease, and increases the risk of other conditions such as cancer, osteoarthritis, or gallbladder problems. The National Audit Office (NAO) estimated that the number of deaths attributable to obesity is about 6% of all deaths a year, or 30.000 deaths in total (The Health and Social Care Information Centre, 2013).

The costs of the treatment of obesity are steadily increasing. The total cost of obesity is about £27 billion per year, of which £19 billion accounts for NHS care, including obesity medications. Many weight loss approaches result in short-term weight loss that is often regained once the intervention stops. Multicomponent interventions recommended by NICE combine lifestyle guidance, improvement of diet quality, decrease in calorie intake, increase in activity levels. Weight Action Program (WAP) aimed at the loss of 5% bodyweight that was expected to have health benefits. It was encouraging that 41% of the participants achieved this goal (NIHR Centre, 2017).

Obesity increases the risk of numerous diseases later in life and all-cause mortality. The Health Survey for England (HSE 2011) analyzed the relationship between BMI, waist circumference, and the prevalence of specific diseases and the use of anti-obesity drugs. Sibutramine (Meridia, Reductil), an appetite suppressor, was withdrawn from the market because of a higher risk of stroke and heart attack. The market authorization for rimonabant (Acomplia) had to be suspended because of the serious psychiatric side effects of the drug (The Health and Social Care Information Centre, 2013).

Obesity in children is becoming a problem for pediatricians as well because of the lack of guidance from NICE on how to manage the condition and associated ailments. Expert advice by the Obesity Services for Children and Adolescents (OSCA) Network Group provides pediatricians with assessment guideline, guide how to identify underlying causes of obesity, how to recognize significant co-morbidities and assist with the choice of appropriate treatments. The guideline primarily deals with cases that require referral to specialized care. A referral shall be considered in children with BMI > 98th percentile and at least one risk factor. Risk factors include short stature or dysmorphic signs, hypertension, sleep apnea, abnormal glucose or insulin metabolism, issues with mobility or joint problems, dyslipidemia, signs of non-alcoholic liver disease, polycystic ovarian syndrome, psychiatric co-morbidities such as eating disorders, family history of type 2 diabetes and early-onset cardiovascular disease. The examination should include screening for glucose and lipid metabolism, liver function, endocrinopathies, genetic obesity syndromes and concomitant drug use, sleep problems, and behavioral and cognitive problems (OSCA (Obesity Services for Children and Adolescents) Network Group, n.d.).

Behavioral factors

Overweight and obesity have a significant impact on young peoples’ lives. The Association for Young People’s Health worked with a group of 12-19-year olds who have been involved in the PROMISE study for the treatment of obesity that was funded by NIHR and carried out by UCL and partners and surveyed people from across the UK. Young people’s views on weight loss vary between age groups. Teenagers love online engagement and mobile apps and appreciate incentives such as gym passes. The barriers perceived by young people include denial, fear of bullying, stigma, and shame. For parents, the main issue is the timing of discussions that is crucial for young people to engage in any communication at all. Self-assessment tools, incentives vouchers, gym membership, and access to information are perceived as essential by parents of overweight children. For many parents, the obesity of their children represents a significant stigma. Health professionals may also require some additional training that would help them understand the impact of stress and bullying on weight gain and facilitate effective communication with young people. Nutrition education is perceived as one of the most critical gaps. Flawed self-assessment is an essential part of any solution: most overweight children viewed their weight as normal. Yet, most believed they are supposed to find out that they are overweight by themselves. The majority of young people would expect others to inform them that they are overweight, should it be their family, teachers, health professionals, or youth workers. For many, the problem of weight is ignored long enough to become unmanageable (Rigby & Perrow, 2015).

School-age children who become obese before ten years of age tend to carry the extra weight for the rest of their lives. Embarrassing holiday experiences with overweight children are often the first impulse than forces parents to join healthy eating and activity programs. For children, the concern is the food choices their families make, eating out and takeaways, and treats and sweets often used as a reward for good behavior. The location of fast-food restaurants within reach of children is a significant risk factor some communities have to tackle (ITV Tonight, 2015).

Obesity is a complex condition caused by a combination of biological, environmental, behavioral, and commercial factors. In obesogenic environments, it is much more challenging to make healthy choices that are either less convenient or more costly. Healthcare professionals need to educate their patients about the impact of obesity and make every contact count. Other actions to be taken by healthcare professionals include the provision of weight management services that should be given the same priority as smoking cessation programs, and implementation of nutritional standards comparable to those used in schools shall soon apply in all UK hospitals. Support for new parents should include elementary food preparation skills to promote breastfeeding. The obesogenic environment can be improved by the implementation of nutritional standards in schools, reducing the presence and accessibility of fast food outlets in the proximity of schools, and a ban on advertising of fatty and sugary foods before 9 pm. It is equally important to make the healthy choice the natural choice by taxing sugary drinks, labeling food, and building an environment that facilitates active travel (Academy of Royal Medical Colleges, 2013). The higher prevalence of obesity among disadvantaged groups is well known; however, the early life factors that attenuate the effect are unclear. A study on more than 11.700 children explored risk factors for childhood obesity thoroughly. Children of mothers with academic qualifications were better off than those whose mothers did not have any academic degrees, despite the same socio-economic status. The highest impact risk factors were maternal pre-pregnancy weight, smoking during pregnancy, and low maternal qualifications (Massion et al., 2016).

Nutrition

Eating behavior and food choices have a profound impact on the development of overweight and obesity in children. Most importantly, the size of the average portion increased substantially. While in the 1960s, the diameter of an average dinner plate was 9 inches, half a century later its size increased to 12 inches. Making portion sizes smaller would reduce the total calorie intake in the UK by 8% in children and by 16% in adults (Marteau, 2015).

Potter et al. (2017) argue that children’s future BMI can be predicted from the portions their parents consider normal. The researchers studied parental and children’s beliefs about the ideal and maximum portion size appropriate for their children. While children’s own beliefs about how much food is appropriate did not predict their future BMI, their parents’ beliefs did. Both children and adults tend to consume more food if given the opportunity to do so. Portion size is an ideal opportunity to decrease the total consumption of food. Children who self-select a larger portion size tend to be overweight. However, not all studies found this relationship. Higher tolerance for large portions may lead to the selection of large portions due to gastric capacity that is higher in obese individuals. Child-parent pairs were presented with a series of 50 images of seven main meals they were familiar with. The pictures varied by portion size, varying by 20 kcal increments. Children were asked to select their ideal and maximum portion size and how much they like the meal. Parents were asked to indicate their own ideal portion size, their child’s ideal and maximum portion size, own maximum portion size and familiarity with the food. Parents, who overestimated their child’s ideal and maximum portion size, were more likely to have an overweight or obese child (Potter et al., 2017).

School meals account for a significant portion of children’s diet and contribute to forming healthy dietary behavior. Lucas et al. (2017) compared school meal policies in the UK, Australia, and Sweden. In the UK, the system of regulation of school meals is varied and decentralized, and the policies are inconsistently applied. In the UK, foods provided in schools are categorized as starchy, dairy, fruits, vegetables, and non-dairy protein, while in Australia, the federal guidelines employ a traffic light approach. The researchers focused on existing standards and their practical implementation and impact on children’s health. The chronological age of children in preschool and primary school, therefore, may vary depending on standards that apply to them. In the UK, children in nurseries receive 1/3 pint (189 ml) of milk a day, and fruit and vegetables three times a week under the Nursery Milk Scheme and the Free School Fruit and Vegetable Scheme. Some standards only apply in Wales and Northern Ireland but are voluntary in England. Guidelines inconsistently apply to packed lunches, although some schools impose restrictions on sweet drinks, sweets, and savory snacks. Because of the part-time attendance of primary schools, it is impossible to know how many preschool children eat lunches that conform to the mandatory preschool standards. The widespread use of packed lunches and additional food sources such as vending machines, bake sales, and tuck shops make it impossible to measure the health benefits of the implementation of school meal standards. The health impact of the provision of nutritionally sound meals to disadvantaged groups is difficult to assess due to complex policies. Moreover, these policies are inconsistently applied and enforced across the country (Lucas, Patterson, Sacks, Billich & Evans, 2017).

Physical activity

The levels of physical activity of adolescents aged 13-15 years fell between 2008 and 2012. In 2008, only 28% of boys and 14% of girls met the recommended daily target of physical activity. By 2012, these numbers fell to 14% for boys and 8% for girls (Hanson, 2015).

According to the Health Survey for England (HSE), the overall activity of children aged 4 to 15 has been steadily declining. The survey used self-reported activity and accelerometer data. Other studies that measured school PE and Sports programs were included in the assessment. Young people and children should spend 60 minutes every day performing moderate or vigorous physical activity, as recommended by the Chief Medical Officer (CMO) of England. The children were categorized into subgroups meet recommendations, some activity, and low activity by their level of activity. In 2008, one-third of boys and one-quarter of girls reported they engage in the recommended activity levels every day. The proportion of girls meeting the physical activity recommendations decreased from 35% at the age of 2 to 12% among 14-year-olds.

Accelerometer data confirmed the self-reported data for boys (33%) but corrected the number of girls who exercised at the recommended level from 21%. The results significantly varied by age: of boys aged 4 to 10, 51% exercised at the recommended level, while only 7% of boys from 11 to 15 met the standard; only 34% of girls aged 4 to 10 met the recommended physical activity standards. However, in the age group from 11 to 15, none of the girls included in the study met the recommended target of 60 minutes a day. Achieving physical activity targets has been a challenge for most children. One way how to achieve this goal is to travel to and from school on foot or by bicycle. In 2011, 43% of children walked to school, and 32% got a ride in their parents' car and only 2.4% rode a bike. The main activities children engaged in were walking, formal sports, and informal activities (The Health and Social Care Information Centre, 2013).

The level of activity also varies with ethnic background. According to a study published by Smith, Aggio, and Hamer (2017), children of South Asian descent are less active than their Caucasian counterparts are, even though all were British born. The researchers investigated the change in activity levels of children based in central London concerning ethnicity using the Actigraph accelerometer. The data from 281 children (64% Caucasian or mixed, 18% Black and 18% South Asian) showed that the life of children of South Asian descent was significantly more sedentary at a 1-year follow-up than the lives of children of Caucasian or mixed descent. Approximately 10% of children in the studied sample were obese. The authors observe that children from minority ethnic groups are at higher risk of type 2 diabetes, central adiposity, and hyperlipidemia compared to Caucasians and children of mixed heritage. There is increasing evidence that British-born children of South Asian descent display signs of insulin resistance already at the age of 10. Besides, there is growing concern that a sedentary lifestyle contributes to the diabetes epidemic along with low levels of physical activity. Compared to 73% of Caucasian 10-year-olds, only 35% of children of South Asian descent meet the recommended 60 minutes of moderate and vigorous activity (MVPA) a day. The Camden Active Spaces study examined children’s physical activity before and after the renovation of a local playground. The children were asked to wear the accelerometer around their waist when walking around and only take it off during sleep or water-based activities such as swimming. Sedentary time was defined as 100 cpm, light exercise 100 – 3000 cpm, and MVPA as >3000 cmp. The measurements were compared to self-reported activity time at school, watching TV, playing video games, or studying. The combination of sedentary behavior and low level of activity promotes visceral adiposity that is the highest risk factor for the development of type 2 diabetes. Children of South Asian descent that display these behaviors early in life are particularly at risk (Smith, Aggio & Hamer, 2017).

Environment

The environment is an essential part of the lifestyle. Two approaches to changing behavior toward making healthier choices include resisting unhealthy environments where calorie-dense food is plentiful and opportunities for exercise scarce, and the modification of environment around us that make us eat healthier foods and move more. Subtle changes, such as a standing desk can have a profound cumulative impact (Marteau, 2015).

Osei-Assibey et al. (2012) reviewed studies relating to the obesogenic environment and its impact on childhood obesity. One of the causes of obesity is the fact that it is difficult to pursue an individual healthy lifestyle in an environment that promotes diet rich in saturated fats and sugar and a sedentary lifestyle. The obesogenic environment is the sum of the influences that the surroundings, opportunities or conditions of life have on promoting obesity in individuals and populations. Parental beliefs and behaviors become the prime target for intervention due to associations between parental influences and children obesity. Early age interventions are researchers because established obesity becomes more challenging to tackle, and tends to continue to adolescence and adulthood. The main dietary drivers of obesity are the demand for palatable, high-energy foods, ease of preparation, large portions, sugary drinks and availability, and access, especially in schools and when eating out. The authors reviewed interventional studies that focused on the exposure of children below the age of nine to dietary, environmental influences, and the BMI outcome of such intervention. The included studies were from the USA (23), the Netherlands (4), UK (4), Germany (3), and Sweden (1).

The Avon Longitudinal Study of Parents and Children in the UK showed that junk food dietary pattern established at 38 months of age leads to overweight and obesity at age 7. The effect of foods that are easy to prepare can be observed on working mothers, and especially those of higher socioeconomic status who often work long hours. Five studies explored the impact of food promotion on food choices and immediate energy intake related to exposure to food adverts. Five studies explored the effect of portion sizes on food consumption and found a positive correlation. Increasing portion size by adding vegetables was an effective way of reducing the total energy intake. Restrictive feeding did not reduce total energy intake. Unsurprisingly, high-energy snack foods were linked to obesity, especially when consumed frequently in front of a TV. Four studies examined the effect of sugary soft drinks. Placing water fountains in schools was an effective way to cut back sugar intake. Interventions in schools that aimed at the reduction of the fat content of school lunches led to a decrease in serum cholesterol but not obesity. Promotion of low-fat products, fruit and vegetables had short-term effects at best; complete elimination of alternatives was required to achieve the desired outcome. The main limitation of the reviewed studies was short duration, only between 4 weeks and six months. Besides, the data derived from the study population may not be generalizable to the target groups (Osei-Assibey et al., 2012).

The slow change in public perception of obesity as a problem corresponds with the shift in reporting. A review of 2,414 articles published between 1996 and 2010 in 7 UK newspapers showed increasing coverage of the topic of obesity and a trend toward a change in the obesogenic environment with less focus on individual behavioral modifications. Most of the coverage was based on information from the World Health Organisation that issued a global health warning that obesity's impact is so diverse and extreme that it should now be regarded as one of the greatest neglected public health problems of our time. UK prevalence of obesity is the highest among the countries of Northern Europe and continues to increase among all age groups. Commercial interests received widespread coverage as well (Hilton, Patterson & Teyhan, 2012).

Policies and Recommendations

Incentives that encourage people to change their behavior range from educational programs to tax imposed on unhealthy foods such as fizzy drinks. Experience from Denmark shows that taxing foods that contain more than 2.3% of saturated fat decreased the sales by 0.9%; however, the change was only marginal in the most at-risk population. In Mexico, a 10% tax on sugary drinks reduced sales by 10%. Other measures aimed at the decrease of consumption of sugary beverages include the reduction of package size or regulation of the packaging shape, location in the store elsewhere out of direct sight, and consumer education. The reduction of package size and taxation has the highest impact and lowest acceptability by the public (Marteau, 2015).

In 2015, a report by the Royal College of Pediatrics and Child Health recommended a series of measures aimed at the reduction of the prevalence of childhood obesity. The measures included a pilot duty of at least 20% on sugary soft drinks, the expansion of food standards to all schools, making personal, social and health education a statutory subject, and the ban on advertising of fatty and sugary foods before 9 pm (RCPCH, 2015).

In August 2016, the UK government published its report Childhood Obesity: A Plan for Action. The timing coincided with the Olympics, and the report received very little media attention. The report fails to address stronger controls on advertising, reformulation of foods available in schools, and nutrition education. The report recognizes that the causes of childhood obesity are a complex combination of biological, behavioral, environmental, and commercial factors. The problem of childhood obesity is especially prevalent in lower socioeconomic groups, where the level of control people have over their environment is the lowest. Mark Hanson et al. (2017) concluded that the cooperation of the UK government with international experts on the topic would help develop more effective policies and standards (Hanson, Mullins & Modi, 2017).

In January 2017, the UK Department of Health, the Cabinet Office published guidance on Childhood obesity: A plan for action. The policy outlines the most important factors that contribute to the epidemic of childhood obesity, such as the introduction of a soft drinks industry levy, a 20% sugar decrease in foodstuffs, making healthy options available in the public sector, and improving conditions at schools to encourage physical activity. A substantial portion of calorie intake consumed by British teenagers comes from sugary drinks, increasing their risk of obesity, tooth decay, and type 2 diabetes. A single can of a sweet drink contains more than a recommended daily intake of sugar. Soft drinks industry levy will be used to support physical activity in schools. The change will be legislated in the Finance Bill 2017. More transparent food labeling and reduction of sugar content per 100g of product, portion size, and total calorie content will affect breakfast cereals, yogurts, biscuits, cakes, confectionery, pastries, puddings, ice cream, and sweet spreads. More food categories will be added in 2017.

Competition Innovate UK was run to support research into new, healthier, processes and products. Update in the nutrient profile will be used to assign a score to individual products that will be subject to advertising restrictions. Physical activity is an integral part of healthy development. At least 60 minutes of moderate to vigorous physical exercise every day are recommended for the healthy development of children. Physical education offered in schools should be complemented by active breaks, active lessons, sports, and other events outside schools and at home. The Sports England Strategy Towards an Active Nation (2016) should contribute to these efforts by providing opportunities for families to be active together. The government also supports projects of walking and cycling to school. A new rating scheme should help schools to increase physical activity of children (Department of Health, 2017).

References

Academy of Royal Medical Colleges. (2013). Measuring Up: The Medical Profession’s Prescription for the Nation’s Obesity Crisis. Retrieved from http://www.rcpch.ac.uk/sites/default/files/page/MU_REPORT.pdf

Baker, C. (2017). Obesity Statistics. House of Commons. Retrieved from http://researchbriefings.files.parliament.uk/documents/SN03336/SN03336.pdf

Department of Health. (2017). Childhood obesity: a plan for action - GOV.UK. Gov.uk. Retrieved 7 August 2017, from https://www.gov.uk/government/publications/childhood-obesity-a-plan-for-action/childhood-obesity-a-plan-for-action

ITV Tonight. (2015). XXL Britain. https://www.youtube.com/watch?v=C8P0HJo-_fg: ITV Tonight.

Hanson, M., Mullins, E., & Modi, N. (2017). Time for the UK to commit to tackling child obesity. BMJ, j762. http://dx.doi.org/10.1136/bmj.j762

Hanson, M. (2015). Early life origins of obesity. Presentation, RCPCH Child Obesity Summit.

Lucas, P., Patterson, E., Sacks, G., Billich, N., & Evans, C. (2017). Preschool and School Meal Policies: An Overview of What We Know about Regulation, Implementation, and Impact on Diet in the UK, Sweden, and Australia. Nutrients, 9(7), 736. http://dx.doi.org/10.3390/nu9070736

Marteau, T. (2015). Interventions to change behaviour: How much can the public bear?. Presentation, Royal College of Paediatrics and Child Health.

Massion, S., Wickham, S., Pearce, A., Barr, B., Law, C., & Taylor-Robinson, D. (2016). Exploring the impact of early life factors on inequalities in risk of overweight in UK children: findings from the UK Millennium Cohort Study. Archives Of Disease In Childhood, 101(8), 724-730. http://dx.doi.org/10.1136/archdischild-2015-309465

NIHR Centre. (2017). A group weight loss programme shows promise compared with usual approach. Discover.dc.nihr.ac.uk. Retrieved 7 August 2017, from https://discover.dc.nihr.ac.uk/portal/article/4000627/a-group-weight-loss-programme-shows-promise-compared-with-usual-approach

OSCA (Obesity Services for Children and Adolescents) Network Group. (n.d.). OSCA consensus statement on the assessment of obese children & adolescents for paediatricians. Retrieved from https://www.cornwallhealthyweight.org.uk/OSCA_Guidelines.pdf

Osei-Assibey, G., Dick, S., Macdiarmid, J., Semple, S., Reilly, J., & Ellaway, A. et al. (2012). The influence of the food environment on overweight and obesity in young children: a systematic review. BMJ Open, 2(6), e001538. http://dx.doi.org/10.1136/bmjopen-2012-001538

Potter, C., Ferriday, D., Griggs, R., Hamilton-Shield, J., Rogers, P., & Brunstrom, J. (2017). Parental beliefs about portion size, not children's own beliefs, predict child BMI. Pediatric Obesity. http://dx.doi.org/10.1111/ijpo.12218

RCPCH. (2015). Tackling England’s childhood obesity crisis. RCPCH. Retrieved from http://www.rcpch.ac.uk/system/files/protected/news/Obesity%20Summit%20report%20FINAL.pdf

Rigby, E., & Perrow, F. (2015). RCPCH Child Obesity Summit. Presentation, RCPCH Child Obesity Summit.

Smith, L., Aggio, D., & Hamer, M. (2017). Longitudinal patterns in objective physical activity and sedentary time in a multi-ethnic sample of children from the UK. Pediatric Obesity. http://dx.doi.org/10.1111/ijpo.12222

The Health and Social Care Information Centre. (2013). Statistics on Obesity, Physical Activity and Diet: England, 2013. NHS. Retrieved from https://catalogue.ic.nhs.uk/publications/public-health/obesity/obes-phys-acti-diet-eng-2013/obes-phys-acti-diet-eng-2013-rep.pdf

Bulimia nervosa

Mon, 20 Jan 2020 11:25:48 GMT

Bulimia nervosa

July 2017

The classification of bulimic-type eating disorders underwent a significant change in 2013. The disease was reclassified from bulimia nervosa to binge-eating disorder. The DSM-5 no longer divides bulimia into purging and purging-types. The main diagnostic criterion is the impaired control over food intake and a sense of distress and shame associated with binge eating. The exact cause and pathophysiology of bulimia are unknown. Patients who are suffering from bulimia nervosa present with a variety of non-specific symptoms. Typical presentation includes dizziness, pharyngeal irritation, abdominal pain, parotid enlargement, electrolyte imbalance, edema, and dental and skin problems. The clinical picture varies depending on the presence or absence of purging (Clinical manifestations include gastrointestinal symptoms, dry skin American Psychiatric Association issued comprehensive guidelines for the treatment of eating disorders. Treatments include cognitive-behavioral therapies and antidepressants such as fluoxetine, in addition to nutritional counseling. The cost of treatment ranges from $12,000 to $20,000 and often requires a significant copay. Complications of bulimia such as gastric distension, esophageal tears, and acute gastric obstruction may require surgical intervention. Correction of enamel damage and dental caries can inflict additional costs. Uninsured patients would have to pay the cost of treatment in full.

Bulimia

Bulimic type of behavior is much more common than anorexia nervosa. Unlike anorexia, bulimia typically occurs in people whose body weight is normal or above normal. Binge eating means that the person eats an excessive amount of food rapidly in a short period, until uncomfortably full. People who engage in binge eating typically employ extreme weight-control measures such as vomiting, fasting, and prolonged bouts of exercise. The reclassification and changes in definition make the diagnosis less focused on women (Mond, 2013). According to the DSM-5, bulimia nervosa is an eating disorder with recurrent episodes of binge eating accompanied by a sense of loss of control, inappropriate compensatory behaviors, recurrence at least once a week for a period of three months, and impaired self-evaluation (Randhawa, 2016).

Clinical manifestation, pathophysiology, epidemiology

Patients with bulimia nervosa present with a variety of non-specific symptoms such as dizziness, palpitations, orthostatic hypotension, pharyngeal irritation due to purging, abdominal pain, parotid enlargement, electrolyte imbalance, edema and dental, and skin problems. The clinical picture varies depending on the presence or absence of purging (Randhawa, 2016).

The exact causes and pathophysiology of bulimia are unknown. A strong genetic predisposition exists; however, no specific gene responsible for the disorder has been located. About three-quarters of all patients with bulimia suffer from depression, and about a quarter are substance abusers. Nearly half of the patients diagnosed with bulimia also have a personality disorder (Mitan, 2008). Swaab et al. (2006) believe that the disorder originates in the hypothalamus. Diminished serotoninergic activity is likely responsible for the development of the disease (Swaab, 2006).

The binge-eating disorder was only formally recognized in 2013 when it was included in the DSM-4. According to the “Validate Attitudes and Lifestyle Issues in Depression, ADHD and Troubles with Eating (VALIDATE)” survey, about 1.6-2.0% of the U.S. adult population meets the criteria for binge eating disorder. Most respondents answered that they had two to three episodes a week, with an average duration of seven to twelve months (Pawaskar et al., 2016).

History of the disease

Eating disorders are not a new phenomenon. Ancient Egyptians and Greeks were familiar with binge eating and subsequent purging. In the Middle Ages, purgation and bloodletting were popular treatments intended to purify the body. Bulimia was first documented in the early 1900s when Pierre Janet published a paper in Obsessions et la Psychasthenie in which he described a woman who engaged in secret eating orgies (James, 2017).

In the 1970s, a series of case studies from U.S. college campuses brought attention to the disorder. The underlying causes are cultural pressures and body image communicated through the media, in addition to depression and compulsive behaviors. Binge eaters can consume tens of thousands of calories a day (Deans, 2017). Binge-eating is only possible in societies where people can easily access such amounts of readily available food. The only way to achieve such a high-calorie intake is by combining multiple sources of food with high-calorie density.

The definition of bulimia changed since 2013 when it was first included in the DSM. The new criteria were designed to facilitate diagnosis and access to care and stimulate research. Purging is no longer required for the diagnosis of bulimia nervosa (Mond, 2013).

Current treatments

The current treatment of bulimia nervosa is based on cognitive-behavioral therapy, interpersonal psychotherapy, family therapy, and nutritional rehabilitation. The only SSRI approved by the FDA for the treatment of bulimia nervosa is fluoxetine. Other pharmacological treatment options include other SSRIs, tricyclic antidepressants and mood stabilizers such as topiramate, lithium or valproic acid. The involvement of a psychiatrist, psychotherapist, and a nutritionist is recommended to achieve the best results. Dental care needs to address any damage to enamel caused by vomiting. The objectives of treatment are to reduce or eliminate binge eating and purging, to treat nutritional complications, and modify attitudes and behaviors as well as perceived self-image. Cognitive-behavioral therapy is the most effective treatment available. In the case of insufficient response after ten sessions, it is recommended to augment the treatment by SSRI antidepressant fluoxetine. Complications such as gastric dilatation, acute gastric obstruction or esophageal tear require surgical treatment (Randhawa, 2016).

The AMERICAN Psychiatric Association published detailed guidelines for the treatment of eating disorders (American Psychiatric Association, 2017).

Innovative approaches include a wide variety of interventions. Most of the relevant clinical trials published at ClinicalTrials.gov concern various psychotherapy protocols. The database contains 98 completed interventional studies for the treatment of bulimia (Search of: Completed Studies: Bulimia, ClinicalTrials.gov, 2017). New experimental pharmacotherapies include baclofen (NCT00320047), topiramate (NCT00768677), opioid receptor antagonist RDC-0313 - ALKS 33 (NCT01098435), dasotraline (NCT02564588), the combination of naltrexone and bupropion (NCT02317744), lisdexamfetamine dimesylate - SPD489 (NCT01291173) and others. The general approach to the treatment of bulimia nervosa has not changed over the last 20 years. The core interventions include cognitive-behavioral therapy, nutritional rehabilitation, and the administration of SSRIs, specifically fluoxetine (Trygstad, 2008).

In the early 1900s, eating disorders were attributed to hormonal imbalances and deficiencies, specifically the deficiency of pituitary gland hormones (Engel, 2007).

Effective treatment for bulimia nervosa exists; however, not all people who suffer from eating disorders seek treatment. Eating disorders are potentially difficult to treat, and the risk of relapse is still relatively high. Bulimia can also be expensive to treat, even with appropriate insurance coverage. The most used protocols in bulimia nervosa and binge eating disorder are stepped care and cognitive-behavioral therapy augmented with fluoxetine when indicated. The tested protocol included 18 50-minute-long therapy sessions over a period of 4 months. The measurement of treatment outcomes included Eating Disorder Examination (EDE), Health Care Diary, Family/Significant Other Questionnaire (FSQQ), and a self-administered Quality of Wellbeing Scale (QWB-SA). The therapists were clinically qualified psychologists who had experience treating eating disorders using cognitive-behavioral therapy. The direct cost of care per patient who completed treatment and abstained from binge eating reached $12,146 for stepped care and $20,317 for cognitive-behavioral therapy. Payer decisions to cover the cost of care are influenced by direct costs rather than societal and indirect costs inflicted by the disorder on the individual and the family. One-fifth of patients responded to the Stepped Care and abstained from binge eating. The success rate of cognitive-behavioral therapy was 26% (Crow et al., 2013).

The quality of coverage plans and the amount of copay vary. For those covered by insurance, the amount of copay varies from one plan to another. Uninsured patients have to pay all the expenses out of pocket, although most centers offer loans and payment plans (UnitedHealth, 2017).

Conclusion

Bulimia is a complex psychological disorder that affects mainly young women. Its exact pathophysiology is not known. The treatments for bulimia and binge eating disorder include cognitive-behavioral therapy with or without fluoxetine and nutritional counseling. The relapse rate is still high, and the cost of treatment may be prohibitive for uninsured and underinsured populations.

References

American Psychiatric Association. (2017). American Psychiatric Association Practice Guidelines. Psychiatryonline.org. Retrieved 3 July 2017, from http://psychiatryonline.org/guidelines

Crow, S., Agras, W., Halmi., K., Fairburn, C., Mitchell, J., & Nyman, J. (2013). A cost effectiveness analysis of stepped care treatment for bulimia nervosa. International Journal Of Eating Disorders, 46(4), 302-307. http://dx.doi.org/10.1002/eat.22087

Deans, E. (2017). A History of Eating Disorders. Psychology Today. Retrieved 3 July 2017, from https://www.psychologytoday.com/blog/evolutionary-psychiatry/201112/history-eating-disorders

Engel, B. (2007). Historical Understandings. Mentalhelp.net. Retrieved 3 July 2017, from https://www.mentalhelp.net/articles/historical-understandings/

James, D. (2017). History of Bulimia: Greek Vomitoriums to Sorority Bathrooms. Eating Disorder Hope. Retrieved 3 July 2017, from https://www.eatingdisorderhope.com/information/bulimia/history-of-bulimia-greek-vomitoriums-to-sorority-bathrooms

Mitan, L. (2008). Eating Disorders. Adolescent Medicine, 276-281. http://dx.doi.org/10.1016/b978-032304073-0.10035-4

Mond, J. (2013). Classification of bulimic-type eating disorders: from DSM-IV to DSM-5. Journal Of Eating Disorders, 1(1), 33. http://dx.doi.org/10.1186/2050-2974-1-33

Pawaskar, M., Solo, K., Valant, J., Schmitt, E., Nwankwo, M., & Herman, B. (2016). Characterization of Binge-Eating Behavior in Individuals With Binge-Eating Disorder in an Adult Population in the United States. The Primary Care Companion For CNS Disorders. http://dx.doi.org/10.4088/pcc.16m01965

Randhawa, G. (2016). Bulimia Nervosa: Practice Essentials, Background, Frequency. Emedicine.medscape.com. Retrieved 3 July 2017, from http://emedicine.medscape.com/article/286485-overview

Search of: Completed Studies | Bulimia - List Results - ClinicalTrials.gov. (2017). Clinicaltrials.gov. Retrieved 3 July 2017, from https://clinicaltrials.gov/ct2/results?cond=Bulimia&Search=Apply&recrs=e&age_v=&gndr=&type=&rslt=#wrapper

Swaab, D. (2006). The human hypothalamus in metabolic and episodic disorders. Progress In Brain Research, 3-45. http://dx.doi.org/10.1016/s0079-6123(06)53001-8

Trygstad, O. (2008). Drugs in the treatment of Bulimia Nervosa. Acta Psychiatrica Scandinavica, 82, 34-37. http://dx.doi.org/10.1111/j.1600-0447.1990.tb11082.x

UnitedHealth. (2017). UnitedHealth Insurance Coverage for Eating Disorder Treatment and Rehab. Rehabs.com. Retrieved 3 July 2017, from http://www.rehabs.com/about/unitedhealth-insurance-coverage-for-eating-disorders/

Patient confidentiality: Ethical and legal ramifications

Mon, 20 Jan 2020 10:56:39 GMT

Patient confidentiality: Ethical and legal ramifications

Jun 2017

Patient confidentiality is a complex ethical and legal area that is subject to detailed regulation in all developed countries. The general principles are shared across all jurisdictions.

In most countries, the maintaining of patient confidentiality is a legal requirement. The extent of the right, as well as the rules for disclosures, varies by jurisdiction. In general, patient confidentiality is not an absolute right and disclosures are permissible to the extent defined in law, especially in emergencies or for law enforcement purposes. These disclosures are limited in extent and scope to protect the patient. In the United States, the governing law is the Health Insurance Portability and Accountability Act of 1996 called HIPAA (U.S. Department of Health & Human Services, 2017). In the European Union, patient confidentiality is subject to Directive 95/46/EC as implemented by individual member states (European Parliament and of the Council, 2017). In the UK, the rules for patient confidentiality are summarized in General Medical Council guideline “Confidentiality: good practice in handling patient information (2017)” (General Medical Council, 2017).

Ethics: Patient Autonomy

„The rule of the self that is free from control and interference from others as well as any personal limitations that prevent the making of a personal choice” (David Weisstub & Guillermo Pintos, 2013). The principal issues in patient autonomy are informed consent, the distinction between two extremes that are medical battery and medical negligence, the nature and purpose of the informed consent, and the relevance of fraud. The right to self-determination includes the right to make medical decisions for self. The breach of the right to autonomy amounts to a medical battery. Medical battery, or trespass to the body, may constitute a criminal offense. On the other hand, the failure to act in patient’s interest may result in claims of negligence.

Breach of Autonomy: Medical battery

As decided in 1914 in Mary E. Schloendorff, Appellant, v. The Society of the New York Hospital, Respondent, ”Every human being of adult years and sound mind has a right to determine what shall be done with his own body; and a surgeon who performs an operation without his patient's consent commits an assault, for which he is liable in damages.” Exceptions apply in cases of emergency ("Basic right to consent to medical care - Schoendorff v. Society of New York Hosp., 105 N.E. 92, 93 (N.Y. 1914)", n.d.).

A medical battery is a criminal offense that can also serve as the basis of a civil lawsuit. Even if the care is intended to be beneficial, forcing it on an unwilling patient can amount to battery. For physicians, a battery is a legal threat if the patient was lied to about the nature of the treatment and if there is another type of fraud involved in obtaining informed consent. The most common scenario involves patients who are mentally incompetent or incapacitated or legally unable to make decisions for them and the care that was forced onto them was inadequate or inappropriate. If a patient refuses care, court authorization is required to override patient’s will (The LSU Medical and Public Health Law Site, n.d.).

Patient Confidentiality

The General Medical Council Good Practice Guideline states that “Trust is an essential part of the doctor-patient relationship and confidentiality is central to this. Patients may avoid seeking medical help or may under-report symptoms if they think their personal information will be disclosed by doctors without consent or without the chance to have some control over the timing or amount of information shared” (General Medical Council, 2017). Doctors have the obligation to protect patients’ personal information from inappropriate disclosures outside direct care for their patients or other legitimate purposes such as medical research, public health reasons, service planning or financial audit. The failure to follow the guidance can result in the loss of registration (General Medical Council, 2017).

The principle of Beneficence

The interpretation of beneficence in medicine shall mean “the doing of good, the active promotion of good, kindness and charity”, or “or any action that is done for the benefit of others”. In medicine, beneficence stands for the obligation of physicians to provide care to the best of their ability while preventing harm. The principle of beneficence is one of the central values of Hippocratic medical ethics, along with confidentiality and non-maleficence, meaning the obligation to do no harm. Only in the 20th century, the principle of patient autonomy started to prevail. The principles of beneficence and autonomy are not absolute and shall be always evaluated in the context of care for the individual patient (Munyaradzi, 2012).

Truthfulness

Honesty is an important part of physician’s respect for the patient. Contrary to popular belief, most patients do wish to know their condition. About 90% of surveyed patients expressed a wish to know about the diagnosis of cancer or Alzheimer’s. This does not mean that patients always need to know all the details. However, they should be informed about the nature of their disease, expected outcomes, and available treatments and their benefits and risks to be able to make an informed decision. Sensitivity and tact are important parts of such conversations. Exceptions include situations when the patient is severely depressed and can become acutely suicidal. And finally, in some instances, it is acceptable to offer the patients placebo, if the response rate is known to be high and alternatives are potentially harmful, especially if the patient has a strong need for some prescription ( the University of Washington, n.d.).

Case study – Conscientious refusal

In 2002, a student from Wisconsin asked a pharmacist in K-Mart to fill her prescription for birth control pills, but the pharmacist refused to do so because of religious beliefs. The pharmacist did inform his manager that he would refuse to fill such prescriptions, however, failed to mention how he would ensure proper care for the patient. The patient filed a complaint and the Wisconsin Department of Regulation and Licensing's Pharmacy Examining Board found that his action constituted "a danger to the health, welfare, or safety of a patient and was practiced in a manner which substantially departs from the standard of care ordinarily exercised by a pharmacist and which harmed or could have harmed a patient." In this case, the pharmacist professional responsibilities were in conflict with his personal beliefs. His professional responsibilities included non-maleficence, justice and patient autonomy (McLean, 2011).

Slide 9 – Medical ethics: practical dilemmas

The field of medical ethics is developing over time and the conclusions of individual cases largely depend on the social, political and historical context of the case. The issue of mental competency and ability to decide for self is essential because of the dividing line is often very blurred. Examples include the care for adolescent patients or people who are gradually developing dementia but oscillate between the states of perfect clarity and diminished capacity. The case of Cassandra, a 17-year-old patient with Hodgkin lymphoma, represents a medical ethical dilemma. The patient refused chemotherapy against the wishes of medical professionals. Because her mother supported Cassandra in this decision, the custody was removed from her mother and the teen was forced to undergo chemotherapy against her will. Not only was the treatment forced on the adolescent, the teen was strapped to the bed. Cassandra was not allowed to communicate with her mother on phone and all means of communication were taken away from her. The case is still unresolved. Whilst the objective and intent to proceed with treatment may be beneficial, the means of achieving such objective raise serious concerns what is appropriate and acceptable (Macklin, 2015).

Key takeaways

Physicians’ obligations in regards to beneficence and patient confidentiality and autonomy are highly regulated. Violations of these obligations can result in severe criminal, civil and administrative liability and loss of professional license to practice. Patients’ right to confidentiality is essential to maintain the trust between physicians and their patients. Disclosures are limited to specific situations. In regards to patient autonomy vs. beneficence, these rights are not absolute but have to be carefully considered when caring for individual patients. Disregard for patient needs can lead to claims of negligence. Medical battery equals care provided without the patient’s consent or against his wishes, using fraudulently obtained consent, or with the intent to cause harm.

Recommendations for change

Medical ethics is a hot topic with the potential to inflict serious reputational damage on medical practice. The potential for criminal, civil and administrative liability can be decreased through continuing professional education, by keeping up to date on landmark cases and seeking specialized legal advice in more complex cases and ambiguous situations.

References

Basic right to consent to medical care - Schoendorff v. Society of New York Hosp., 105 N.E. 92, 93 (N.Y. 1914). Biotech.law.lsu.edu. Retrieved 19 June 2017, from http://biotech.law.lsu.edu/cases/consent/Schoendorff.htm

David Weisstub & Guillermo Pintos. (2013). Autonomy and Human Rights in Health Care: An International Perspective. New York : Springer Books.

General Medical Council. (2017). GMC | Confidentiality: good practice in handling patient information (2017). Gmc-uk.org. Retrieved 19 June 2017, from http://www.gmc-uk.org/guidance/ethical_guidance/confidentiality.asp

General Medical Council. (2017). GMC | Contents: Confidentiality: good practice in handling patient information. Gmc-uk.org. Retrieved 19 June 2017, from http://www.gmc-uk.org/guidance/ethical_guidance/30579.asp

European Parliament and of the Council. (2017). EUR-Lex - 31995L0046 - EN - EUR-Lex. Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data. Retrieved 19 June 2017, from http://eur-lex.europa.eu/legal-content/en/TXT/?uri=CELEX:31995L0046

Macklin, R. (2015). The Ethical Dilemma of Forced Chemotherapy on a Teen. The Doctor's Tablet. Retrieved 19 June 2017, from http://blogs.einstein.yu.edu/the-ethical-dilemma-of-forced-chemotherapy-on-a-teen/

McLean, M. (2011). Conscientious Refusal. Scu.edu. Retrieved 19 June 2017, from https://www.scu.edu/ethics/focus-areas/bioethics/resources/conscientious-refusal/

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Approach to preparing for a biological attack

Mon, 20 Jan 2020 09:58:28 GMT

Approach to preparing for a biological attack

June 2017

Hospital risk management series

The debate on critical issues in science, health, and security encompasses many controversies and ethical challenges. The difference between a naturally occurring outbreak and criminal act of bioterrorism is often challenging to establish, and emergencies have to be handled as they come, regardless of the origin of the incident. The post-incident forensic analysis may or may not offer satisfactory answers in regards to attribution, liability, and the responsibility for compensation. The underlying issue for all ethical concerns examined in this work is the balance between individual rights and the needs of public health systems to protect others.

The Director of National Intelligence James R Clapper in his Worldwide Threat Assessment of the U.S. Intelligence Community provided to the Senate Armed Services Committee (2016) highlighted the danger posed by infectious diseases and their ability to cross-national and regional boundaries due to globalization and increases in human-animal interactions resulting from population growth and expansion of human settlements. Increasingly globalized medical supply chains vulnerable to disruption and uncoordinated international response compound the issue. At the hospital level, networked medical devices, electronic health records, and other facets of hospital information systems increasingly affect patient outcomes. At the same time, healthcare infrastructure became an attractive target for large-scale data theft for both economic fraud and espionage (Clapper, 2016).

In 2015, the Blue Ribbon Study Panel released a report with the assessment of gaps in the U.S. biodefense as outlined in the Homeland Security Presidential Directive No. 10 (HSPD-10) and provided 33 recommendations how to improve the status quo. The key points stressed in the report relate to the importance of centralized leadership entrusted in the office of the Vice President of the United States, the creation of a Biodefense Council and a National Biodefense Strategy, and the ability to improve attribution capability as a condition of successful deterrence. The integration of animal and human health addresses the fact that many dangerous infections are zoonoses, and the appreciation for the interaction between environmental, animal, and human health needs to come from the top leadership. Numerous biological crises already affected the nation due to a combination of increasingly sophisticated threats, vulnerabilities in the system itself, and adverse consequences that increase the overall risk. Recommendations span all aspects of biodefense. The topics range from a notification system on animal health to the funding of essential programs to biosurveillance capability, medical countermeasures and environmental decontamination (Blue Ribbon Study Panel on Biodefense, 2015).

In a follow-up report from 2016, the Blue Ribbon Panel stressed that the consequences of a biological attack would be worse than chemical or radiological. The authors mentioned documented efforts of terrorist organizations such as al-Qaeda and the Islamic State of Iraq and Levant (ISIL) to acquire biological weapons, precisely ISIL plan to contaminate water supplies in Turkey with Francisella tularensis. However, a terrorist attack is not the only concern; accidents, accidental releases of deadly pathogens, and institutional failures may be another source of dangerous pathogens. A year later, the Blue Ribbon Study Panel found out that of the 46 items mentioned in the recommendations section, only two were completed, and some progress was made in just 17 (Blue Ribbon Study Panel on Biodefense, 2016).

The U.S. discontinued the biological warfare program in 1959. Some other countries, however, still keep their stockpiles and recruit experts. Dr. Parker, former commander of the U.S. Army Medical Research Institute of Infectious Diseases (USAMRID), stressed the importance of rapid diagnostics, reliable detection and situational awareness to be embedded in the new National Biodefense Strategy. While past concerns related to al-Qaeda’s attempts to weaponized anthrax, this could hardly compare to the current efforts of ISIL that are far more sophisticated due to better funding and access to educated people. While the traditional biological warfare agents are still relevant, the possibilities expanded considerably due to biotechnology and genomics, and the protection of this critical information is essential (House of Representatives 114th Congress 2nd Session, 2016).

Background

The rapid evolution of information systems in healthcare, cross networking of patient records and medical devices with information support functions affect patient outcomes in ways never before imagined. The large-scale theft of healthcare data poses a unique risk to the infrastructure and the patients (Clapper, 2016).

Information protection

The Blue Ribbon Panel on Biodefense recommends the hardening of cybersecurity to protect pathogen data and biotechnology information from cyber-attacks. Biological information can be hazardous in the wrong hands, as the gene-sequencing technology is becoming more accessible. Additional recommendations include the creation of platforms for sharing information on cyber-threats within the advanced biotechnology communities. The highest-risk platforms involve data sharing in unsecured clouds and poorly secured data centers, especially in academia. Particularly risky is the utilization of big data analytics technologies in life sciences and networks that contain information on pathogen knowledge, and information on genetic sequences of pathogens and select agents. Such databases then become attractive targets for hackers. The threat of data compromise needs to become a factor when awarding funding for research in biodefense (Blue Ribbon Study Panel on Biodefense, 2015).

In 2015, the biggest U.S. health insurance provider Anthem, Inc suffered a massive data breach that affected 78.8 million patients. The hack was linked to Chinese group Black Vine that is known for its ties to the Chinese government. Cyber-security firm Symantec in their postmortem of the incident, concluded that the motivation was not financial but most likely espionage. However, it is not entirely clear what kind of information were the hackers looking for. Some suggested that the stolen data can be used in HUMINT operations later on (HIPAA Journal, 2015).

A data breach of the Office of Personnel Management (OPM) resulted in the compromise of records of federal employees and sensitive data from clearance forms. According to iSight Partners Inc., there was a link between the OPM breach and the health insurers’ hacks (HIPAA Journal, 2015). The incidents were, in fact, two. The first cyber-attack compromised the data of 4.2 million of past and current federal employees. A separate attack resulted in the breach of the database of background investigations submitted by 21.5 million individuals who submitted their e-QIP forms when applying for a security clearance. The potential use of this data, apart from financial cybercrime, includes theft and espionage. While economic crime is pursued through the criminal justice system, the response to state-sponsored hacker groups involves diplomatic and military means. The OPM breach fell into the category of espionage rather than commercial activity (Finklea, Christensen, Fischer, Lawrence & Theohary, 2015).

Chinese economy relies heavily on stolen intellectual property. Many industries are targeted by the Chinese state and contracted hackers, from defense and academic research to manufacturing, satellite communications, and healthcare. The U.S. economy is exceptionally dependent on knowledge and intellectual property as the most relevant driver of investment into new technologies. American healthcare became one of the prime targets of Chinese hackers. The group that was responsible for hacking multiple insurers such as Anthem, VAE, BlueCross/Blue Shield and Carefirst, as well as the OPM hacks, is nicknamed Deep Panda, or APT 19, Shell Crew, Black Vine or Kung Fu Kitten (Scott & Spaniel, 2017).

Dual-use of biotechnology

The risk of occurrence of potentially harmful biological agents or products, intentionally or not, increases with the advancing research in genome editing and affordability of the technology. While the editing of human germline remains a significant challenge for scientists, the creation of recombinant microorganisms and their synthesis de novo is a realistic possibility (Clapper, 2016).

The development of the Ebola vaccine was a remarkable achievement; however, success may not be universal. Medical Countermeasures (MCMs), just like tropical diseases, are a small market segment where significant investment is required to produce substantial innovation and corresponding results. The MCM research and development function is very risk-averse and concentrated in small biotechnology firms that have difficulty accessing contracts within the DOD that are not designed for small businesses. To address the issue, the National Biodefense Strategy needs to plan for periods between epidemics and such as the national stockpile and not just for crises (House of Representatives 114th Congress 2nd Session, 2016).

The Blue Ribbon Panel recommends greater sharing of information on threats, vulnerabilities, and potential consequences with state and local administration, strengthening of the Joint Counterterrorism Assessment Team (JCAT), and strengthening of the ability of police units to respond to biological incidents at a local level. The Intelligence Community declassified some of their findings to be able to share them more effectively with their partners in the administration at state, local, territorial, and tribal levels. However, institutional prohibitions are still hard to overcome and often prevent information sharing with emergency services. Also, fusion centers shall be established to collect and collate information on biological threats from all relevant sources and share it appropriately (Blue Ribbon Study Panel on Biodefense, 2015).

Making sense of data

China is currently the leading power in genome sequencing. In 2010, Shenzen firm, with its 128 sequencers, had more than 50% of the total global sequencing capacity. With the introduction of BGISEC-500, the cost of sequencing the full human genome dropped from $1.000 in 2010 to close to $200 today. The current share of Chinese sequencers is about 20-30% of world capacity with a plan to sequence 1.000.000 human genomes in the near future, followed by the USA (1.000.000 genomes and the U.K. with 100.000 genomes. Chinese National Genebank houses data on animals, humans, microbes, and plants. Unlike American firms, Chinese industry can rely on reimbursement from the Chinese health insurance in the future. (Cyranoski, 2016).

Significant computer power is necessary to make sense of information produced in the life science and biotechnology sectors. According to Top 500, China remains No. 1 on the list of the world’s most powerful supercomputers. Chinese Sunway TaihuLight that is located in National Supercomputing Center in Wuxi, ranks No. 1 and Tianhe-2, also called MilkyWay-2, situated in the National Supercomputing Center in Guangzhou, ranks No. 2. With a total number of 167 supercomputers, China also has the highest number of supercomputing systems in the world, ahead of the U.S. that has 165 and ranks No. 2. U.S. supercomputing systems Titan, Sequoia, Mira, and Trinity, rank No. 3, 4, 6, and 7 (Top 500, 2017). In the U.S., the private sector is primarily responsible for the production and protection of valuable data it produces. However, in the face of advanced persistent threats sponsored by state actors, this is not a leveled field.

Position –Tread lightly on civil rights

The debate on biodefense encompasses numerous ethical challenges and controversies. These dilemmas can be reduced to one simple overarching theme: how far shall we go in the pursuit of public health when the interests of the community and the individual collide? What dod we do in situations of public health emergencies when individual citizens and private entities refuse to comply with the presented good ideas voluntarily and challenge them as unconstitutional?

In August 2016, the Center for Disease Control and Prevention proposed a rule that would make it easier to deal with public health emergencies, and allow the agency to perform screening and testing, and to quarantine travelers. Lawyers and health organizations, but also other professionals such as epidemiologists, raised concerns about the rule’s disregard for due process and informed consent, lack of time limitation for detention, and the absence of the right to a legal counsel. A similar effort in 2005 failed due to overwhelming rejection by the public (Yong, 2017).

The debate about federal powers to interfere with civil liberties during public emergencies needs to strengthen the ability of the U.S. to counter any biological threats without scarifying civil rights in the process. During the Ebola outbreak, the CDC extensively monitored more than 30.000 travelers and barred them from any public places for three weeks, including public transport, shopping malls, and the workplace. None of them was infected. Hodge et al. (2017) argue that any measures implemented have to meet the standard of effectiveness, especially when it comes to isolation, quarantine, screening, monitoring, travel restrictions, and treatment, minimum restriction of civil liberties, and be acceptable to the public. The agency also should be able to prove that any failure to comply increases the risk to others. The main challenges of such broad-sweeping rules are the right to due process and informed consent (Hodge, Gostin, Parmet, Nuzzo & Phelan, 2017).

When it comes to emerging infections, the science that supports the diagnostic screening tests, vaccination schedules, prophylactic, and therapeutic measures is likely to be less than definitive. Gaps in knowledge result in significant ambiguity about safety, the efficacy of measures implemented, and the effect on the probability of disease transmission. This uncertainty means that, to a large degree, many diagnostic, prophylactic, and therapeutic interventions will be experimental. While the Food and Drug Administration (FDA) allows the use of certain unapproved products in the case of public health emergencies or on compassionate grounds, there is no obligation to submit to an experimental treatment.

The capability to attribute an attack or accidental release to its source is a significant deterrent and a driver of implementation of security improvements at facilities that handle dangerous pathogens. For the victims, attribution can pave the way to eventual compensation in civil liability and mass tort claims. Microbial forensics is a new scientific discipline that may allow tracking of a biological agent directly to its source. The Middle East and the North African region experienced numerous biological threats in the past decade, specifically H1N1, MERS-CoV, and the use of ricin. However, due to gaps in knowledge, it is easy to misinterpret microbial forensics evidence as to both a false positive and a false negative (Bidwell & Murch, 2016).

Attribution capability needs to include both scientific and legal components of proof, and be understandable to the public at large. The Daubert standard of evidence (Daubert v. Merrell Dow Pharmaceuticals) stands that evidence presented in court needs to be “relevant and rest on a reliable foundation.” This standard means that the theory or technique has to be tested, and subject to peer review and publication, must have known potential error rate operational standards have to exist and must be widely accepted in the scientific community. The evidence may not always be admissible in common and civil law, under Islamic law or in front of international tribunals. Solid proof is required for the U.S. Government to be able to persuade other nations to join military action, impose sanctions, or take a domestic regulatory action. To conform with the Daubert standard, and to become a useful policy tool, microbial forensics needs to overcome general suspicions and unrealistic expectations. The perception of the method suffered due to wrong accusations made in the 2001 Amerithrax and 2015 Mississippi cases. A review of 156 wrongful convictions all over the United States showed that 60% of these cases involved invalid forensic testimony coming from 52 forensic labs in 25 states (Bidwell & Bhatt, 2016).

This ambiguity may make it impossible to attribute a biological incident to a malicious actor or a specific facility responsible for its accidental release. The difference between a naturally occurring outbreak and criminal act of bioterrorism is likely to be uncertain. As a result, the grounds for public health emergency may become very shaky if the original narrative proves to be incorrect. The post-incident forensic analysis may or may not offer satisfactory answers in regards to attribution, liability, and the responsibility for compensation. Compulsory sharing of information that may be abused is yet another issue that deserves careful consideration. Draconian measures based on a narrative that does not pass scientific and legal scrutiny will likely backfire and further erode public trust.

Counter-Position: Public health approach

When it comes to potentially deadly infections, individual rights end where other people’s rights begin. The acceptance of screening, prophylactic measures, and treatment at the cost of a minor personal inconvenience does not need to be questioned as “too much to ask.”

Relevant recommendations by the Blue Ribbon Study Panel regarding the last mile MCM delivery to patients in need include the need for adequate funding of Public Health Emergency Preparedness functions, a comprehensive Hospital Preparedness Program, and the preparation of Clinical Infection Control Guidelines and related training (Blue Ribbon Study Panel on Biodefense, 2015).

The threat of biological attacks (anthrax), criminal attacks (ricin), and natural outbreaks such as multidrug-resistant bacteria, Ebola, Zika, H1N1, avian influenza, and re-emerging diseases overlap. The threat is coming from international terrorist organizations such as al-Qaeda and ISIL, homegrown terrorists, rogue states, effects of climate change, and global connectivity, but also from technological advances in synthetic biology and gene editing. The BioWatch Program, implemented by the Office of Health Affairs (OHA) and the Science and Technology Directorate (S&T) of the Department of Homeland Security (DHS), is an early warning program against aerosolized biological attack (Department of Homeland Security, 2016). The program came under scrutiny by the Government Accountability Office (GAO) due to planned upgrades from Gen-2 to Gen-3. The GAO reviewed the technological capabilities of the Gen-2 system as it is currently deployed, the testing of the Gen-3 system, and the option of autonomous detection of biological threats that could eventually replace BioWatch. GAO concluded that the DHS lacks a reliable assessment of the Gen-2 system that would allow it to make an informed decision on its cost-effectiveness. While the Gen-2 system needs to be manually administered, the Gen-3 collects airborne particles autonomously and sends the results automatically. False positives remain a concern, however (U.S. Government Accountability Office, 2015). The stated example shows that there are controls in place that keep the government’s intrusions into people’s lives in check and that no error of judgment within the administration goes unpunished.

Interagency body Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) comprises a list of agencies such as CDC, NIH, FDA, VA, DOD, DHS and USDA and coordinates the development, acquisition, stockpiling and use of MCMs. Its strategic implementation plan (SIP) implements the requirements stated in the Public Health Service Act (Section 2811d) as amended by the Pandemic and All-Hazards Preparedness Reauthorization Act. MCMs provided through PHEMCE are made available to the public as the need arises. Special attention is paid to vulnerable populations such as children and pregnant women (U.S. Department of Health and Human Services, 2017). It is the responsibility of PHEMCE to ensure the ability to deliver MCMs held in the National Strategic Stockpile to the patients who need them should a crisis occur (U.S. Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response & Public Health Emergency Medical Countermeasures Enterprise, 2016).

Conclusions/Recommendations

A balanced approach is essential when asking individuals to comply with any public health measures that are supposed to protect them, with their consent or not, and people around them. Any public health emergency that requires significant cooperation from the public needs to be based on information that is true when it comes to the origin and nature of the threat. The ability to attribute confidently attacks and accidental releases to the source is essential for the formulation of an appropriate response. Any restrictions that are imposed on the public need to be based on rigorous risk assessment and rooted in sound science. Such restrictions have to be proportionate, appropriate, and acceptable for the public. After all, the condition of a legitimate government is the consent of the governed. Because of the experimental nature of many new treatments for emergency use, great caution needs to be exercised when obtaining or waving consent, as appropriate and relevant. Due process and third party review need to be part of the emergency isolation process to maintain general public approval of the measures implemented.

References

Bidwell, C., & Bhatt, K. (2016). Use of Attribution and Forensic Science in Addressing Biological Weapon Threats: A Multi - Faceted Study A special report published by the Federation of American Scientists. federation of American Scientists. Retrieved from https://fas.org/wp-content/uploads/2016/03/bioattribution-nps-report-3-14.pdf

Bidwell, C., & Murch, R. (2016). Use of Microbial Forensics in the Middle East/North Africa Region An analysis prepared for the Department of State Bureau of Arms Control and Verification. Federation of American Scientists. Retrieved from https://fas.org/wp-content/uploads/2016/03/Vfund-DoS-paper_finaldraft.pdf

Blue Ribbon Study Panel on Biodefense. (2015). A National Blueprint for Biodefense: Leadership and Major Reform Needed to Optimize Efforts – Bipartisan Report of the Blue Ribbon Study Panel on Biodefense.. Washington, DC: Hudson Institute. Retrieved from https://s3.amazonaws.com/media.hudson.org/20151028ANATIONALBLUEPRINTFORBIODEFENSE.pdf

Blue Ribbon Study Panel on Biodefense. (2016). Biodefense Indicators: One Year Later, Events Outpacing Efforts to Defend the Nation. Arlington, VA. Retrieved from www.biodefensestudy.org/LiteratureRetrieve.aspx?ID=144256

Clapper, J. (2016). Statement for the Record Worldwide Threat Assessment of the US Intelligence Community Senate Armed Services Committee. The U.S. Senate. Retrieved from https://www.armed-services.senate.gov/imo/media/doc/Clapper_02-09-16.pdf

Cyranoski, D. (2016). China’s bid to be a DNA superpower. Nature, 534(7608), 462-463. http://dx.doi.org/10.1038/534462a

Department of Homeland Security. (2016). Written testimony of OHA and S&T for a House Homeland Security Subcommittee on Emergency Preparedness, Response & Communications hearing titled “Improving the Department of Homeland Security’s Biological Detection and Surveillance Programs” | Homeland Security. Dhs.gov. Retrieved 10 June 2017, from https://www.dhs.gov/news/2016/02/11/written-testimony-oha-and-st-house-homeland-security-subcommittee-emergency

Finklea, K., Christensen, M., Fischer, E., Lawrence, S., & Theohary, C. (2015). Cyber Intrusion into U.S. Office of Personnel Management: In Brief. Washington D.C.: Congressional Research Service. Retrieved from https://fas.org/sgp/crs/natsec/R44111.pdf

HIPAA Journal. (2015). Hackers Stole Anthem Data for Espionage; Not Fraud. HIPAA Journal. Retrieved 11 June 2017, from http://www.hipaajournal.com/hackers-stole-anthem-data-for-espionage-not-fraud-8053/

HIPAA Journal. (2015). OPM 4M-Record Data Theft Linked to Recent HIPAA Data Breaches. HIPAA Journal. Retrieved 11 June 2017, from http://www.hipaajournal.com/opm-4m-record-data-theft-linked-to-recent-hipaa-data-breaches-7054/

Hodge, J., Gostin, L., Parmet, W., Nuzzo, J., & Phelan, A. (2017). Federal Powers to Control Communicable Conditions: Call for Reforms to Assure National Preparedness and Promote Global Security. Health Security, 15(1), 123-126. http://dx.doi.org/10.1089/hs.2016.0114

House of Representatives 114th Congress 2nd session. (2016). Outside views on biodefense for the Department of Defense hearing before the Subcommittee on emerging threats and capabilities of the Committee on Armed Services. Washington, D.C.: U.S. Government Printing Office. Retrieved from https://www.hsdl.org/?view&did=797147

Scott, J., & Spaniel, D. (2017). China's Espionage Dynasty: Economic Death by a Thousand Cuts. Institute for Critical Infrastructure Technology. Retrieved from http://icitech.org/icit-brief-chinas-espionage-dynasty-economic-death-by-a-thousand-cuts/

Top 500. (2017). June 2016 | TOP500 Supercomputer Sites. Top500.org. Retrieved 11 June 2017, from https://www.top500.org/lists/2016/06/

U.S. Government Accountability Office. (2015). Biosurveillance DHS Should Not Pursue BioWatch Upgrades or Enhancements Until System Capabilities Are Established. U.S. Government Accountability Office. Retrieved 10 June 2017, from http://www.gao.gov/products/GAO-16-99

U.S. Department of Health and Human Services. (2017). 2016 Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy and Implementation Plan. U.S. Department of Health and Human Services. Retrieved from https://www.phe.gov/Preparedness/mcm/phemce/Documents/2016-phemce-sip.pdf

U.S. Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, & Public Health Emergency Medical Countermeasures Enterprise. (2016). 2016 Public Health Emergency Medical Countermeasures Enterprise Stakeholders Workshop Report. Bethesda, MD: U.S. Department of Health and Human Services. Retrieved from https://www.phe.gov/Preparedness/mcm/phemce/PHEMCEworkshop/Documents/phemce-stkhldr-wkshp-rpt.pdf

U.S. Department of Health and Human Services, & U.S. Department of Agriculture. (2016). Annual Report of the Federal Select Agent Program. U.S. Department of Health and Human Services. Retrieved from https://www.selectagents.gov/resources/FSAP_Annual_Report_2015.pdf

Yong, E. (2017). The CDC’s New Quarantine Rule Could Violate Civil Liberties. The Atlantic. Retrieved 12 June 2017, from https://www.theatlantic.com/science/archive/2016/12/cdc-quarantine-rule-violate-civil-liberties/511823/

Ethical Dilemmas in Gerontology

Sun, 19 Jan 2020 21:27:26 GMT

Ethical Dilemmas in Gerontology

Published April 2017

Part of hospital test scenarios, escalation to ethics committee

Patients with a terminal illness who communicate their wish to die to a nurse shall receive appropriate care that is in line with institutional procedures, local laws, and their personal preferences. A nurse should be able to rely on the support of the institution he or she works for in terms of training, clear line of responsibility for such decisions, and unambiguously communicated expectations defined in organizational procedures. Assisted suicide is legal in Switzerland and several other European countries, in several states in the U.S., and in Canada. The mental capacity of the patient has to be considered in addition to locally applicable laws. Medical Power of Attorney is helpful if the patient previously described his or her wishes regarding end-of-life decisions and became incapacitated in the meantime. Financial toxicity, in addition to dubious effectiveness, contributes to the reluctance of some patients to undergo aggressive and invasive therapies. German physician Albert Moll in his book Medical Ethics (1902), argues that aggressive care in incurably ill patients is unethical. Healthcare staff, including nurses, can conscientiously object to assisting with suicide.

In geriatric care, nurses and other healthcare workers, including support staff, witness the decline of terminally ill patients regularly. Patients who are gradually approaching the end of their lives express a wide variety of attitudes, wishes, and preferences regarding their care. Considerable differences exist in the level and quality of support from family and friends, overall fitness and resilience, personal values and philosophical beliefs, and religious and spiritual affiliations.

Every geriatric nurse can expect to face patients whose ability and willingness to continue their journey has ended. The circumstances and motivations may vary, depending on personal and cultural background and life experiences as well as a set of beliefs and attitudes of family members the patient would have to depend on. However, the desire to leave peacefully is innate to all humans, regardless of accent, complexion, or cuisine. Confining thoughts of suicide in a nurse is a logical step for a patient. Nurses are usually the closest and most familiar people geriatric patients have at this point in their lives. For nurses, however, such knowledge can represent significant distress due to professional obligations, personal beliefs, and religious affiliation.

In an institution dedicated to geriatric care, it is reasonable to expect that a nurse would not have to handle such requests alone. Short of disclosing the identity of the patient in his or her care, a nurse can request assistance from the institution’s dedicated functions, typically through her supervisor or manager. Procedures for how to handle decision-making in end-of-life care and conditions necessary for its cessation, as well as relevant disclosures, have to be in place to protect the institution from liability due to malpractice, medical error, or negligence. Appropriate training on existing procedures provided to staff shall define roles and responsibilities as applicable in specific situations, and prevent improvisation and human error.

Where end-of-life decisions are concerned, the considerations include the mental competency of the individual to make decisions regarding his or her care previously expressed wishes recorded in Medical Power of Attorney and locally applicable laws in regards to assisted suicide.

According to Euthanasia Research & Guidance Organization (ERGO), an organization dedicated to providing resources and educational materials on assisted suicide and euthanasia, only Canada, Colombia, six U.S. states, and five European countries currently allow some form of assisted suicide. The site is instrumental in clarifying some of the terminologies and explaining the distinction between assisted suicide and physician-assisted suicide, voluntary and non-voluntary euthanasia, and terminal sedation. According to the site, terminal sedation means the use of medications to induce deep sleep, during which the patient dies of the underlying illness, dehydration, or starvation. Terminal sedation is widely practiced and is generally accepted as ethical and lawful (“Assisted Suicide”, n.d.).

Switzerland is often cited as a country with the most liberal euthanasia laws in the world. According to Article 115 of the Penal Code of Switzerland, “Whoever, from selfish motives, induces another to commit suicide or assist him therein shall be punished, if the suicide was successful or attempted, by confinement in a penitentiary for not more than five years or by imprisonment.” Organization Patient Rights Council argues that assisted suicide is not legal, only unpunishable unless a selfish motive is proven. (“Patients Rights Council”, n.d.).

The situation in Switzerland is explained in detail by Andorno (2013). While active euthanasia (killing on request) is illegal, the administration of medication to relieve the severe pain of a terminal patient is accepted as morally and legally justified. The law does not provide for punishment for the withdrawal or withholding of life-sustaining treatments. The peculiarity of Swiss laws is in the fact that no terminal medical condition is required and in the limited role of physicians. Unlike in the Netherlands and Belgium, in Switzerland, the physician can only prescribe the lethal drug and assess the patient’s mental capacity (Andorno, 2013).

Schwarzenegger and Summers (2005) explain in detail the legal difference between Intentional killing (Article 111), Murder (Article 112), Manslaughter (Article 113), Killing on request (Article 114), Inciting and assisting someone to commit suicide (Article 115) and Negligent killing (Article 117). Legal problems related to assisted suicide include a question of whether or not a person has the legal capacity to request such assistance. It matters whether it was the victim or the person who assists who performed the act of self-termination and details and circumstances of prescription of deadly barbiturates to eliminate pain. Assistance provided by Swiss organizations such as EXIT or Dignitas is considered lawful because of the absence of selfish motive, should it be pecuniary profit, publicity, or inheritance (Schwarzenegger & Summers, 2005).

Similar rules apply in the State of Oregon in the U.S. The Death with Dignity Act, enacted in October 1997. The act allows the residents of Oregon to self-administer a lethal dose of medications, prescribed for that purpose by a physician, providing they are terminally ill and that such deed is voluntary (“Oregon Health Authority”). Experience with this law shows that most of the 204 patients who received prescriptions under the Death With Dignity Act opted for this kind of end were 65 years of age or older, and nearly 80% of them had cancer. (Oregon Health Authority, 2017).

The mental capacity of elderly patients to decide is a problem that nurses face daily. The cognitive ability of elderly patients can deteriorate gradually over time and is not necessarily consistent during the day. For example, patients who are not legally incapacitated can experience periods of confusion. On the other hand, patients who are no longer considered competent to make their own decisions can still have a good understanding of their condition and options at some time of day. Whether or not a patient has the capacity to request assistance with suicide is a question that needs to be answered by a physician.

In general, the situation is much easier if there is a Medical Power of Attorney available that details the patient’s desires and preferences in a way that is clear and unambiguous. The document may empower a specific individual to decide about the withdrawal or withholding of life-saving treatment, and allow the administration of pain relief that may lead to the patient’s death. Medical Power of Attorney also makes it clear who is entrusted with the person’s medical care and end-of-life decisions. In instances, when family relationships are less than straightforward, powers granted to a trusted friend are the only way to ensure the protection of the patient’s rights and interests. Relevant examples include family disputes over inheritance, unfinished separation or divorce proceedings due to family honor concerns, or unaddressed paternity issues.

Financial toxicity of many end-of-life treatments and especially innovative cancer therapies introduces additional ethical dilemmas. Patients’ ability to sustain their end-of-life care often comes at the expense of other family members. Pressures to maintain the family quality of life and sustainable finances, including preservation of inheritance that may be passed on to survivors, may be one motivation to refuse prolonged and aggressive treatments, especially if these therapies are invasive, expensive, and likely futile.

A survey of more than 10.000 patients conducted by the Center for Disease Cancer care found that financial problems caused by cancer were the strongest predictor of quality of life (“Cost of Cancer Care”). Besides, innovative cancer care does not always bring the expected benefits. For example, gemtuzumab ozogamicin (Mylotarg) was a drug approved in 2000 for the treatment of Acute Myeloid Leukemia. Mylotarg was eventually withdrawn from the U.S. market in 2010 because of no clinical benefit to patients (“GEN”).

In December 2012, Amgen Inc. pleaded guilty to the federal charge in Brooklyn, N.Y., and paid $762 Million to resolve criminal liability and False Claims Act allegations arising from the sale and off-label promotion of its product Aranesp. Aranesp is a drug that stimulates erythropoiesis that was approved by the U.S. Food and Drug Administration for a specific patient population with anemia. According to the Department of Justice Amgen also marketed the drug to patients with anemia caused by cancer chemotherapy, for which it was never approved, exposing these patients to a higher risk of death (United States Department of Justice, 2012).

Ethical dilemmas relating to medical care for terminally ill patients are not a new problem. In the late 1800s, German physician Albert Moll collected numerous case studies on medical ethics as practiced in his days in Germany, and in 1902 published his 650-page book Medical Ethics: The Doctor’s Duties in All Relations of His Work. Moll fiercely rejected social Darwinism and eugenic theories so widespread in his time and advocated the contractual relationship between physicians and their patients. This relationship extended to truth-telling and deception when dealing with incurably ill patients and their families. Moll rejected heroic treatment efforts that only led to prolonged suffering on terminally ill patients as unethical and would not undertake them even if the relatives were asking for them. In regards to medical experimentation on dying patients, Moll condemned such experiments as shameful, brutal, and entirely unacceptable (Maehle, 2012).

In 2012, the Liverpool Care Pathway made headlines in the United Kingdom. The National Health Service program was intended to deliver palliative care to dying patients. However, in practice, the guideline was not implemented with fidelity, and many patients and their families felt they and their loved ones were denied care and left to die without their knowledge or consent (“Nursing Times”).

Patient’s wishes aside, if a nurse faces a request from a patient for assistance with suicide, he or she may decide to opt-out from the patient’s care based on conscience. Healthcare providers and physicians, but also individual staff such as nurses, administrative staff, emergency medical technicians, and pharmacists, can object to providing certain medical services. Most often, healthcare professionals object to providing abortions, reproductive healthcare services, sterilizations, contraceptives, or blood transfusions. U.S. federal law allows conscientious objectors may request exemptions from policy and even legal obligations and excuses such individuals and even institutions from the provision of services they find morally objectionable. Galston and Rogers (2012) argue that not just doctors, but also nurses and other healthcare workers, can be excused from performing such duties if they find them morally or religiously objectionable. (Galston & Rogers, 2012)

If a patient confides plans to commit suicide to a nurse, or even requests assistance to do so, nurses should be able to turn to supervisors for support rather than tackling the dilemma alone. Geriatric nurses are likely to encounter such requests at some point in their careers and should receive specialized training for such situations. Institutions that treat the geriatric patient population should prepare relevant procedures and train staff to ensure legal compliance and appropriate and ethical medical practice. In some states, assisted suicide is legal and subject to strict regulation. Mental competence is a major issue in geriatric patients. It is the responsibility of a physician to decide whether the patient requesting assistance with suicide is of sound mind or not. Medical Power of Attorney makes it clear what the patient’s preferences are in regards to end-of-life care, including withholding and withdrawing life-sustaining treatment and administering a potentially lethal dose of pain relief. For a nurse, however, such requests can represent a significant moral dilemma. A conscientious objection can be used to opt-out of providing care to a patient who wishes to die.

References

Andorno, R. (2013). Nonphysician-Assisted Suicide in Switzerland. Cambridge Quarterly of Healthcare Ethics,22(03), 246-253. doi:10.1017/s0963180113000054

Dutton, G. (2010). Mylotarg Withdrawal Raises Questions | GEN Genetic Engineering & Biotechnology News - Biotech from Bench to Business. Retrieved March 23, 2017, from http://www.genengnews.com/gen-articles/mylotarg-withdrawal-raises-questions/4489

Euthanasia Research & Guidance Organization (ERGO). (n.d.). Assisted Suicide - Information on right-to-die and euthanasia laws and history. Retrieved March 23, 2017, from http://assistedsuicide.org/

Galston, W. A., & Rogers, M. (2012). Health Care Providers’ Consciences and Patients’ Needs: The Quest for Balance (pp. 22-35, Rep.). Governance studies at Brookings.

Maehle, A. (2012). ‘God’s Ethicist’: Albert Moll and His Medical Ethics in Theory and Practice. Medical History,56(02), 217-236. doi:10.1017/mdh.2011.34

NHS Choices. (2012). What is the Liverpool Care Pathway? Retrieved March 23, 2017, from https://www.nursingtimes.net/clinical-archive/end-of-life-and-palliative-care/what-is-the-liverpool-care-pathway/5051586.article

Oregon Health Authority. (n.d.). Death with Dignity Act. Retrieved March 23, 2017, from https://public.health.oregon.gov/ProviderPartnerResources/Evaluationresearch/deathwithdignityact/Pages/index.aspx

Oregon Health Authority, Public Health Division, Center for Health Statistics. (2017). Oregon Death with Dignity Act Data summary 2016 (p. 3, Rep.). OR: Oregon Health Authority.

Patients Rights Council. (n.d.). Switzerland Current law regarding assisted suicide. Retrieved March 23, 2017, from http://www.patientsrightscouncil.org/site/switzerland/

Schwarzenegger, C., & Summers, S. J. (2005). Criminal Law and Assisted Suicide in Switzerland. Hearing with the Select Committee on the Assisted Dying for the Terminally Ill Bill, House of Lords Zurich, 3 February 2005. In Universität Zürich. Retrieved March 23, 2017, from http://www.rwi.uzh.ch/lehreforschung/alphabetisch/schwarzenegger/publikationen/assisted-suicide-Switzerland.pdf

The United States Department of Justice. (2012). Amgen Inc. Pleads Guilty to Federal Charge in Brooklyn, NY.; Pays $762 Million to Resolve Criminal Liability and False Claims Act Allegations. Retrieved March 23, 2017, from https://www.justice.gov/opa/pr/amgen-inc-pleads-guilty-federal-charge-brooklyn-ny-pays-762-million-resolve-criminal

The University of Chicago Cost of Cancer Care. (n.d.). Financial Toxicity Facts. Retrieved March 23, 2017, from https://costofcancercare.uchicago.edu/page/financial-toxicity-facts

Addressing pediatric medication errors in ED setting

Sun, 19 Jan 2020 21:13:22 GMT

Addressing pediatric medication errors in ED setting utilizing Computerized Provider Order Entry (CPOE) systems

Published April, 2017

Part of scenarios for detection of medication errors

Pediatric patients who are treated in general acute care hospitals are at increased risk of medication errors. The main reasons are the lack of experience with the special needs of pediatric patients, their lower ability to tolerate medication errors, medication-related problems such as forms and packaging designed primarily for adults and labeling with insufficient information on the dosing of pediatric patients. Medication errors can be reduced significantly by appropriate medication management systems. Computerized Provider Order Entry (CPOE) systems reduce the frequency of medication errors in all stages of the process. IT technology introduces an additional vulnerability in the form of IT-related medication errors. Nurses are the last individuals in the medication management process who can detect and intercept a medication error and prevent incorrect medication orders from reaching and harming their patients. To be able to do so, nurses have to be familiar with the medication management system in their hospital and escalate incorrect orders as appropriate and relevant.

The pediatric patient population treated in an emergency setting in general acute care hospitals is at increased risk of medication errors. The underlying reasons fall into three broad categories: Lack of experience with pediatric patient population, causes relating to medication form, packaging and labeling, and special needs of pediatric patients.

The U.S. Department of Health and Human Services (2014) in their report “National Action Plan for Adverse Drug Event Prevention” recognized pediatric population as especially vulnerable to adverse drug effects, along with elderly patients and people with low socio-economic status or those with difficult access to healthcare (p. 7). Adverse Drug Events account for a large share of hospital-related complications and post-discharge complications. They are the reason for approximately 1 million emergency department visits annually, of which about 125,000 are hospital admissions. (p.5). Grissinger (2015) stated that pediatric inpatients may experience three-times more medication errors than adults and that 1% of all 100 errors have a significant potential for harm (p. 96).

According to the Agency for Healthcare Research and Quality (AHQR, 2015), an adverse drug event (ADE) stands for “harm experienced by a patient as a result of exposure to a medication.” Not all ADEs are caused by a medication error, and not all medication errors result in harm to a patient. A medication error stands for any error in the process, from prescription to administering the drug to a patient, regardless of the harm caused. Medication errors that did not reach the patient but could easily have are called potential ADEs. Whilst preventable ADEs are caused by a medication error, non-preventable ADEs, or side effects (adverse drug effects) are linked to the nature of the medication itself (AHQR, 2015).

In addition, pediatric patients are at increased risk of adverse drug effects due to pharmacokinetic differences at various developmental stages, complex calculations required to adjust individual doses, and the need for precise medication delivery systems. Packaging and formulation of most medications are designed primarily for adults, and reliable information on pediatric use is often unavailable. Moreover, young, small, or sick children have a lower capacity to tolerate medication errors because their organ systems are still maturing. The inability of small children to communicate any undesired effect of medications compounds the problem (Grissinger, 2015).

Medication management is a complex process that starts with a physician prescribing the drug and continues through transcription by assistants to a pharmacist who prepares and dispenses the drug, labeling for individual patients, and administration to patients as appropriate. Once dosed, nurses and clinicians monitor patients for therapeutic and unintended effects of medications. Patients who receive high-risk medications may also be monitored for pharmacokinetic effects of the medication (Carayon et al., 2014).

Each hospital has a unique medication management system. Some hospitals have their medication management systems entirely paper-based; others use entirely computerized solutions, including electronic health records and interfaces with automated dispensing cabinets, storage and logistics systems, prescription order systems, pharmacy information systems, faxes, and printers, infusion pumps, and laboratory diagnostic equipment. In most instances, however, the systems consist of the combination of a wide range of electronic solutions in various stages of implementation and paper-based legacy systems that also serve as a back-up should the computers fail.

Computerized Provider Order Entry (CPOE) systems are increasingly popular due to their ability to reduce medication errors. Radley et al. (2012) studied how many medication errors were averted by the processing of medication orders through CPOE since the implementation of HITECH Act in 2008, and argued that CPOE systems significantly reduced the likelihood of medication errors in inpatient acute-care settings by 48% (p. 480).

Carayon et al. (2014), in their paper “Characterizing the complexity of medication safety using a human factors approach: An observational study in two intensive care units,” examined medication safety in two intensive care units. Medication errors tended to cluster in groups, meaning that a single step in the process includes more than one error. Sequential errors span multiple stages of the process. A detailed overview of the medication management process identified all steps and potential vulnerabilities where errors could occur. Specifically, the team was looking for incomplete orders, order modifications and pharmacy clarifications, duplicates, illegibility, unapproved abbreviations, instances when a patient received a medication despite documented allergy, delayed or omitted administration, the use of antidotes, patient symptoms and out-of-range laboratory values, and references to medication errors in medical notes (p.5). Most errors occurred at the ordering (prescription) and administration stages. Most frequent types of errors were late and omitted administration; medications dispensed late or not at all, wrong order information, omitted information, and wrong dose. The reason for late or omitted administration of medication was often due to the unavailability of the drug in the medication room (p. 8). Information about temporal sequences and grouping of errors is important for system redesign (Carayon et al., 2014).

Grissinger (2015), in his analysis of pediatric medication errors, mentions additional sources of human error, namely IV line mix-ups, mix-ups of look-alike and sound-alike medication packaging and names, and bioavailability problems linked to modification of adult drug forms for pediatric use (p. 99).

While the implementation of CPOE systems in hospitals is effective in preventing a significant number of medication errors, the system itself can become a major source of an additional type of errors. Cheung et al. (2013) analyzed over 4.000 IT-related medication incidents caused either by the technology itself or by human-machine interaction. A significant number of erroneous exchanges concerned choosing the wrong medicine due to poor design of computer screens, and data exchange failures when communicating with other interfaces such as bar code scanning systems, automated dispensing cabinets, health information systems, printers and infusion pumps (p. e63). To analyze IT-related medication errors, Cheung et al. adapted the 2012 version of the Magrabi classification. Magrabi classification defines 32 preferred terms to describe the source of the IT problem and the nature of the error. Nature of the IT-related medication errors included “no input”, “wrong input”, “failure to communicate after input”, “data retrieval”, “no output”, “wrong output”, “unclear output”, “failure to react on signal”, “other output”, “data transfer”, “mistranslation of data between two systems” and “no data transfer between two systems” (p. e66). IT-related errors can affect all stages of the medication management process, from prescribing, transcription, data entry into the pharmacy information systems, compounding, dispensing, administration, patient monitoring and storage, and logistics (p. e68). The practical implications of IT-related medication errors include an awareness that errors of this kind can occur, and the need for a back-up solution recognized at an organizational level (Cheung et al., 2013).

Drug shortages further complicate medication management due to the need for correcting and reprocessing existing orders and replacing standardly used medications with other, less familiar, and less suitable options. Improvisation forced by the unavailability of certain medications leads to additional delays and adverse outcomes in patients. A recent study sponsored by the Office for Clinical Practice Innovation, The George Washington School of Medicine and Health Sciences (2015), explored trends in U.S. drug shortages for medications used in emergency departments in the past 13 years. Of the 1.798 studied shortages, 610 (33.9%) fell into the scope of emergency medicine. Drugs most frequently on shortage included acyclovir injection, hydromorphone, polyvalent antivenin injection, epinephrine, pantoprazole, dexamethasone, calcium chloride, diphenhydramine, tetracaine eye drops and many others (Hawley, Mazer-Amirshahi, Zocchi, Fox & Pines, 2015).

Nurses find themselves at the end of the hospital’s medication management systems. As such, nurses are the last line of defense and the last individuals who have the ability to detect a medication error and intercept the erroneous flow of information before the medication reaches the patient. Nurses are also the people who have to follow-up any missing information, incomplete orders, miscommunication, and errors to be able to administer the correct dose of the right medication to the right patient at the right time. In the case of IT-related failures, nurses have to be able to retrieve the correct information from hospital back-up systems, and bridge information flow between systems that are either not designed to communicate or that occasionally fail to do so.

To be able to detect and intercept a medication error, nurses have to be intimately familiar with their hospital’s medication management system and understand the vulnerabilities to human or machine error such systems have. Awareness of common sources of errors improves the ability of nurses to detect medication errors, respond appropriately, and prevent erroneous orders from reaching and harming their patients. Easy-to-use and punishment-free error reporting systems are essential for the system to self-correct and continuously improve.

Pediatric patients are at increased risk of medication errors when treated in non-specialized emergency care hospitals. Errors can occur in all stages of the process, from prescription and transcription to compounding, dispensing, administration, and monitoring. Computerized provider order entry systems are an essential tool implemented in many hospitals to manage information related to medication flow intended to decrease the incidence of medication errors. Although effective, these systems can become an additional source of errors due to the nature of machines and human-machine interaction. Drug shortages are a common complication in the medication management chain. Nurses are the last line of defense in the medication management system, and the last individuals capable of detecting and intercepting medication errors before an incorrect medication reaches the patient. Familiarity with the whole medication flow is necessary for the individual ability to mitigate such errors.

References

Agency for Healthcare Research and Quality. (2015, March). Medication Errors. Retrieved March 25, 2017, from https://psnet.ahrq.gov/primers/primer/23/medication-errors

Carayon, P., Wetterneck, T. B., Cartmill, R., Blosky, M., Brown, R., Kim, R. Walker, J. (2013). Characterizing the Complexity of Medication Safety using a Human Factors Approach: An Observational Study in Two Intensive Care Units. British Medical Journal, 23(1), 56-65. doi:10.1136/bmjqs-2013-001828

Cheung, K., Veen, W. V., Bouvy, M. L., Wensing, M., Patricia M L A Van Den Bemt, & Peter A G M De Smet. (2014). Classification of medication incidents associated with information technology. Journal of the American Medical Informatics Association, 21(E1). doi:10.1136/amiajnl-2013-001818

Grissinger, M. (2015). Medication Errors Affecting Pediatric Patients: Unique Challenges For This Special Population. Pennsylvania Patient Safety Advisory, 12(3), 96-102. Retrieved March 25, 2017, from http://patientsafetyauthority.org/ADVISORIES/AdvisoryLibrary/2015/Sep;12(3)/Pages/96.aspx

Hawley, K. L., Mazer-Amirshahi, M., Zocchi, M. S., Fox, E. R., & Pines, J. M. (2015). Longitudinal Trends in U.S. Drug Shortages for Medications Used in Emergency Departments (2001-2014). Academic Emergency Medicine, 23(1), 63-69. doi:10.1111/acem.12838

Office of Disease Prevention and Health Promotion. (2014). National Action Plan for Adverse Drug Event Prevention (Rep.). Washington, DC: U.S. Department of Health and Human Services.

Radley, D. C., Wasserman, M. R., Olsho, L. E., Shoemaker, S. J., Spranca, M. D., & Bradshaw, B. (2013). Reduction in medication errors in hospitals due to adoption of computerized provider order entry systems. Journal of the American Medical Informatics Association,20(3), 470-476. doi:10.1136/amiajnl-2012-001241

Deteriorating Patient with Sepsis: Early Diagnosis and Intervention

Sun, 19 Jan 2020 20:27:12 GMT

Deteriorating Patient with Sepsis: Early Diagnosis and Intervention

Published April 2017

Part of test scenarios for implementation of new sepsis guidelines

On Friday night, JB, a 23-year-old Caucasian female, presented at the emergency department with fever, chills, malaise, nausea, increasing confusion, and mild diffuse abdominal pain. Sepsis was suspected because of elevated temperature at 38.9˚C, elevated respiratory rate at 20 breaths per minute, and signs of generalized infection. The study follows the patient's condition, her development, diagnostic steps, and significant findings that led to the establishment of the diagnosis and decision which interventions to use. Full description of the patient’s condition at transfer to a non-emergency ward is described in Identification, Situation, Background, Assessment, and Recommendation forms (ISBAR) chart that is included in Appendices. In 2016, the Surviving Sepsis Campaign (SSC) prepared new revised International Guidelines for Management of Sepsis and Septic Shock (2016) (Surviving Sepsis Campaign). The progression and management of sepsis and septic shock are explained utilizing the new 2016 Surviving Sepsis Guidelines as published by Rhodes et al. (2017).

Sepsis: definition, assessment, and management

The definition of sepsis and septic shock has changed multiple times in the last three decades to reflect new research and clinical observations. As of 2016, sepsis is defined as a "life-threatening organ dysfunction caused by a dysregulated host response to infection" (Kleinpell, Schorr & Balk, 2016). The new diagnostic criteria for sepsis consist of an alteration of mental status, expressed as GCS score at 13 or below, a decrease in systolic blood pressure below 100 mm Hg, and respiration rate higher than 22 breaths per minute. A patient with two or more qSOFA criteria should be examined for organ failure (Seymour et al., 2016). The qSOFA tool is not meant to replace previously developed tools but to be used in addition to them. Systemic Inflammatory Response Syndrome (SIRS) significantly overlaps with sepsis and systemic infection (Vincent, Martin, & Levy, 2016).

The initial clinical assessment was made using the Australasian Triage Scale (ATS) approach. The Primary survey is aimed at the identification of life-threatening conditions, whilst the Secondary Survey includes a full set of vitals, comfort measures, and head-to-toe assessment (Brown, 2013). JB, a 23-year-old Caucasian female, presented at the emergency department on Friday night with fever, chills, malaise, nausea, and mild diffuse abdominal pain. The initial examination revealed heart rate at 92 bpm, SpO2 at 100%, blood pressure 140/70 mm Hg, respiratory rate 20 breaths per minute, and temperature 39.9˚C, steady regular symmetric pulse, petechial rash and adequate skin perfusion with CRT 1.5 sec. Her consciousness was assessed as 14 at the Glasgow Coma Scale (GCS) due to confusion and lethargy. The patient appeared breathless and somewhat incoherent when talking. The patient was hemodynamically stable. The condition was consistent with a generalized infection, although it did not meet the qSOFA standard for sepsis.

Early recognition of sepsis is essential for treatment success through screening. Core sets of recommendations issued by the Surviving Sepsis Campaign include routine obtaining microbiologic cultures, including blood, before starting antimicrobial therapy, providing doing so results in no substantial delay in care. Isolation of the pathogen allows the de-escalation of antimicrobial therapy (Rhodes, 2016).

Initial management of a patient with sepsis includes the stabilization of hemodynamic parameters by the administration of crystalloids and a concerted effort to identify the offending agent. The treatment of sepsis is organized into two recommendations called "bundles": the initial management that takes place within six hours after the presentation for care, and the management bundle that takes place in the intensive care unit (Dellinger et al., 2013).

The goals of the initial bundle are to lessen the immediate impact of uncontrolled infection and to assist the cardiac and respiratory systems through the use of intravenous administration of fluids and vasopressors and administration of oxygen therapy. Early diagnosis and aggressive resuscitation therapy are of critical importance — delayed or inappropriate antibiotic treatment results in higher mortality rates (Paul et al., 2010).

Once the samples for blood cultures and other parameters are collected, intravenous antibiotics shall be administered to cover all possible sources of infection. The choice of antibiotics depends on the suspected pathogen and its virulence and resistance patterns. The revised guideline recommends the administration of initial antibiotic treatment within an hour of diagnosis of sepsis or septic shock after the blood culture samples were taken. The combination of antibiotics shall then be adjusted according to the laboratory findings ("Surviving Sepsis Campaign").

Empiric broad-spectrum antimicrobial therapy is recommended to cover all likely pathogens. Antimicrobial therapy shall be revised and narrowed once the offending agent has been identified and sensitivity established, or if adequate clinical improvement occurs. The revised guideline suggests lowering of doses of antimicrobials and adjustment to the patient’s organ functions to ensure optimal pharmacokinetic and pharmacodynamics profile and decrease side effects (Rhodes, 2016). The most common bacteria isolated from patients with sepsis include Staphylococcus aureus (S. aureus), Streptococcus pyogenes (S. pyogenes), Klebsiella spp., Escherichia coli (E. coli), and Pseudomonas aeruginosa (P. aureginosa). Pathogens isolated from seriously ill patients display a wide array of virulence factors such as endotoxins, lipopolysaccharides, exotoxins and enterotoxins. Bacterial toxins modulate host cell defenses and allow the spread of infection throughout the body (Ramachandran, 2013).

JB was started on crystalloids at 30 mL/kg, a combination of two broad-spectrum antibiotics, and low flow oxygen closely monitored for any changes in hemodynamic parameters. Blood cultures, taken before the first administration of antibiotics, revealed the presence of Gram-positive cocci, eventually identified as Streptococcus pyogenes. The initial procedures were aimed at the localization of the source of infection. Ultrasound of abdomen, pelvis, and chest X-rays did not show any abnormalities. Cerebrospinal fluid was sterile. During the initial series of examinations, the patient became increasingly confused and lethargic. Chronic skin infection previously diagnosed as acne and unspecified joint pain were suspected as the most likely sources of the generalized infection. At this stage, the patient was still hemodynamically stable. The full description of the patient’s condition is in the ISBAR chart, Appendix 1.

Handover: diagnostic tests and safe parameters

Intra-hospital transfers of critically ill patients lead to increased risk of adverse events. Incidents were most likely related to equipment failure and physiological deterioration of the patient, including hypotension and hypoxia. The number of incidents can be reduced through the implementation of standardized protocols, procedures, and checklists relating to patient condition, personnel roles and responsibilities, and organization and equipment and information exchange (Brunsveld-Reinders, Arbous, Kuiper, & de Jonge, 2015). An example of such a checklist presented by Silva and Amante (2015) includes a comprehensive review of the patient’s condition before, during, and after the intra-hospital transport.

Due to multiple other medical emergencies that night, some of JB’s essential readings were not performed and recorded. The nurse who was accepting the transfer of the patient to her noticed that there were no new test results and no record of monitoring from the night before. The two most critically important measures in this particular instance were slowly progressing hypotension, significant because of a trend rather than absolute value, and hypoxemia expressed as blood lactate level. Mean arterial pressure is the critical indicator for the initiation of vasopressor treatment. Patients with mean arterial pressure (MAP) below 65 mm Hg shall be started on vasopressors such as norepinephrine and titrated up to 35-90 μg/min (Dellinger, Schorr, & Levy, 2017).

The high level of lactate is defined as > 4 mmol/L. In shock states, the elevation of lactate is caused by hypoperfusion and resulting tissue hypoxia. The functional cause of hypoperfusion is macro and microcirculatory dysfunction and mitochondrial dysfunction. The patient presentation shows a hypermetabolic state (Andersen et al., 2013). Blood lactate levels in septic patients are the indicator of cellular metabolic failure and low tissue oxygenation rather than global hypoperfusion. Lactate is the most important indicator in patients with sepsis because of its implications on treatment decisions. All patients with elevated lactate > 4 mmol/L (36 mg/dL) shall be treated for septic shock regardless of blood pressure (Dellinger, Schorr, & Levy, 2017).

The rationale for transfer to a non-emergency ward was that the patient no longer met the MET criteria while on medication that could be administered elsewhere. Her normalizing body temperature at 37˚C was misinterpreted as a sign of recovery from the infection. Her blood pressure was 90/60 mm Hg, respiratory rate at 18, and she was˚ alert. Ominous trends that would suggest otherwise were not available. Accurate and current clinical assessment is essential for a clinician to be able to make a decision whether or not the patient can be transferred to non-emergency care. In JB’s case, the patient’s dropping temperature was misinterpreted as improvement and a sign of a clearing infection rather than a symptom of developing sepsis. However, it would be incorrect to blame a nurse at ICU for failure that is of organizational nature. Comprehensive checklists and protocols relevant to patient transfer would substantially improve patient safety.

Septic shock: pathophysiology and assessment

“Septic shock is a subset of sepsis in which circulatory, cellular, and metabolic alterations are associated with a higher mortality rate than sepsis alone” (“Surviving Sepsis Campaign”). Septic shock is the result of the maldistribution of blood flow. Hypo-perfusion of tissues leads to tissue hypoxia, metabolic acidosis, the release of cytokines and oxygen free radicals, and cell death. The dysfunction of multiple organ systems is quickly followed by multiple organ failure if the process is not halted. Systemic Inflammatory Response Syndrome (SIRS) is characterized by elevated or lowered white blood cell count or an increase in immature neutrophils (bands). Resulting progressive sepsis-related organ dysfunction is called Multiple Organ Dysfunction Syndrome (MODS) (Kleinpell, Schorr & Balk, 2016).

Septic shock is the most critical stage of sepsis and results in the highest mortality rates. When the infection is cleared, and tissue recovers, organ injury and secondary infections may occur. It is important to understand that sepsis involves inflammatory, hemodynamic, tissue-perfusion, and organ dysfunction variables, with the potential to advance to organ dysfunction. The complexity of sepsis and the possible deterioration of septic shock are dependent on the virulence and load of the causative pathogen and the present state of health and genetics of the host. Pro-inflammatory reactions that attack the pathogen are responsible for parallel tissue damage. Anti-inflammatory responses limit tissue injury, but also promote susceptibility to secondary infection (Angus, & van der Poll, 2013).

Septic shock develops in patients who remain hypotensive despite the administration of vasopressors and whose serum lactate levels increase above 2 mmol/L despite adequate fluid resuscitation. Tissue hypo-perfusion results in hypoxia, which triggers a cascade of biochemical processes within the cell due to anaerobic metabolism and the resulting production of lactate. Release of cytokines, namely tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and other pro-inflammatory mediators, leads to increased permeability of membranes and leakage of intravascular fluid into interstitial space. Some bacterial toxins activate the same cascade. Activation of interleukins 6 and 8 (IL-6 and IL-8) leads to the release of platelet-activating factor and formation of micro-thrombi within the vascular system. The combination of these factors results in the impaired distribution of blood volume, vasodilatation, and hypoperfusion — resulting in tissue hypoxia, which further exacerbates and worsens the problem. Activation of the central nervous system and hypophyseal-adrenocortical axis leads to hypermetabolic state, increasing tissue demand for oxygen. The effect of TNF-α and IL-1 on the myocardium is the cause of depressed myocardial function, decreased ejection volume, and worsening hypotension. Hypovolemia leads to centralization of blood circulation, limiting the flow of blood in the kidneys and mesenterium, causing additional complications such as acute kidney injury (Brown, 2013).

Indicators of septic shock include persisting hypotension below 65 mm Hg despite vasopressors use, and blood lactate > 2 mmoL/L despite adequate volume resuscitation (Seymour et al., 2016). Lactate is the product of anaerobic metabolism, produced by most cells in the human body. Under anaerobic conditions, it is the end-product of glucose metabolism. Under normal conditions, lactate is rapidly cleared from the bloodstream by the liver. Elevated lactate is defined as 2 to 2.5 mmol/L by different sources. The high level of lactate is defined as > 4 mmol/L. The term lactic acidosis shall be used if the patient has high lactate and pH<7.35. In shock states, the elevation of lactate is caused by hypoperfusion due to macro and microcirculatory dysfunction, mitochondrial dysfunction, and the presence of a hypermetabolic state (Andersen et al., 2013). Blood lactate levels in septic patients are the indicator of cellular metabolic failure and low tissue oxygenation rather than global hypoperfusion. Although lactate does not provide a full picture of metabolic status as blood gases do, it is considered as the most important indicator in patients with sepsis because of its implications on treatment decisions. All patients with elevated lactate > 4 mmol/L (36 mg/dL) shall be treated for septic shock regardless of blood pressure (Dellinger, Schorr, & Levy, 2017).

Accurate and rapid assessment is vital to halt the progression of the sepsis into septic shock. The patient may or may not present with symptoms of bacteremia with or without complications such as acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), disseminated intravascular coagulation (DIC), myocardial ischemia and dysfunction, mesenteric ischemia and other complications relating to hypo-perfusion and organ dysfunction (Kalil and Bailey, 2016).

Invasive monitoring of patient conditions in septic shock is possible through the use of transpulmonary thermodilution (Saugel et al., 2016). The technique is performed through the insertion of a central venous catheter into the inferior or superior vena cava; a thermistor-tipped arterial catheter is usually placed through the femoral artery into the abdominal aorta (Bendjelid, Giraud, Siegenthaler, & Michard, 2010). Cooled saline is introduced into the central venous circulation and passes through the right heart, pulmonary circulation, and the left heart. Then the thermistor detects the thermal indicator bolus of sale at the end of the arterial catheter, allowing the realization of a curve that shows how the cold indicator is diluted through the patient’s cardiopulmonary circulation. Other hemodynamic values available are CO assessment, cardiac preload, myocardial contractility, and the extravascular lung water index (Kiefer et al., 2012; Tagami et al., 2010 and Casserly, Read, & Levy, 2011).

After transfer, JB’s GCS was still 13; her blood pressure dropped to 90/60 mm Hg heart rate increased to 141 bpm, and the temperature dropped to 37˚C and continued to drop. Her pulse was weak and narrow, and respiratory rate > 22 breaths per minute. Peripheral capillary oxygen saturation (SpO2) dropped to 90%. Her skin turned very pale and showed signs of hypo-perfusion and edema. Laboratory findings included leukocytosis, neutrophilia with a left shift, and hyperglycemia. JB’s qSOFA score increased from one on the Friday night to three by Sunday mid-day when she developed tachypnea and systolic hypotension in addition to the Glasgow Coma Scale score (GCS) of 13. JB’s condition indicated that she is developing septic shock. She was hypotensive, and her mean arterial pressure (MAP) was dropping, and her lactate level was 3.5 mmol/L. By Sunday night, JB was unable to void despite high fluid intake. Oliguria increased creatinine and blood urea nitrogen, and electrolyte imbalance pointed to kidney dysfunction. Moreover, JB started showing signs of dyspnea. Using the Berlin Definition, her ADRS was 200 mm Hg and PaO2/FIO2 ≤ 300 mm Hg, which qualifies as mild (Ranieri, Rubenfeld, Thompson, & et al., 2012).

Septic shock: management

It is essential to ensure good perfusion and oxygenation of tissues. It is key to halt the deterioration of a patient with sepsis into septic shock and prevent additional tissue injury. A patient with sepsis-induced hypotension or lactate above 4 mmol/L shall receive a rapid infusion of crystalloids and low flow oxygen. Patients with pneumonia or acute lung-injury may require high flow oxygen and intubation or mechanical ventilation. When large volumes of crystalloids are required, supplementation of albumin fluid should be considered to maintain intravascular volume. The septic shock is characterized by hypotension that has not responded to previous efforts at fluid resuscitation. The first consideration is, therefore, the use of vasopressors. The current vasopressor of choice is norepinephrine to maintain a MAP of ≥65 mmHg, followed by vasopressin, epinephrine, and phenylephrine (Rhodes et al., 2016 and Pittman, 2016)

Patients with mean arterial pressure (MAP) below 65 mm Hg shall be started on vasopressors such as norepinephrine and titrated up to 35-90 μg/min. Once stabilized, norepinephrine can be continued alone or in combination with vasopressin at 0.03 units/min, and the dose of norepinephrine can be gradually decreased. If the patient continues to deteriorate, epinephrine and phenylephrine can be added to achieve the MAP target (Dellinger, Schorr, & Levy, 2017). Care must be taken to avoid excessive fluid resuscitation, as a negative fluid balance is preferred with sepsis patients; particularly in patients with ARDS, negative fluid balance improves organ function (Saugel et al., 2016).

The new guidelines suggest the use of dobutamine only patients with low risk of tachycardia and only in low doses for renal protection. Attempts to increase cardiac output with dobutamine did not improve outcomes. Dobutamine, and to a limited extent some other inotropes, may improve tissue perfusion through increasing oxygen delivery (Rhodes et al., 2016). Recommended interventions include prophylaxis of gastric ulcers and venous thromboembolism and insulin for glucose control. Other interventions, such as sedation or dialysis, are reserved for special situations. It is of critical importance to locate the source of infection. Corticosteroids, immunoglobulins, blood purification, administration of blood products, bicarbonates, parenteral nutrition, and inotropes are not recommended in patients with septic shock (Rhodes, 2017).

JB did not initially respond to norepinephrine but eventually stabilized when vasopressin and epinephrine were added to the infusion. Oxygen was administered per nasal cannula. Antibiotic treatment was adjusted to kidney function and to target Gram-positive cocci. Because of a large volume of crystalloids and continuing extravasation, she received albumin to maintain intravascular volume. A central venous catheter capable of hemodynamic measuring was inserted to enable peripheral access and administration of intravenous fluids. To normalize her blood glucose levels, she received insulin.

Conclusion

Sepsis is a serious condition that still has a high mortality despite advanced care. The key to successful treatment is early diagnosis and aggressive treatment. Recently revised treatment guideline offers an excellent opportunity to review hospital practices in regards to the diagnosis and early aggressive treatment of sepsis and septic shock. Screening for infections, including blood cultures, facilitates early diagnosis and enables timely intervention. The case scenario presents a relatively low-risk patient demographic presented with symptoms that could have been easily misdiagnosed. The clinical symptoms corresponded with sepsis and rapidly progressed into septic shock. The patient benefited from early diagnosis and aggressive intervention based on newly revised guidelines, and the fact that these guidelines were implemented in clinical practice with fidelity. However, the patient later deteriorated during a poorly controlled intra-hospital transfer that was signed off by a nurse who used a standard that should not have been applied in this situation, consequently causing a delay in the detection of deterioration and delayed care. Whilst the case shows evidence-based medicine at its best, more can be done at the organizational level to facilitate communication during transfers, hospital information management during handovers, including the design of checklists and application of appropriate standards as well as roles and responsibilities for standard situations.

References

Andersen, L., Mackenhauer, J., Roberts, J., Berg, K., Cocchi, M., & Donnino, M. (2013). Etiology and Therapeutic Approach to Elevated Lactate Levels. Mayo Clinic Proceedings, 88(10), 1127-1140. http://dx.doi.org/10.1016/j.mayocp.2013.06.012

Angus, D., & van der Poll, T. (2013). Severe Sepsis and Septic Shock. New England Journal of Medicine, 369(9), 840-851. http://dx.doi.org/10.1056/nejmra1208623

Bendjelid, K., Giraud, R., Siegenthaler, N., & Michard, F. (2010). Validation of a new transpulmonary thermodilution system to assess global end-diastolic volume and extra- vascular lung water. Critical Care, 14(6), R209. http://dx.doi.org/10.1186/cc9332

Brown, D. (2013). Lewis's Medical Surgical Nursing (1st ed., pp. 1706-1729). Elsevier Health Sciences APAC.

Brunsveld-Reinders, A., Arbous, M., Kuiper, S., & de Jonge, E. (2015). A comprehensive method to develop a checklist to increase safety of intra-hospital transport of critically ill patients. Critical Care, 19(1). http://dx.doi.org/10.1186/s13054-015-0938-1

Casserly, B., Read, R., & Levy, M. (2011). Hemodynamic Monitoring in Sepsis. Critical Care Nursing Clinics Of North America, 23(1), 149-169. http://dx.doi.org/10.1016/j.ccell.2010.12.009

Dellinger, R., Levy, M., Rhodes, A., Annane, D., Gerlach, H., & Opal, S. et al. (2013). Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med., 41(2), 580-637. http://dx.doi.org/10.1097/CCM.0b013e31827e83af.

Dellinger, R., Schorr, C., & Levy, M. (2017). A users’ guide to the 2016 Surviving Sepsis Guidelines. Intensive Care Medicine, 43(3), 299-303. http://dx.doi.org/10.1007/s00134-017-4681-8

Kalil, Andre, and Kristina L Bailey. "Septic Shock". Medscape (2016): n. pag. Web. 10 Apr. 2017.

Kiefer, N., Hofer, C., Marx, G., Geisen, M., Giraud, R., & Siegenthaler, N. et al. (2012). Clinical validation of a new thermodilution system for the assessment of cardiac output and volumetric parameters. Critical Care, 16(3), R98. http://dx.doi.org/10.1186/cc11366

Kleinpell, R., Schorr, C., & Balk, R. (2016). The New Sepsis Definitions: Implications for Critical Care Practitioners. American Journal Of Critical Care, 25(5), 457-464. http://dx.doi.org/10.4037/ajcc2016574

Paul, M., Shani, V., Muchtar, E., Kariv, G., Robenshtok, E., & Leibovici, L. (2010). Systematic Review and Meta-Analysis of the Efficacy of Appropriate Empiric Antibiotic Therapy for Sepsis. Antimicrobial Agents and Chemotherapy, 54(11), 4851-4863. http://dx.doi.org/10.1128/aac.00627-10

Pittman, R. (2016). Regulation of Tissue Oxygenation, Second Edition (1st ed.). San Rafael: Biota Publishing.

Ramachandran, G. (2013). Gram-positive and gram-negative bacterial toxins in sepsis. Virulence, 5(1), 213-218. http://dx.doi.org/10.4161/viru.27024

Ranieri, V., Rubenfeld, G., Thompson, B., & et al. (2012). Acute respiratory distress syndrome: the Berlin Definition. JAMA, 307, 2526-2533. http://dx.doi.org/10.1001/jama.2012.5669

Rhodes, A., Evans, L., Alhazzani, W., Levy, M., Antonelli, M., & Ferrer, R. et al. (2017). Surviving Sepsis Campaign. Critical Care Medicine, 45(3), 486-552. http://dx.doi.org/10.1097/ccm.0000000000002255

Saugel, Bernd et al. "Advanced Hemodynamic Management In Patients With Septic Shock". BioMed Research International 2016 (2016): 1-11. Web.

Silva, R., & Amante, L. (2015). Checklist for the intrahospital transport of patients admitted to the Intensive Care Unit. Texto & Contexto - Enfermagem, 24(2), 539-547. http://dx.doi.org/10.1590/0104-07072015001772014

Seymour, C., Liu, V., Iwashyna, T., Brunkhorst, F., Rea, T., & Scherag, A. et al. (2016). Assessment of Clinical Criteria for Sepsis. JAMA, 315(8), 762. http://dx.doi.org/10.1001/jama.2016.0288

Surviving Sepsis Campaign. (2017). Survivingsepsis.org. Retrieved 8 April 2017, from http://www.survivingsepsis.org/About-SSC/Pages/default.aspx

Tagami, T., Kushimoto, S., Yamamoto, Y., Atsumi, T., Tosa, R., & Matsuda, K. et al. (2010). Validation of extravascular lung water measurement by single transpulmonary thermodilution: human autopsy study. Critical Care, 14(5), R162. http://dx.doi.org/10.1186/cc9250

Vincent, J., Martin, G., & Levy, M. (2016). qSOFA does not replace SIRS in the definition of sepsis. Critical Care, 20(1). http://dx.doi.org/10.1186/s13054-016-1389-z

Availability of Drugs for Alimentary Tract and Metabolic Diseases: a Balanced Approach

Sun, 19 Jan 2020 18:34:08 GMT

Availability of Drugs for Alimentary Tract and Metabolic Diseases: a Balanced Approach

Author: Veronika Valdova, DVM

Translated by: Piret Pedas, MD

Souhrn

Valdová V. Dostupnost léčiv pro trávicí trakt a metabolická onemocnění: kouzlo rovnováhy. Remedia 2017; 27: 250–256.

V ATC skupině a je možno nalézt přípravky pro léčbu v oblasti trávicího traktu a metabolických chorob. Z 34 léčiv považovaných Světovou zdravotnickou organizací za nepostradatelná jich v České republice chybí devět. některé skupiny léčiv, jako např. léčiva pro funkční poruchy trávicího systému, jsou zastoupeny jen velmi spoře. Řada nezbytných léčiv je zastoupena jen minimálním počtem registrací. nedostatek léčiv ve světě se týká především steril- ních injekčních přípravků, včetně komponent pro parenterální výživu. Dále chybějí některá důležitá léčiva uváděná ve standardních postupech napří- klad pro léčbu infekcí H. pylori a Cl. difficile. Posouzení přiměřenosti zastoupení jednotlivých indikačních podskupin je již otázkou pro klinické specialisty. anabolika a léky proti obezitě zasluhují zvláštní pozornost, a to z důvodu jejich popularity na černém trhu. V České republice jsou tato léčiva „k mání“ velmi snadno i navzdory rozsáhlé regulaci.

Summary

Valdova V. Availability of medicines used for alimentary tract and metabolic diseases treatment. Remedia 2017; 27: 250–256.

The group a of the ATC classification contains products for the treatment of alimentary tract and metabolic diseases. Of the 34 drugs considered essential by the World Health Organization, 9 are not available in the Czech Republic. Some subgroups, such as drugs for treatment of functional disorders of gastrointestinal tract, are represented very sparsely. Numerous other indispensable drugs are represented only by a very limited number of registrations. Worldwide shortage of drugs pertains mainly to sterile injectable drugs, including components for parenteral nutrition. Furthermore, some important medicines listed in current guidelines, for example drugs used for treatment of H. pylori, and Cl. difficile infections, are unavailable as well. Appropriateness of individual indication subgroups representation should be assessed by clinical specialists. Anabolic steroids and anti‑obesity medications deserve special attention due to their popularity on the black market. These drugs are easily available in the Czech Republic despite their strict regulation.

How is the situation concerning drug availability in the Czech Republic?

Sun, 19 Jan 2020 18:24:26 GMT

How is the Situation Concerning Drug Availability in the Czech Republic?

Author: MVDr. Veronika Valdová

Translated by: Piret Pedas, MD

Souhrn (Czech)

Valdová V. Jak je to s dostupností léků v České republice? Remedia 2017; 27: 1–4.

Česká republika je malý, vysoce regulovaný trh v rámci zemí Evropské unie. Nedávno se začaly objevovat obavy ohledně dostupnosti některých nepostra- datelných léčiv. V České republice je registrováno celkem 58 217 variant léčivých přípravků, z nichž 8 157 (14 %) je v současné době aktivně obchodováno. Důvody neochoty zavést přípravky po registraci na trh jsou mimo jiné komplikovaná národní legislativa, netransparentní a nekonzistentní vymáhání práva, nepředvídatelnost administrativních postihů, nejednoznačná pravidla pro vyjednávání cen a posuny v postupech v závislosti na politických změnách. Ačkoliv je současná situace dávána za vinu reexportům, žádná vyčerpávající studie o rozsahu a původu nedostatku léků neexistuje. Analýza Arete‑Zoe srovnává počty registrovaných a obchodovaných léčivých přípravků dle indikačních skupin a poskytuje vhled do dostupnosti léčiv v České republice ze seznamu nepostradatelných léčiv Světové zdravotnické organizace (WHO). Údaje pocházejí z databáze Státního ústavu pro kontrolu léčiv. Vizualizace dat ukazují vysoké zastoupení v některých terapeutických oblastech (neurologie a psychiatrie, kardiovaskulární léky), zatímco jiné skupiny jsou zastoupeny jen stěží. Z celkového počtu 427 nepostradatelných léčiv ze seznamu WHO je jich v současné době v České republice nedostupných 135. Nejhůře jsou na tom antiinfektiva, antiparazitika a dermatologika. nedostatek některých nepostradatelných léčiv, specificky injekčních přípravků a starších léčiv, jimž vypršela patentová ochrana, je globálním problémem. Příčiny jsou komplexní, mj. konsolidace průmyslu, potíže při výrobě, zadávání výroby do produkce výrobcům v Číně a Indii, administrativní postihy vůči výrobcům pro nedodržení zásad Správné výrobní praxe, nedostupnost zdrojových materiálů, obchodní bariéry, případně ukončení výroby z ryze obchodních důvodů. Zpráva Úřadu pro odpovědnost vlády (GaO) z července 2016 podrobně zkoumá příčiny nedostatku léčiv ve Spojených státech amerických a navrhuje řešení na národní úrovni. Zdravotnické systémy mají často potíže definovat, jaké jsou potřeby jejich populace. Zároveň nemocnice jsou velmi omezeny v možnostech volby a musejí nakupovat pouze s ohledem na cenu. Světová zdravotnická organizace ve své zprávě (2016) navrhuje minimální garantované ceny pro určité nepostradatelné léky, aby byla zaručena jejich dostupnost v přijatelné kvalitě.

Summary (English)

Valdova V. How is the situation concerning drug availability in the Czech Republic? Remedia 2017; 27: 1–4.

Czech Republic is a small, highly regulated EU market. Recently, concerns emerged regarding availability of certain essential medicines. There are 58 217 variants of medicinal products registered in the Czech Republic, of which 8 157 (14%) are currently actively marketed. Reasons for reluctance to launch products after approval include complex national regulations, lack of transparency and inconsistent enforcement, unpredictability of administrative actions, ambiguity in price negotiations, and policy shifts in response to political changes. Although the current situation is mainly blamed on re‑exports, there is no comprehensive study of the extent and nature of the shortages. Arete‑Zoe analysis compares numbers of approvals and marketed drugs by indication groups, and provides insight into the availability of World Health Organization (WHO) essential medicines in the Czech Republic. The dataset was obtained from the Czech Institute of Drug Control. Data visualizations show high representation in some therapeutic areas (neurology and psychiatry, cardiovascular drugs), whilst other groups are hardly present at all. Of the 427 WHO essential medicines, 135 are currently unavailable in the Czech Republic. The worst affected groups are anti‑infectives, anti‑parasitics and dermatologicals. Shortage of certain essential medicines, especially injectables and old off‑patent medicines is a global problem. Its causes are complex and include consolidation of the industry, production issues, outsourcing of manufacturing to India and China, administrative actions against manufacturers for good manufacture practice (GMP) non‑compliance, unavailability of raw materials, trade barriers, as well as discontinuation of production for purely business reasons. Government Accountability Office report from July 2016 scrutinizes in detail causes of shortages in the US and suggests solutions at national level. Health systems have often difficulty defining their populations’ needs. At the same time, hospitals are highly restricted in their choices beyond the sole criterion of price. WHO report (2016) suggested guaranteed minimum prices for certain essential drugs to ensure their availability in appropriate quality.

Mitigating consequences of a drug-facilitated sexual assault

Sun, 19 Jan 2020 17:47:57 GMT

Mitigating consequences of a drug-facilitated sexual assault

First published 27 Jan 2017

Revised 19 Jan 2020

Drug-facilitated sexual assault (DFSA) is not just bad sex. It occurs either without the victim’s consent or with consent that cannot be considered valid due to incapacitation of the victim by alcohol or drugs. While opportunistic DFSA is carried out once the victim has been rendered unconscious by own actions, pro-active DFSA describes situations when the perpetrator spikes the victim’s drinks covertly [1].

The most frequently used drug in DFSA is alcohol. Other drugs often involved include flunitrazepam (Rohypnol), gamma-hydroxybutyrate (GHB), gamma-butyrolactone (GBL), carisoprodol (Soma) and ketamine. Ecstasy (MDMA) and other benzodiazepines are occasionally used also. These drugs rapidly induce drowsiness, sedation and muscle relaxation. Typical symptom is decreased inhibition. Most of the drugs used for DFSA are odorless and tasteless, with the exception of GBL that has a bitter taste. Memoryy loss is common, most victims have little to no recollection of the previous night [2].

The most common way of obtaining these drugs is through the darknet [3]. Benzodiazepines, GHB (Xyrem) [4], and ketamine (an anesthetic used in human and veterinary medicine) are often diverted from legitimate medical use for illicit purposes.

In 2012, in U.S. v. Caronia [5] became one of the landmark cases in the promotion of prescription drugs for unapproved (off-label) indications. Physicians who prescribe Xyrem (GHB) have to pass special certification to ensure safe prescription, handling, and storage of the drug (REMS) [6].

Sedative or tranquilizer Flunitrazepam is still legally manufactured in Europe and some countries in Latin America. The drug has been reformulated, so it imparts an easily identifiable blue color to clear beverages and haziness to colored drinks [7]. Drugs obtained from illegal manufacturing sources naturally do not display this effect.

DFSAs are increasingly popular in bars, clubs, and raves, but also fraternities and at college campuses. Mishandling of cases of sexual assault at college campuses has been subject to much criticism [8].

It is very difficult to estimate the total number of DFSAs. The main reason for failure to report sexual assault is the reluctance of the victims to go to the police. Indications exist that the numbers are on the increase [9], [10]. Because of memory loss associated with these drugs, victims often feel embarrassed or guilty. Additional reasons for not reporting sexual assault include need to avoid further stigmatization, especially when the evidence does not seem to be sufficient to support the claim confidently. Forensic evidence is difficult to obtain and often lost after first urination the morning after. All drugs used for DFSA are metabolized rapidly by the body, rendering them undetectable within 24 to 48 hours after ingestion [11].

Suggestions for prevention include limiting drinking to slow consumption of one to two drinks per hour, caution when accepting drinks provided by strangers or male acquaintances, avoiding punch bowls and beverages that are passed around, and refraining from participation in drinking games. A glass that was left unattended is better left alone. Finally, the first signs of intoxication mean it is the last opportunity to call for help [12].

There are ways how to detect DFSAs in spiked drinks. In a laboratory, the method of choice is Gas Chromatography-Mass Spectrometry [1]. Field tests have been developed, such as fluorescent dye [13], that makes spiked drinks change color. Nail polish designed by Undercover Colors received a lot of media attention long before it reached the market [14]. The most reliable detection technology currently on the market is pd.id produced by High-Tech [15].

Telltale signs of intoxication can be difficulty breathing and feeling too drunk, considering the amount of alcohol consumed. Additional symptoms include loss of bladder or bowel control, nausea, sudden body temperature change, dizziness, disorientation, or blurred vision. Victims typically wake up with no recollection of the events of the last night [16]. With no memory of having sex the night before, the first sign of something being amiss is waking up in unfamiliar location sore in the wrong places, with a hangover, and clothes in a strange condition. It is essential to get to the hospital as early as possible. Ideally, the woman should not shower and should wait with the first pee for the hospital so forensic evidence can be obtained.

Urine is the body fluid of choice, and the earlier it is collected, the better. The longer time has passed, the lower the concentration of the drug, and the higher the chance of the drug being missed [7].

Source: UN Drug Report, 2016 [3]

Increasingly politicized healthcare makes post-incident management potentially a nightmare. Treatment of most STDs is usually straightforward [17], and even if HIV is suspected, an antiviral cocktail of drugs called Post-Exposure Prophylaxis [18] should prevent infection [17]. Obtaining emergency contraception can still be difficult in some hospitals and some regions [19]. Achieving justice is a different matter altogether. Not only some hospitals charge rape victims $1.000 or more for rape kits [20], [21], most of these rape kits are only processed with very long delays due to the long backlog [22], [23].

Handling of rape cases by the police [24] and the courts [25] further discourages women from speaking up. Those who wish to go ahead despite all odds, and report the incident, should leave the premises intact and leave any glasses, clothing, biological fluids and hair for forensic examination [26].

To add insult to injury, videos and photographs of sexual assault can quickly end up online for everyone to see, causing even more damage to the victim’s reputation and making a recovery effectively impossible [27].

Long story short, sexual assault, primarily when facilitated by alcohol and date rape drugs, can be a devastating and life-changing event. Post-incident care can be costly, especially if rape-kits and STD prophylaxis have to be paid out of pocket.

References

[1] Gautam, L., Sharratt, S., & Cole, M. (2014). Drug Facilitated Sexual Assault: Detection and Stability of Benzodiazepines in Spiked Drinks Using Gas Chromatography-Mass Spectrometry. Plos ONE, 9(2), e89031. doi: 10.1371/journal.pone.0089031

[2] WV FRIS. (2020). Drug Facilitated Sexual Assault | Sexual Violence | West Virginia Foundation for Rape Information and Services (WV FRIS). Retrieved 19 January 2020, from http://www.fris.org/SexualViolence/DrugFacilitated.html

[3] United Nations Office of Drug and Crime. (2016). World Drug Report 2016. New York: UNODC. Retrieved from https://www.unodc.org/doc/wdr2016/WORLD_DRUG_REPORT_2016_web.pdf

[4] Jazz Pharmaceuticals. (2020). XYREM® - Treatment for Narcolepsy with Cataplexy and Excessive Daytime Sleepiness. Retrieved 19 January 2020, from https://www.xyrem.com/

[5] Recent cases. First Amendment - Commercial Speech - Second Circuit Holds that prohibiting truthful off-label promotion of FDA-approved drugs by pharmaceutical representatives violates First Amendment. United States v. Caronia, 703 F.3d 149 (2d Cir. 2012). (2013). Harvard Law Review, 127:795(795), 795-802. Retrieved from http://cdn.harvardlawreview.org/wp-content/uploads/pdfs/vol127_united_states_v_caronia.pdf

[6] Jazz Pharmaceuticals, Inc. (2015). Xyrem REMS Document. Food and Drug Administration. Retrieved from https://www.fda.gov/media/90866/download

[7] Schwartz, MD, R., & Milteer, MD, R. (2000). Drug-Facilitated Sexual Assault ('Date Rape'). Retrieved 19 January 2020, from http://www.medscape.com/viewarticle/410558_3

[8] Kingkade, T. (2016). HuffPost is now a part of Verizon Media. Retrieved 19 January 2020, from https://www.huffpost.com/entry/federal-funding-campus-rape-investigations_n_568af080e4b014efe0db5f76

[9] BJS. (2020). Bureau of Justice Statistics (BJS) - Rape and Sexual Assault. Retrieved 19 January 2020, from https://www.bjs.gov/index.cfm?ty=tp&tid=317

[10] FBI. (2016). January to June 2015–2016 Offenses Reported to Law Enforcement by State by City 100,000 and over in population. Retrieved 19 January 2020, from https://ucr.fbi.gov/crime-in-the-u.s/2016/preliminary-semiannual-uniform-crime-report-januaryjune-2016/tables/table-4/table_4_january_to_june_2015_offenses_reported_to_law_enforcement_by_state_by_city_100-000_and_over_in_population/view

[11] National Drug Intelligence Center. (2004). National Drug Intelligence Center. National Drug Intelligence Center. Retrieved from https://www.justice.gov/archive/ndic/pubs8/8872/8872p.pdf

[12] West Virginia Foundation for Rape Information and Services. Drugs Used to Facilitate Rape. FRIS. Retrieved from http://www.fris.org/Resources/PDFs/Brochures/Bro-DrugRapeWeb.pdf

[13] Prigg, M. (2014). The date rape drug test that can change the colour of your drink. Retrieved 19 January 2020, from https://www.dailymail.co.uk/sciencetech/article-2591069/The-date-rape-drug-test-works-seconds-light-drink.html

[14] AOL. (2016). AOL is now a part of Verizon Media. Retrieved 19 January 2020, from https://www.aol.com/article/lifestyle/2016/11/21/new-nail-polish-will-help-detect-the-date-rape-drug/21611278/

[15] Brunner, G. (2014). Handheld device allows anyone to instantly test drinks for date rape drugs - ExtremeTech. Retrieved 19 January 2020, from https://www.extremetech.com/extreme/186647-handheld-device-allows-anyone-to-instantly-test-drinks-for-date-rape-drugs

[16] RAINN. (2020). Drug-Facilitated Sexual Assault | RAINN. Retrieved 19 January 2020, from https://www.rainn.org/articles/drug-facilitated-sexual-assault

[17] Miller, MD, C. (2014). Preventing STDs After Sexual Assault: A Guide for Clinicians. Retrieved 19 January 2020, from https://www.medscape.com/viewarticle/822563

[18] HIV.gov. (2019). Post-Exposure Prophylaxis. Retrieved 19 January 2020, from https://www.aids.gov/hiv-aids-basics/prevention/reduce-your-risk/post-exposure-prophylaxis/

[19] ACOG. (2017). Access to Emergency Contraception - ACOG. Retrieved 19 January 2020, from https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Health-Care-for-Underserved-Women/Access-to-Emergency-Contraception?IsMobileSet=false

[20] RAINN. (2020). What Is a Sexual Assault Forensic Exam? | RAINN. Retrieved 19 January 2020, from https://www.rainn.org/articles/rape-kit

[21] Caplan-Bricker, N. (2015). Rape Victims Are Still Being Charged for Rape Kits. Retrieved 19 January 2020, from https://slate.com/human-interest/2015/12/rape-victims-are-still-being-charged-for-rape-kits.html

[22] NPR. (2016). NPR Choice page. Retrieved 19 January 2020, from https://www.npr.org/2016/01/17/463358406/whats-being-done-to-address-the-countrys-backlog-of-untested-rape-kits

[23] RAINN. (2020). Addressing the Rape Kit Backlog | RAINN. Retrieved 19 January 2020, from https://www.rainn.org/articles/addressing-rape-kit-backlog

[24] Newman, M. (2014). Revealed: Why the police are failing most rape victims. Retrieved 19 January 2020, from https://www.thebureauinvestigates.com/stories/2014-02-28/revealed-why-the-police-are-failing-most-rape-victims

[25] Beaven, A. Rape girl 'driven to suicide by her ordeal in court'. Retrieved 19 January 2020, from https://www.dailymail.co.uk/news/article-129105/Rape-girl-driven-suicide-ordeal-court.html

[26] DHHS. (2019). Date rape drugs | Womenshealth.gov. Retrieved 19 January 2020, from https://www.womenshealth.gov/a-z-topics/date-rape-drugs#h

[27] Rucke, K. (2013). Double Tragedy: Rape Victims Commit Suicide After Cyberbullying Incidents. Retrieved 19 January 2020, from https://www.mintpressnews.com/double-tragedy-rape-victims-commit-suicide-after-cyberbullying-incidents/59365/

Availability of antiinfectives in the Czech Republic

Mon, 13 Jan 2020 19:32:18 GMT

Dostupnost antiinfektiv v České republice (CZ)

Author: Veronika Valdová, translated by Piret Pedas, MD

Published in Remedia 2017; 27: 509–513.

Na Seznamu nepostradatelných léčiv Světové zdravotnické organizace figuruje 119 antiinfektiv, z nichž v České republice není registrováno 29. Dalších 10 léčiv je registrováno, ale neobchodováno. Dostupnost antibiotik a dalších nezbytných léčiv má přímý dopad na klinickou praxi. Příkladem je aktualizovaný postup pro léčbu sepse a septického šoku, který doporučuje deeskalaci a zacílení na identifikovaný patogen ihned po jeho identifikaci z důvodu snížení zátěže pro organismus pacienta. Aktualizované léčebné postupy je nutno brát v úvahu při sestavování národních seznamů nepostradatelných léčiv. Z nepostradatelných tuberkulostatik a antivirotik chybějí v ČR některé fixní kombinace určené pro první linii léčby tuberkulózy a HIV/aIDS. Padělky léčivých přípravků a nedoléčené infekce jsou hlavními příčinami vzniku multirezistentních kmenů původce tuberkulózy. Z hyperimunních sér v ČR chybí sérum proti záškrtu. Vakcíny se potýkají s celosvětovým nedostatkem v důsledku délky a náročnosti výroby.

Klíčová slova: antiinfektiva – nepostradatelná léčiva – dostupnost léčiv – nedostatek léčiv – tuberkulóza – HIV/aIDS – sepse.

Availability of antiinfectives in the Czech Republic (EN)

The World Health Organization (WHO) lists 119 anti-infectives on the list of essential medicines. Of these, 29 are not registered in the Czech Republic, and another 10 are registered but not marketed. availability of antimicrobials and other essential medicines directly affects clinical practice. One such example is the newly revised guidelines for the treatment of sepsis and septic shock, which recommends de-escalation of antibiotic treatment and targeting the causative pathogen immediately after its identification to minimize toxicity to the patient’s metabolism. Newly compiled national lists of essential medicines shall consider revised treatment guidelines and not just the WHO list. Some fixed combinations of anti-tuberculars and anti-retrovirals for first-line treatment of HIV/AIDS are unavailable in the Czech Republic. Counterfeit drugs and undertreated infections are the main drivers of microbial resistance. Diphtheria antitoxin and rabies immunoglobulin are the only immune sera unavailable in the Czech Republic. Shortage of vaccines occurs globally as a result of complexity and length of the manufacturing process.

Key words: antiinfectives – essential medicines – availability of medicines – drug shortages – tuberculosis – HIV/AIDS – sepsis.

Review of data breaches in healthcare

Sat, 14 Dec 2019 17:14:23 GMT

As required by section 13402(e)(4) of the HITECH Act, the public has the right to know which entities failed to secure protected health information and be able to access a list of PHI data breaches affecting 500 or more individuals.

The Wall of Shame, as the OCR portal is called, allows users to search and sort the posted breaches.

Analysis of OCR data shows a breakdown of summary figures for the number of individuals affected and the number of incidents for the entire covered period 2009-2016 and for 2016, as well as trends.

Curious look into the quality of evidence produced in clinical trials

Sat, 14 Dec 2019 14:12:09 GMT

Interventional studies: quality of evidence

As of today, there are 256,092 interventional studies in the ClinicalTrials.gov registry. This NIH-operated database is not the only one but the most relevant and complete source of information on ongoing and completed clinical trials. The available information includes basic study descriptors such as phase, type, interventions, funding, and sponsors and co-sponsors; number of enrolled subjects and their demographic characteristics such as gender and age, and more detailed descriptors of study design such as masking, intervention model and allocation; as well as primary purpose and endpoint classification. This article is the first piece from a series of analyses of interventional trials on this database.

In interventional trials, the participants are assigned to receive one or more interventions or none at all, as assigned in the protocol. The objective is to gather and evaluate data from comparable groups of participants who only differ in the intervention they receive so that researchers can assess the effects of these interventions on biomedical or health-related outcomes. In general, interventions can be diagnostic, therapeutic, or behavioral.

Level of Evidence

For a biomedical researcher, the level of evidence produced in clinical trials is essential to determine the overall impact of the study on benefit-risk assessments of the studied interventions, treatment guidelines, recommendations for reimbursement, and other assessments. Most organizations have a structured and comprehensive way of assessing scientific evidence that is coming in. However, there are no universal standards or generally accepted guidelines for doing so, and these evaluations differ from one organization or journal to another.

Level I evidence includes:

High-quality randomized trial or prospective study;
Testing of previously developed diagnostic criteria on consecutive patients;
Sensible costs and alternatives;
Values obtained from many studies with multiway sensitivity analyses;
A systematic review of Level I RCTs and Level I studies.

Some past scandals illustrate the extent of the problem very clearly: scientific opinions on the value, power, and level of evidence produced by the RECORD study meant the difference between acceptance and rejection of GSK’s drug Avandia. Assessment of quality of evidence produced in a study has real-life consequences, both medically and financially.

Unfortunately, ClinicalTrials.gov does not provide an assessment of evidence produced by studies included in the registry. The NIH leaves it solely to the assessor to decide how valuable each trial is in the context of all other available information.

Data

Processing the dataset before analysis included deletion of extra columns, standardization of null values, and removal of trials scheduled to start after 2016. The material, therefore, does not serve as a prediction but solely as a review of studies that already started.
Enrollment figures are skewed by a small number of studies with a very high number of participants (millions of subjects). Three studies listed the total number of participants at 99,999,999. These outlier figures skew the trends. Moreover, the number of planned and enrolled subjects can differ significantly, so the reliability of this data depends on the stage of the trial (plan, estimate, in progress, or completed and updated).

Type of Interventions

About half of all clinical trials studied drugs as the intervention in question. Biologics, devices, procedures, and other types of interventions account for most of the remaining 50%. A relatively small number of interventions concerned radiation therapy and dietary supplements. Breakdown by phase shows similar distribution by each phase: the majority of interventions for trials in phase I to IV are drugs, followed by biologics, devices and procedures. A relatively high number of trials does not have any phase stated; for these, the interventions fall almost evenly fall into categories “other”, “behavioral”, “device”, “drug” and “procedure”.

Phases

As mentioned previously, about one-third of clinical trials have no phase stated. Early-stage trials (phase I and II) create one third, and the remaining third goes to phase III and IV studies. One would expect that the highest number of enrolled subjects would be in late-stage and post-marketing studies, but that’s not the case: the few previously mentioned studies with a very high declared number of subjects are Phase I and undeclared.

Primary purpose

Nearly half of the studies are conducted for treatment purposes. About 40% of all studies have no primary purpose stated.

Funding

The highest share of studies, about a half, is funded by entities categorized as “other”, even more, if we include “other” in cooperation with other entities. The category "other" is a very broad category that includes academic institutions, individuals, and community-based organizations, including hospitals. About one-third of all trials are funded by industry.

Endpoint classification

The majority of all studies are conducted to satisfy safety and efficacy-related questions. More than a third of studies have no endpoint stated.

Quality attributes

The main quality attributes readily available for scrutiny are characteristics of study design: masking, allocation, and intervention model.

Allocation is a clinical trial design strategy used to assign participants to an arm of a study. In a Randomized Controlled Trial, the participants are assigned to intervention groups by chance. If the trial is non-randomized, the participants are expressly assigned to intervention groups through a non-random method, such as physician choice. Allocation is not relevant for single-arm studies where all participants receive the same treatment. The gold standard scientific evidence is produced through randomized controlled trials.

Masking is a design strategy in which one or more parties involved in the trial, usually the investigator or participants, do not know which participants have been assigned which interventions. The primary purpose of masking is to prevent placebo effect, post-randomization confounding bias, selection bias, or group differences n loss to follow-up and information bias - that is bias due to differences in reporting of symptoms.

"Open-label" study describes a clinical trial in which masking is not used, and all parties involved in the trial know which participants have been assigned which interventions.
In single-blinded studies, one party involved in the clinical trial, typically the investigator or participants, does not know which participants have been assigned which interventions.
In double-blinded studies, two or more parties do not know which participants have been assigned which interventions. Typically, the parties include the investigator and participants, but sometimes also the assessor or caregiver.

Finally, the intervention model describes the design of the strategy for assigning interventions to participants in a clinical study.

Parallel Study Design means that two or more groups of participants receive different interventions "in parallel“.
In a Cross-Over Study design, groups of participants receive two or more interventions in a particular order, so the participants "cross over" from one drug to the other.
Single Group Study Design means that all participants receive the same intervention.
In Factorial Study Design, groups of participants receive one of several combinations of interventions so, during the trial, all possible combinations of the two drugs are given to different groups of participants.

Randomized Cotrolled Trials, the gold standard

In Randomized Controlled Trials, direct comparison is made between two or more treatments groups. Randomization eliminates baseline differences in risk between treatment and control groups. Randomization should make all groups similar in terms of the distribution of risk factors whether these risks are known or unknown. The larger the groups, the greater the probability of equal baseline risks. However, participants in randomized controlled trials are often not representative of the target population, which introduces selection bias and generalizability.

Data available in the ClinicalTrial.gov registry cannot satisfactorily answer the poignant question of quality of evidence studies generate. It would make life of health professionals and researchers much easier, if study results and level of evidence became standard part of all trial reports.

If a tree falls in a forest and no one is around to hear it, does it make a sound?

Fri, 29 Nov 2019 14:05:56 GMT

Ray of light: the invisible results of clinical trials

Physicians adjust their prescribing practices in response to information that is available to them. Unbiased information from clinical trials is a crucial component of health technology assessments as well as clinical decision-making support algorithms.

The European Medicines Agency (EMA) has taken the initiative to develop a policy on publication of clinical data. The rationale for such a step is article 80 of Regulation (EC) No 726/2004 :

The clinical data publication website was developed to implement EMA Policy 0070 and is maintained by the EMA communications department ( EMA/144064/2019 ).

The policy covers clinical data, both clinical reports and individual patient data, submitted under the centralized marketing authorization procedure after 1st Jan 2015, and extension of indication / line extension applications submitted after 1st Jul 2015, or as part of a proceeding under Article 58 of Regulation (EC) No 726/2004, or data provided by a third party in the context of a Market Authorization Application (MAA) or post-authorization procedure, or as additional clinical data for scientific assessment.

There are two categories of access to the published clinical data:

The general information purposes terms of use are for general information and other non-commercial purposes.
The academic and other non-commercial research purposes terms of use are for educational and other non-commercial research purposes. This type of access allows more rights but requires some additional procedural steps.

Online access to clinical data for medicinal products for human use

The terms of use, by definition, exclude all commercial research as well as investors and sponsors who could use the data to analyze available evidence and to assess the performance and value of new therapies under development and compare them to the current standard of care. Since many insurers and payers are commercial entities as well, this resource is not available to them either. Many hospitals and research centers are public-private partnerships, would they count as non-commercial entities? The terms of use also exclude consultants who could use the resource to analyze and benchmark their clients' data.

Clinical reports include the following types of documents:

Clinical overview: a critical analysis of the clinical data submitted in the dossier, that presents the risks and limitations of the study, the study results, analysis of benefits and risks of the medicinal product, and description how the study results support the prescribing information;

Clinical summary: a detailed factual summary of the clinical data, including information provided in clinical study reports from any meta-analyses or other cross-study analyses, as well as post-marketing data for products that have been marketed outside of the EU;

Clinical study report: a detailed scientific document about the methods and results of a clinical trial addressing safety and efficacy. Protocol and protocol amendments describe the objectives, design, methodology, statistical considerations, and organization of a clinical trial. The sample case report form is a questionnaire used by the trial sponsor to collect data from each participating site. Finally, documentation of statistical methods describes the methods for collection, analysis, interpretation, presentation, and organization of the data.

The AllTrials initiative has been asking very legitimate questions about trials that are never published and never presented to the professional public.

"AllTrials is an international initiative of Ben Goldacre, BMJ, Centre for Evidence-based Medicine, Cochrane Collaboration, James Lind Initiative, PLOS and Sense About Science and is being led in the US by Sense About Science USA, Dartmouth’s Geisel School of Medicine and the Dartmouth Institute for Health Policy & Clinical Practice. Overall, 89300 people and 703 organizations have signed the AllTrials petition." ( AllTrials.net )

The first version of ClinicalTrials.gov was made available to the public on February 29, 2000. In September 2005, the International Committee of Medical Journal Editors began requiring trial registration as a condition of publication. Two years later, in December 2007, the implementation of expanded registration requirements of FDAAA launched. Both events substantially increased the number of registered trials.

Map of all clinical trials listed in the ClinicalTrials.gov database as of 29 Nov 2019

Of 173245 Completed studies (as of 29 Nov 2019), only 33824 (19.5%) had results posted in the registry.

Professional e-magazine STAT was the first to draw significant attention to the problem of unreported study results. Out of the 118, 981 completed studies registered in ClinicalTrials.gov, only 16% have posted results. The remaining 84% do not. Out of 110,565 trials completed more than a year ago, only 19,246 have results available to the public. Section 801 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) requires the submission of "basic results" for specific clinical trials, generally no later than one year after their Completion Date ( STAT Investigation, 2015 ).

The situation did not get any better since the 2015 investigation. The lack of enforcement of the reporting obligation compounds the problem ( CASW Showcase, 2017 )

"The worst offenders included four of the top 10 recipients of federal medical research funding from the National Institutes of Health: Stanford, the University of Pennsylvania, the University of Pittsburgh, and the University of California, San Diego. All disclosed research results late or not at all at least 95 percent of the time since reporting became mandatory in 2008." ( The Open Notebook, 2017 )

Charles Piller: Law Ignored, Patients at Risk (STAT, December 2015)

Under section 402(j) of the PHS Act, sponsors of some clinical trials of FDA-regulated products have been required to register them at ClinicalTrials.gov since December 26, 2007. Summary results information for clinical trials of approved products has to be submitted as of September 27, 2008, and adverse events information since September 27, 2009.

This final rule clarifies which clinical trials of FDA-regulated products must be submitted to ClinicalTrials.gov. The final rule also describes an approach for evaluating, before registration, whether a particular clinical trial or study is an applicable clinical trial (see Section IV.A.5 and Section IV.B.2).

FR: Clinical trials registration and results information submission, a rule by the DHHS on 09/21/2016

So it seems that results from clinical trials are slowly but surely becoming publicly available for public scrutiny. The next issue to solve will be the standardization of results to make them comparable.

CONSORT 2010

Standardization of reporting of clinical trials is essential for their review and assessment. CONSORT 2010, as developed by the CONSORT group, contains a 25-item checklist and flow diagram. Extensions of the CONSORT Statement have been developed for different types of trial designs, various interventions, and different kinds of data.

COS-STAR

An international group that included experienced COS developers, methodologists, journal editors, potential users such as clinical trialists, systematic reviewers, and clinical guideline developers, as well as patient representatives, developed the Core Outcome Set–STAndards for Reporting (COS-STAR) Statement as a reporting guideline for COS studies.

On October 18, the group published their work in PLOS Medicine: "Core Outcome Set–STAndards for Reporting: The COS-STAR Statement". The COS-STAR Statement consists of a checklist of 18 items considered essential for transparent and complete reporting in all COS studies ( The COS-STAR Statement, 2016 ):

The current regulatory framework in Europe, as well as in the United States, demands the publication of clinical trial results and access to data. However, enforcement of the obligation to publish study results is lacking. Despite all efforts and numerous initiatives, the share of study results posted in clinical trial registries remains unsatisfactory.

Uncertainty about the product's actual performance represents a liability for the prescribing physician due to the information gaps available about medicines they administer to their patients. For the pharmaceutical industry, uncertainty about the rates of occurrence of adverse experiences and lack of efficacy does not represent a problem as the failure to warn concept does not require data on prevalence and incidence but merely listing a specific drug side effect on the label.

The lack of availability of study results is not the only problem healthcare professionals, and researchers face. The diversity of study designs, outcome measures, inclusion/exclusion criteria, and formats of data presentation complicate interpretation of study results even further.

Pharmacovigilance as an integral part of hospital Quality Management Systems

Mon, 18 Nov 2019 21:47:20 GMT

Rethinking post-market drug safety surveillance

Regulatory requirements are the primary drivers of drug safety surveillance activities. The desire is to avoid adverse consequences stemming from non-compliance.

Boyd cycle, or OODA loop, explains fundamental principles of decision-making loop based on observation, orientation, decision, and action. Observation part of the loop follows requirements detailed in law and regulations and consists of a systematic screening of defined sources for specific information about marketed drugs. Collection of Individual Case Safety Reports (ICSRs) is a very structured process that conforms to the established industry standard limited by dominant technology providers for the processing of these cases. Outsourcing and off-shoring of critical operations bring different cultural traditions. The same information in the same context will be evaluated differently depending on individual background. Risk-perception or communication of safety concerns or potential risks depends on cultural traditions and the norms of acceptable behavior. Information collected during pharmacovigilance activities is used to update product labels and in extreme cases, may lead to the withdrawal of a product from the market and adjust prescribing behavior and clinical decisions in the treatment of individual patients.

The scope of pharmacovigilance activities defined in regulations and guidelines. The sole desire to comply with rules does not necessarily ensure full situational awareness and a complete and objective picture of the drug’s safety profile. Examples of post-market surveillance failure include diabetes drug Avandia or anti-inflammatory drug Vioxx. The sole focus on accuracy, completeness, and correctness of data within a very narrow scope results in overspecialization that further limits the organization’s ability to appreciate the full picture.

Uptake of new drugs and technologies into clinical practice depends on the target population, the disease, and other drugs available to treat the condition, pharmacoeconomic evaluations, reimbursement rules, and other factors. New drugs become part of standard treatment protocols based on an assessment by professional societies and often prescribed in ways that were not originally anticipated or intended. One such example is the intravitreal use of bevacizumab (Avastin). Many new oncology drugs are used in patient populations that were not part of clinical trials, to treat a wide variety of different tumors and in combinations untested in clinical trials. Information from real-world use would be especially valuable when the post-authorization patterns of use differ significantly from the use tested in clinical trials. Patient creativity, as influenced by information spread via informal channels, including social networks, compounds the problem. In the U.S., only a fraction of adverse drug events are reported to FAERS directly by health professionals; 95% of all reports come in from the industry. Another unknown lies in the presence of counterfeit and substandard medications in some markets. All this information can affect the assessment of the causal relationship between the drug and the event.

The most significant limitation of data collected after authorization is the fact that there is no baseline, no exposure data, to which the data on adverse drug reactions can relate. The current post-market safety surveillance systems cannot detect the incidence and prevalence of adverse drug reactions and change in trends. Neuropsychiatric reactions to antimalarial medication mefloquine are an example of this shortcoming. While the adverse reaction itself is known, the actual rates of occurrence are unknown. The drug first caused concerns in 2002 at Fort Bragg, N.C., after a series of violent incidents. In 2004, the Army requested a study into a comparative rate of adverse effects of mefloquine. Exposure data help by the Army were critical to the understanding of the true extent of the problem.

The extent of off-label use complicates the assessment of Benefit: Risk profile of medications. Benefit: Risk profile of a drug depends on the context of its use, and it is impossible to evaluate if data on total exposure and indication are not available. Newly launched medicines, especially in oncology, become part of treatment protocols for cancers and in populations for which they were not tested. The benefit: risk profile of such combinations is impossible to establish from passive post-market surveillance.

And finally, the risk of overdose and abuse is impossible to detect in real-time since cases of overdose are typically not subject to expedited reporting and only need to be included in periodic reports.

Orientation is a critical part of the decision-making process. Nature and nurture affect our ability to detect and communicate safety issues before they become self-evident. Different types of intelligence play a role – recognition of patterns, risk-assessment, as well as the ability to deliver the message to the leadership without endangering own career. In the pharma industry, teams are often built to avoid personality clashes and ensure smooth function in the office environment. Education, training, personal values, and individual biases affect reasoning and perception of risk.

In pharmacovigilance, the main barriers to accurate and timely orientation result from the detailed regulation that emphasizes form at the expense of purpose. Dominant IT providers in the industry designed their products to comply with regulatory requirements to the letter. The methods used in the detection of safety signals rely on the comparison of the review of a single case or a case series and disproportionality analysis. These techniques lack the power to detect true rate, incidence, and prevalence of events due to the lack of exposure data. These methodologies make the detection of safety signals and evaluation of benefit: risk profile very subjective.

The difference between pharmacovigilance and quality management systems in inpatient and outpatient healthcare settings is the nature and purpose of the information collected. While drug safety surveillance systems are primarily designed to collect information on adverse drug events, hospital quality management systems exist to collect information that measures the quality of care. Quality management systems in hospitals collect all events, including adverse experiences relating to drugs and medication errors.

Hospitals in the U.S. collect a variety of information on adverse drug events as part of the monitoring of the quality of care they provide. A study of Medicare beneficiaries revealed that 30% of inpatients experienced an adverse drug event in 2011. This figure amounts to 1.9 million ADEs in inpatients a year, ranging from no harm to death. The risk of ADEs increases with age and number of medications. Participation in Hospital Engagement Network Initiatives led to the reduction of ADEs from 49.5 events per 1.000 hospital discharges to 41.4 ADEs. Pediatric patients and the elderly are particularly at risk, along with patients on multiple medications.

The highest number of adverse drug events in inpatient settings can be attributed to insulins, anticoagulants, and opioid analgesics. The National Action Plan, therefore, focuses on the reduction of the rate of emergency department visits for injury associated with the therapeutic use of opioid analgesics, insulins, and oral anticoagulants. The number of emergency department visits for injury from a specific drug serves as a numerator, and the number of patients receiving the drug serves as a denominator.

Signal detection in pharmacovigilance relies primarily on the review of individual case reports and case series. Another method is a disproportionality analysis of data reported in corporate databases. Actual incidence, prevalence, and rate are impossible to establish due to a lack of exposure data. Market Authorization Holders are now encouraged to implement multi-regional PASS as part of post-market surveillance activities. The objective of conducting post-authorization safety studies (PASS) is to gather additional safety information, assess patterns of drug utilization, to measure the effectiveness of a risk minimization activity.

Confidence intervals on reliability, validity, or unattenuated validity are accurate as long as the selection ratio is at least 20%, and the selected sample size is 100 or larger. When the selection ratio is less than 20%, estimators tend to underestimate their parameters. A way how to achieve high reliability, validity, and confidence interval of safety information from post-authorization use is to utilize samples of real-world data that includes information on exposure. This monitoring technique is especially valuable in off-label uses and special populations. Mere collection of ICSRs without actual epidemiological evaluation using real-world data is not going to produce valid and reliable results.

Pharmacovigilance information collected through post-authorization surveillance systems is used to change drug labeling and update benefit: risk profile of marketed drugs. Physicians make clinical decisions based on this information. An accurate assessment is in the interest of all stakeholders in the system, from patients and physicians to manufacturers and insurers. Denial of a useful drug to a patient who may benefit from it is as harmful as prescribing it to a patient who is likely to develop an adverse effect. The system should, therefore, strive for greater accuracy and speed of detection of safety data to provide valid, reliable, and accurate information for benefit: risk assessment.

Pharmacovigilance information collected through post-authorization surveillance systems is used to change drug labeling and update benefit: risk profile of marketed drugs. Physicians make clinical decisions based on this information. Accurate information on the benefit: risk profile of medications is in the interest of all stakeholders in the system. Patients and physicians have as much interest in good-quality insight as manufacturers and insurers. Denial of a useful drug to a patient who may benefit from it is as harmful as prescribing it to a patient who is likely to develop an adverse effect. The system should, therefore, strive for greater accuracy and speed of detection of safety data to provide valid, reliable, and accurate information for benefit: risk assessment.

Between 1953 and 2013, 462 medicinal products were withdrawn from the EU market. The most common reason leading to withdrawal was hepatotoxicity. In more than 70% instances, the supporting evidence consisted of anecdotal reports. Only 43 (less than 10%) drugs were withdrawn worldwide, and 179 (39 %) were withdrawn in one country only. The median interval between the first reported adverse reaction and the year of first withdrawal was six years. The interval between first detection and authorization withdrawal did not significantly shorten since 1953.

Nancy Leveson, in her analysis of VIOXX, identified stakeholders in the U.S. healthcare system and defined system hazards relating to the use of prescription drugs. The public is exposed to an unsafe drug in the following situations:

if the drug is released with a label that does not correctly specify the conditions for its safe use,
when an approved drug is found to be unsafe, and appropriate responses are not taken,
or if patients are exposed to unacceptable risk during clinical trials.

Unsafe use of drugs includes prescribing and dispensing errors, unsafe combinations, and patient non-compliance. The lack of effective treatment counts as a distinct system hazard. This situation occurs when an effective drug is not developed, approved or is withdrawn, is unaffordable, not accessible to physicians or patients, its introduction to the market is delayed, or when patients stop taking it because of intolerable side effects. Leveson, in her paper, advocates the introduction of additional controls and policy changes that would modify the information environment.

Compliance failure is not the only threat to the enterprise. The purpose of drug safety surveillance is to produce accurate and reliable information about drug benefit: risk profile to all stakeholders in the system who rely on such information, including patients and physicians. Shortages of prescription drugs, especially generics and sterile injectables in emergency medicine, may force clinicians to change treatment protocols to less familiar or less appropriate options. PHI breaches undermine patient and physician trust in hospital and clinical trial data management systems, potentially limiting their willingness to participate in clinical trials and consent to sharing their data for non-interventional studies. Dominant IT providers make it very difficult to take an innovative approach to data integration with other sources and new strategies to signal detection and evaluation. Mergers and acquisitions, stove-piping, and compartmentation of operations to protect intellectual property influence selection of staff for narrowly defined roles, stalling innovation even further.

The Availability of Essential Medicines in Hungary

Tue, 12 Nov 2019 18:26:39 GMT

"We have essentially been avoiding this elephant in the room for the past twenty years, never daring to state what we know: namely that the use of public healthcare services does not reflect the needs of society, but rather the interests of the institutional system." Dr. Zoltán Ónodi-Szűcs, Hungarian Secretary of State for Health (Haynes, 2017)

The WHO List of Essential Medicines and the National Substition List

Lack of availability

In April 2017, the Minister of Human Resources Zoltán Balog discussed the complex situation in the Hungarian healthcare industry in thorough detail. The interview was published in The Budapest Times. Minister Balog, who has been leading the ministry since 2012, stressed the importance of structural changes in healthcare in order to make the system economically feasible without sacrificing the health of the population. The new ministry employs about 3.000 staff members and integrates health and health care, education, family and social affairs, health and pension insurance as well as some research institutions. Some of the priorities of the government are the integration of the Roma minority and the improvement of German-Hungarian relations (Mainka, 2017).

Underfunded system

According to PharExec, the vast majority of stakeholders agree that the Hungarian system remains severely underfinanced even when compared to its neighbors in Central and Eastern Europe. The system is perceived as overburdened, underfinanced, inefficient, and worse than it used to be. Hungarian pharmaceutical industry enjoys a good reputation due to its ability to offer the same products as in more advanced economies, due to its contribution to the national economy, and investment in innovation. Under the previous government, in 2011, the industry had to put up with 30% drop in pharmaceutical spending, in addition, competitive taxation and a blind-bidding mechanism, measures that collectively led to a decrease in prices of medicines. Local manufacturing was also affected by decreased consumption in its traditional markets because of the Russian invasion of Ukraine. Communist legacy manifests in a passive and paternalistic relationship between doctors and their patients. Many believe that the obligation to improve the health literacy belongs to the pharmaceutical industry. Hungarian health insurance system accounts for all health situations, from outpatient care and drug reimbursement to a hospital stay, including innovative oncology therapies (Pharmaceutical Executive Editors, 2017).

Local impact of a global problem

Root causes of global shortages

Counterfeit, falsified and substandard medications

Consequences

Suggested solution

Europe consists of multiple small disparate national markets with a complex regulatory environment and inconsistently applied and enforced rules that often change in response to a political demand. Systematic mapping of the essential medicines availability gap within public health systems in Europe should be conducted. The analysis has to include the burden of disease, assessment of the ability of individual countries to cope with existing and newly introduced infectious and parasitic, especially vector-borne diseases, multi-drug resistant tuberculosis, and increased caseload due to refugees and migrants, and the ability of individual countries to tackle mass-casualty incidents.

Needs analysis has to include a definition of treatment standards for specific conditions and availability of essential medicines at the national level in line with these guidelines. Although national registrations in Europe should be available through EudraPharm, the database does not contain the necessary data to be useful. Shortages in Europe are poorly mapped at a supranational level. Treatment of neglected tropical diseases, multidrug-resistant tuberculosis, and HIV/AIDS can be very expensive, especially if high numbers of people with no health insurance are concentrated in countries that have limited resources to care for them. The last mile obstructions may be due to social upheaval that obstructs access to the point of need. Analysis and solution development must extend beyond simply connecting the dots in the logistical framework. The objective shall be to identify needs that require supranational coordination and solution, such as a shared procurement system for essential medicines that are needed in low and unpredictable amounts, and the definition of requirements for transnational emergency stockpiles. The objective shall be to identify opportunities to optimize established information management systems that emphasize the reduction of these gaps in essential medicines availability necessary to enable pooling demand, regionally shared procurement of essential medicines, and their supply on an as-needed basis for both national domestic populations and for uninsured/transient populations.

References

World Health Organization. (2015). The Selection And Use Of Essential Medicines. Report Of The WHO Expert Committee, 2015 (Including The 19Th WHO Model List Of Essential Medicines And The 5th WHO Model List Of Essential Medicines For Children). WHO Technical Report Series 994. (1st ed.). World Health Organization. Retrieved from http://apps.who.int/iris/bitstream/10665/189763/1/9789241209946_eng.pdf?ua=1

Mainka, J. (2017). More dialogue, please: Interview with Minister Zoltán Balog. The Budapest Times. Retrieved from http://budapesttimes.hu/2017/04/09/more-dialogue-please/

Pharmaceutical Executive Editors. (2017). Country Report: Hungary. Pharmaceutical Executive, 36(8). Retrieved from http://www.pharmexec.com/country-report-hungary?pageID=1

United States Government Accountability Office. (2016). Drug Shortages Certain Factors Are Strongly Associated With This Persistent Public Health Challenge. GAO-16-595 (1st ed.). Washington, DC: GAO. Retrieved from http://www.gao.gov/assets/680/678281.pdf

The Multi-stakeholder Steering Committee on drug shortages in Canada. (2017). Preventing Drug Shortages: Identifying Risks and Strategies to Address Manufacturing-Related Drug Shortages in Canada (1st ed.). MSSC. Retrieved from https://www.drugshortagescanada.ca/files/MSSC_Causes_and_Prevention_2017.pdf

Yang, C., Wu, L., Cai, W., Zhu, W., Shen, Q., Li, Z., & Fang, Y. (2016). Current Situation, Determinants, and Solutions to Drug Shortages in Shaanxi Province, China: A Qualitative Study. PLOS ONE, 11(10), e0165183. http://dx.doi.org/10.1371/journal.pone.0165183

Ossola, A. (2015). The Fake Drug Industry Is Exploding, And We Can't Do Anything About It. Newsweek. Retrieved from http://www.newsweek.com/2015/09/25/fake-drug-industry-exploding-and-we-cant-do-anything-about-it-373088.html

Europol. (2015). Situation Report On Counterfeiting In The European Union (1st ed.). Europol. Retrieved from https://euipo.europa.eu/ohimportal/documents/11370/80606/2015+Situation+Report+on+Counterfeiting+in+the+EU

Safe Medicines. (n.d.). Counterfeit HIV Medication: Profitable for Criminals but Dangerous for Patients – Partnership for Safe Medicines. Safemedicines.org. Retrieved 12 May 2017, from http://www.safemedicines.org/counterfeit-hiv-medication-profitable-for-criminals-but-dangerous-for-patients

Kelesidis, T., & Falagas, M. (2015). Substandard/Counterfeit Antimicrobial Drugs. Clinical Microbiology Reviews, 28(2), 443-464. http://dx.doi.org/10.1128/cmr.00072-14

Almuzaini, T., Choonara, I., & Sammons, H. (2013). Substandard and counterfeit medicines: a systematic review of the literature. BMJ Open, 3(8), e002923. http://dx.doi.org/10.1136/bmjopen-2013-002923

European Medicines Agency. (2017). European Medicines Agency - Public health threats - Falsified medicines. Ema.europa.eu. Retrieved 12 May 2017, from http://www.ema.europa.eu/ema/index.jsp?

curl=pages/special_topics/general/general_content_000186.jsp

Europol. (2017). Two Turkish nationals arrested for smuggling counterfeit cancer drugs. Europol. Retrieved 12 May 2017, from https://www.europol.europa.eu/newsroom/news/two-turkish-nationals-arrested-for-smuggling-counterfeit-cancer-drugs

Campbell, H. (2017). Dangers of drug importation: A case of counterfeit cancer drugs. Catalyst.phrma.org. Retrieved 12 May 2017, from http://catalyst.phrma.org/dangers-of-drug-importation-a-case-of-counterfeit-cancer-drugs

FDA. (2017). Another counterfeit cancer medicine found in U.S. - Illegal practice puts patients at risk. Fda.gov. Retrieved 12 May 2017, from https://www.fda.gov/Drugs/DrugSafety/DrugIntegrityandSupplyChainSecurity/ucm298047.htm

Johnson, M. (2014). European Medicines Agency Warns Against Counterfeit Roche Drug. Outsourcedpharma.com. Retrieved 12 May 2017, from https://www.outsourcedpharma.com/doc/european-medicines-agency-warns-against-counterfeit-roche-drug-0001

The business case for more robust pre-clinical research

Tue, 12 Nov 2019 17:04:30 GMT

In the high consequence environment of pharmaceutical development, any assumption made earlier in the process can prove extremely costly if uncorrected once more information becomes available.

Compliance, IND submissions, and business incentives

The Food and Drug Administration (FDA) requires researchers to provide specific data about new drug candidates before the drug can to proceed to human clinical trials. The IND submission package includes preclinical data on animal pharmacology and toxicology as a proof that the drug candidate is reasonably safe for human trials; manufacturing information to ensure consistent quality of the product; and clinical protocols and investigator information. The application also includes information on clinical professionals and a commitment to obtain informed consent and a review by the institutional review board (Food and Drug Administration, 2017).

The pharmacology/toxicology package contains pharmacology studies, acute, subchronic and chronic toxicity studies, special toxicity, carcinogenicity, reproduction toxicity, mutagenicity and absorption, distribution, metabolism, and excretion (ADME) studies (Food and Drug Administration, 2017). This information generally comes from in vitro tests, computer modeling, and from experiments on laboratory animals. All experiments on animals in the U.S. have to conform to Part 58 of Title 21 of the Code of Federal Regulations Good Clinical Practice for Nonclinical Laboratory Studies (eCFR — Code of Federal Regulations, 2017).

From a business risk perspective, compliance and due diligence are the easy parts. The hard part is the predictive power of this information, whether or not the drug candidate has the potential to show safety and efficacy in clinical trials and obtain approval. There is a universal pressure to conduct these tests in the timeliest manner practicable, to pass the IND submission landmark. This step typically indicates the company's willingness to undertake a huge investment in clinical trials, without any guarantees of success. The impact of IND submission on stock price is typically neutral (Picardo, 2017).

The dropout rate is especially high for new molecular entities with the potential of becoming first-in-class. The dropout rate in phase III is especially worrying.

Publication bias in preclinical research

Reproducibility of preclinical research

The low reproducibility of preclinical research is an important source of assumptions made in the early stages of preclinical research. Freedman et al. (2015) argue that 50% of all preclinical research is irreproducible. Research that produces no useful results exceeds US$28 billion in the United States only. The reasons include study design, methodology, materials, reference standards and reagents used, laboratory protocols, and analysis and reporting (Freedman, Cockburn and Simcoe, 2015).

The predictive power of animal research data

Early failures

Phase III failures

Emerging technologies

Better times ahead?

The published materials seem to be a tip of the iceberg of extensive research that explores the potential of the technology in drug discovery and development. The reduction of attrition rate in clinical trials and especially in the advanced stages, requires a combination of technological solutions and organizational changes. Information without appropriate action is meaningless. To facilitate appropriate organizational response to new coming information that is likely to halt a high-value project, the perceptions, incentives, and motivators within R&D functions have to change to accommodate timely termination of a potentially costly project as a good outcome that is good for business rather than an individual or team failure.

References

Food and Drug Administration (2017). Drugs: Guidance, Compliance & Regulatory Information - Guidances (Drugs) - Pharmacology / Toxicology. [online] Food and Drug Administration. Available at: https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm065014.htm [Accessed 2 Jun. 2017].

Shanley, A. (2017). Preventing Phase III Failures. [online] Pharmtech.com. Available at: http://www.pharmtech.com/preventing-phase-iii-failures [Accessed 2 Jun. 2017].

World Health Organization (2017). ICTRP Search Portal. [online] Apps.who.int. Available at: http://apps.who.int/trialsearch/ [Accessed 1 Jun. 2017].

US. National Institute of Health (2017). Home - ClinicalTrials.gov. [online] Clinicaltrials.gov. Available at: https://clinicaltrials.gov/ [Accessed 1 Jun. 2017].

Wyss Institute (2017). Human Organs-on-Chips. [online] Wyss Institute. Available at: https://wyss.harvard.edu/technology/human-organs-on-chips/ [Accessed 2 Jun. 2017].

Freedman, L., Cockburn, I. and Simcoe, T. (2015). The Economics of Reproducibility in Preclinical Research. PLOS Biology, 13(6), p.e1002165.

Manning, F. and Swartz, M. (1995). Review of the Fialuridine (FIAU) clinical trials. 1st ed. Washington, DC: National Academy Press.

Attarwala, H. (2010). TGN1412: From Discovery to Disaster. Journal of Young Pharmacists, 2(3), pp.332-336.

European Medicines Agency (2017). European Medicines Agency - News and Events - Proposals to revise guidance on first-in-human clinical trials. [online] Ema.europa.eu. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/07/news_detail_002572.jsp&mid=WC0b01ac058004d5c1 [Accessed 1 Jun. 2017].

Abaci, H. and Shuler, M. (2015). Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling. Integr. Biol., 7(4), pp.383-391.

Hickman, J. (2016). Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs. Scientific Reports, 6(1).

Equitable and Economical Access to Effective Therapies (E3T)

Tue, 12 Nov 2019 15:53:48 GMT

Our motivation to organize and present the Czech Republic data profile is intentionally non-political. In regards to the quality of health services, the Czech Republic has progressed in the last 20 years and positive developments can be observed in all aspects of healthcare with a resulting increase in life expectancy. However, this success does burden public health system sustainability by increasing demand and corresponding costs of providing services.

Medications included in the World Health Organization's List of Essential Medicines (WHO EML) represent the most efficacious, safe and cost-effective treatment options available using a rigorous method for inclusion and exclusion. Many (if not most) developing countries adopted the list as is. In developed countries, it is indispensable for the treatment of conditions such as tuberculosis, malaria, leishmaniasis, plague, bacterial meningitis, common childhood conditions and many others.

Arete Zoe has developed a presentation to accompany the country report titled "Equitable and Economic access to Effective Therapies (E3T)" to explain how this can be used as one element in assessment and refinement of Public health approach, which differ from one country to another.

Modern healthcare should be set in evidence-based medicine, defined as the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. Most developed countries use some kind of Standard of Care, also called best practice, standard medical care, and standard therapy. Standard of Care is defined as “the caution that a reasonable person in similar circumstances would exercise in providing care to a patient.” The definition of “Best practice” for specific conditions is essential to ensure the consistent and measurable quality of care delivered to patients and limit the social and financial burden inflicted by the burden of disability. The standard of care is not necessarily always the most expensive solution available. Equitable and Economical access to Effective Therapies is a key to facilitate discourse for sustainable healthcare and a resilient society.

Population turbulence from migration is protracted or indirect, but cannot be dismissed as irrelevant and serves as both an exposure opportunity and vector for illnesses previously non-existent or effectively controlled. Restrictive immigration policies do not significantly reduce the potential because of mobility within the EU to countries with larger refugee populations. Discretionary vacation travel and citizens who may settle in another EU country for career choice continue returning to the country of origin.

The new reality of globalization forces an essential paradigm shift for the probability of disease occurrence and necessitates deliberate provisions for reliable access to these essential medications which are further challenged by pharmaceutical profit motives that reduce production in favor of newer drugs but with less adverse reaction histories.

References

World Health Organization. (2015). The Selection and Use of Essential Medicines. Report of the WHO Expert Committee, 2015 (including the 19th WHO Model List of Essential Medicines and the 5th WHO Model List of Essential Medicines for Children). WHO Technical Report Series No. 994 (1st ed.). World Health Organization. Retrieved from http://apps.who.int/iris/bitstream/10665/189763/1/9789241209946_eng.pdf

Eurosurveillance. (2017). Surveillance Atlas. Atlas.ecdc.europa.eu. Retrieved 27 May 2017, from http://atlas.ecdc.europa.eu/public/index.aspx?Instance=GeneralAtlas

Státní Ústav pro Kontrolu Léčiv. (2017). Státní ústav pro kontrolu léčiv. Sukl.cz. Retrieved 28 May 2017, from http://www.sukl.cz/

Moffett, P., & Moore, G. (2011). The Standard of Care: Legal History and Definitions: the Bad and Good News. Western Journal Of Emergency Medicine, 12(1), 109-112. http://dx.doi.org/PMC3088386

Otranto, D., Dantas-Torres, F., Brianti, E., Traversa, D., Petrić, D., Genchi, C., & Capelli, G. (2013). Vector-borne helminths of dogs and humans in Europe. Parasites & Vectors, 6(1), 16. http://dx.doi.org/10.1186/1756-3305-6-16

Štěpánek, í. (2017). Dovolená v roce 2015: nejistota za hranicemi, Češi objeví Česko - iDNES.cz. iDNES.cz. Retrieved 27 May 2017, from http://cestovani.idnes.cz/turisticke-trendy-pro-rok-2016-dij-/kolem-sveta.aspx?c=A151128_181235_kolem-sveta_hig

Connor, P. (2016). Illegal migration to EU rises for routes both well-worn and less-traveled. Pew Research Center. Retrieved 27 May 2017, from http://www.pewresearch.org/fact-tank/2016/03/18/illegal-migration-to-eu-rises-for-routes-both-well-worn-and-less-traveled/

Frontex. (2017). Risk Analysis for 2017 (1st ed.). Warsaw: Frontex. Retrieved from http://frontex.europa.eu/assets/Publications/Risk_Analysis/Annual_Risk_Analysis_2017.pdf

European Commission. (2016). Europe without borders The Schengen area (1st ed.). European Commission. Retrieved from http://ec.europa.eu/home-affairs/sites/homeaffairs/files/e-library/docs/schengen_brochure/schengen_brochure_dr3111126_en.pdf

MVČR. (2017). Aktuální statistiky - Aktuální informace o migraci. Mvcr.cz. Retrieved 27 May 2017, from http://www.mvcr.cz/migrace/clanek/aktualni-statistiky.aspx

NATO. (2017). Medical support. NATO. Retrieved 28 May 2017, from http://www.nato.int/cps/en/natohq/topics_49168.htm

Navy Medicine. (2017). Cite a Website - Cite This For Me. Navymedicine.navylive.dodlive.mil. Retrieved 28 May 2017, from http://navymedicine.navylive.dodlive.mil/files/2012/11/KAF-Role-3-OR_web.jpg

Strauss, D., & Thomas, J. (2009). What Does the Medical Profession Mean By “Standard of Care?”. Journal Of Clinical Oncology, 27(32), e192-e193. http://dx.doi.org/10.1200/jco.2009.24.6678

Migrant crisis: Migration to Europe explained in seven charts - BBC News. (2017). BBC News. Retrieved 31 May 2017, from http://www.bbc.com/news/world-europe-34131911

MVCR. (2017). Cizinci s povoleným pobytem - Ministerstvo vnitra České republiky. Mvcr.cz. Retrieved 31 May 2017, from http://www.mvcr.cz/clanek/cizinci-s-povolenym-pobytem.aspx

Hughes, R. (2008). Patient safety and quality. Rockville, MD: Agency for Healthcare Research and Quality.

Fatty liver and drug metabolism

Tue, 12 Nov 2019 09:06:14 GMT

Non-alcoholic fatty liver disease: the silent killer.

The incidence of non-alcoholic fatty liver disease (NAFLD) is rising. It is a common and often under-appreciated comorbidity in patients with obesity, insulin resistance, diabetes, metabolic syndrome, and cardiovascular disease. These patients are likely to be on multiple medications for prolonged periods. Drug uptake, distribution, metabolism, transport, and excretion change over time in patients with fatty liver.

The progression of NAFLD to NASH leads to changes in excretion and toxicity of drugs that are typically well-tolerated.

Liver biopsy remains the gold standard for the accurate diagnosis and definition of staging and grading relating to chronic liver disease. Liver biopsy provides information on the degree of fibrosis, inflammation, necrosis, and steatosis, and quantifies the amount of iron and copper in the parenchyma. Various grading systems are then used to evaluate the degree and stage of the disease and choose an appropriate management regime (Caviglia et al., 2014). The accurate assessment of chronic liver disease and its progression into fibrosis, cirrhosis, and hepatocellular carcinoma has been a continuing challenge. Non-invasive biomarkers in accessible fluids that correlate with type and extent of liver tissue damage and prognosis are of great interest to clinicians.

Insulin resistance and metabolic syndrome

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are referred to as fatty liver. Fatty liver is strongly associated with insulin resistance, diabetes mellitus, dyslipidemia, and hypertension, summarily known as metabolic syndrome. Adiponectines adiponectin, leptin, resistin, and visfatin are the most relevant indicators of metabolic syndrome. Hepatocellular apoptosis is one of the typical features of NASH. The laboratory clues include the increase in the messenger RNA expression of the adiponectin receptor (ApoR2). Inverse correlation between adiponectin and bile acids exists in NASH.

Proteohormone leptin that regulates food intake and energy expenditure reflects the total amount of body fat and is one of the indicators of insulin resistance. Ghrelin, a peptide produced by the stomach, influences insulin secretion and glucose and lipid metabolism. Ghrelin and retinol-binding protein 4 (RBP4) can also serve as indicators of insulin resistance. As such, adiponectines are useful biomarkers of metabolic syndrome, NAFLD, and its progression to NASH (Neuman, Cohen and Nanau, 2014).

Diagnosis of fatty liver (NAFLD and NASH)

Non-invasive tests and imaging have an increasing role in the diagnosis of NAFLD/NASH. BAAT score considers body mass index (BMI), age at liver biopsy, ALT, and serum triglycerides. It is used to identify patients who would most benefit from liver biopsy (Neuman et al., 2016).

Clinical parameters standardly evaluated in NAFLD/NASH patients include body mass index or waist circumference. Biochemical parameters include transaminase levels, gamma-glutamyl transferase, cholesterol, triglycerides, glucose, and C-peptide. Diagnostic indicators of insulin resistance in NASH are cytokines tumor necrosis factor (TNF) α and interleukin (IL)-6, CC-chemokine ligand-2 (chemo-attractant protein-1) and C-reactive protein (hs-CRP).

Complementary information can be gained from markers of cell death and mitochondrial dysfunction. These biomarkers include apolipoprotein A1 and B, leptin, adiponectin, free fatty acids, ghrelin, and cytokeratins. Initial stages of the disease only show minimum elevations in transaminases, ALP, and GGT. These biomarkers have to be evaluated in the context of other risk factors (Neuman, Cohen and Nanau, 2014).

Alcoholic liver disease (ALD)

Alcohol is one of the significant sources of oxidative stress. Alcoholic liver disease (ALD) develops as the consequence of oxidative stress associated with alcohol metabolism, glutathione depletion, abnormal metabolism of methionine, malnutrition, the release of intestinal endotoxins, and subsequent activation of Kupffer cells. Progression to the fatty liver through lipoperoxidation affects more than 90% of heavy drinkers. In about 30%, the disease progresses to fibrosis and cirrhosis (Gao and Bataller, 2011). Oxidative stress, one of the NAFLD risk factors, is detected by elevated plasma reactive carbonyl species levels and is assessed based on the balance of SOD2 antioxidant enzyme and cytochrome from the p450 family CYP2E1.

Free fatty acids are lipotoxic. The biological mechanism involved is the downregulation of mitochondrial beta-oxidation. Consequently, the accumulation of ceramides and diacylglycerol occurs (Neuman, Cohen and Nanau, 2014).

Liver biopsy and venous pressure gradient (HVPG) are the best measurements of disease severity. It also sheds light on the risk of complications such as bleeding, infections, ascites, encephalopathy and hepatocellular carcinoma. Additional options include transient elastography (Fibroscan), real-time shear wave elastography and MR elastography that can assess the whole liver and avoid sampling error (Karsdal et al., 2014).

Diagnostic performance of biomarkers

The most commonly used indirect serum markers are platelet count, coagulation factors, and transaminases. Direct markers reflect matrix turnover and include products of matrix synthesis or degradation. The most relevant markers include TNF-β, collagens (procollagen I C terminal, procollagen Ⅲ N terminal, procollagen Ⅳ C peptide and N peptide and collagen Ⅳ), tenascin, undulin, matrix metalloproteinases, urinary desmosine and hydroxylysypyridinoline (Chrostek, 2014).

The diagnostic performance of indirect non-invasive markers of liver fibrosis is evaluated by calculating the area under the receiver operating characteristic curve (AUROC). The plot shows the sensitivity and specificity of the tests (Schiavon, 2014). Commercially available plots include FibroTest (median AUROC in ALD 0.83), FibrometerA (0.83), Hepascore (0.83), Forns (0.38), APRI (0.59), FIB-4 (0.70), hyaluronic acid (0.79) and the algorithm combining PI, α-2 macroglobulin and hyaluronic acid (0.96). FibroTest, FibrometerA, and Hepascore showed the highest diagnostic accuracy, with prognostic values comparable to biopsy (Chrostek, 2014).

Chronic viral hepatitis

Hepatitis B (HBV)

The choice of antiviral therapy depends on stage and grade of the disease depending on serum ALT, HBV DNA, hepatitis B e antigen (HBeAg) status, and the level of hepatic necro-inflammation and fibrosis. Novel approaches include a variety of imaging techniques such as transient elastography, ultrasonography, computed tomography, and magnetic resonance imaging. No single marker can accurately measure fibrosis in HBV patients. Practitioners use a wide range of algorithms and combinations. The most relevant markers, according to Zeng et al., are platelet count, AST, and ALT, globin, serum HBsAg, ceruloplasmin, red blood cell distribution width, IL-2R, TGF-α and serum Golgi protein 73 (Zeng et al., 2016). Serum biomarkers used in HBV include haptoglobin, α-2 macroglobulin, apolipoprotein A1, GGT, total bilirubin, gamma globulin, AST, ALT, platelets, cholesterol, INR, albumin and bilirubin. Batteries of these tests are available commercially as Fibrotest, APRI, FIB-4, Forn’s, GUCI and Hui’s. Some of the diagnostic algorithms were developed as a measure of response to treatment (Branchi, 2014).

Hepatitis C (HCV)

Indirect serum biomarkers of liver fibrosis include routine liver function tests such as AST, ALT, GGT, platelet count, bilirubin, haptoglobin, apolipoprotein A1, and α-2 macroglobulin. The most common models for fibrosis estimation in hepatitis C are the AST/ALT ratio, AST-to-Platelet Ratio Index – APRI (median AUROC in HCV 0.77) and FIB-4 (0.74), Forns index (0.76) and Fibroindex (0.76) (Schiavon, 2014).

Fibrosis

Chronic liver diseases such as the progressive form of hepatitis C, NASH, autoimmune hepatitis, and primary biliary cirrhosis represent a significant risk of liver fibrosis. Non-invasive markers of NAFLD-induced fibrosis that correlate with high-risk of liver complications and death include NAFLD fibrosis score, AST/platelet ratio index, FIB-4 score, and BARD score. These markers are valuable when ruling out fibrosis in patients who would not benefit from liver biopsy (Neuman, Cohen, and Nanau, 2014). The NAFLD Fibrosis Score is designed to rule out advanced fibrosis based on age, hyperglycemia, BMI, platelet count, albumin, and AST/ALT ratio. Commercially available algorithms designed for staging and grading of the disease include Fib-4, FibroTest, NashTest, and SteatoTest (Neuman et al., 2016). Non-invasive direct biomarkers of liver fibrinogenesis indicate deposition or removal of extracellular matrix in the liver, while indirect markers reflect changes in processes induced by fibrosis. Direct markers include glycoproteins hyaluronic acid and laminin, collagens (type IV, type III and N-terminal peptide), matrix metalloproteinases, and cytokines TNF α and TGF β, in addition to standard liver function tests such as platelet count, alanine transaminases (ALT and AST), and AST-to-platelets ratio (APRI).

More sophisticated tests include Fibrotest (Bio-predictive), Forn’s index, and Hepascore (PathWest), in addition to imaging methods such as ultrasound-based elastography (Caviglia et al., 2014).

Stiffness is another indicator of liver fibrosis; however, obesity often prevents proper interpretation of the results. The use of transient elastography (FibroScan) XL probe, acoustic radiation force impulse (ARFI), proton magnetic resonance imaging (MRI), two-dimensional magnetic resonance elastography (2D MRI), and novel 3D MRI can further assist grading and staging of liver fibrosis (Neuman et al., 2016).

Metabolomics and proteomics in NAFLD/NASH

Additional markers can be identified using metabolomics and proteomics techniques. Metabolomics analysis shows an association of NAFLD with elevated glycocholate, taurocholate and glyco-cheno-deoxycholate as well as homocysteine and total cysteine and lower plasma glutathione. In NASH and steatosis, plasma levels of long-chain fatty acids and cysteine-glutathione were lower while the levels of several glutamyl dipeptides, free carnitine, butyrylcarnitine and methylbutyrylcarnitine were increased. Proteomic analysis shows that metabolic profile correlates with level of obesity. Proteins upregulated in NAFLD include afamin, apolipoprotein E, CD5 molecule-like, complement C3, insulin-like growth factorbinding protein 3, vitamin D-binding protein and lymphocyte cytosolic protein. Proteins upregulated in NASH are apolipoprotein E, catalase, CD5 molecule-like, lymphocyte cytosolic protein 1 and vitamin D-binding protein. Additional variants of metabolic and proteomic profile can be found in different ethnic groups (Neuman, Cohen and Nanau, 2014).

Inflammatory markers

Cytokines imbalance lead to liver injury through lipotoxicity and signaling processes. Lipopolysaccharides absorbed from the gut is transferred from the portal vein to the liver depends on gut microbiota. Inflammatory markers present in NAFLD/NASH include TNF-α, interleukin (IL)-6 and IL-8, matrix metalloproteinases and high-sensitivity C-reactive protein (hsCRP). Elevated levels of hyaluronic acid indicate advanced fibrosis and steatosis (Neuman et al., 2016).

Cell death markers

The most relevant markers of apoptosis are cytokeratin (CK)-18. The protein’s fragments can be detected in peripheral blood by immunoassay. The M30 assay, M65 and M65ED detect total cell death with varying range of sensitivity and specificity. Fibrosis patterns can be evaluated by immunostaining technique CK-7 that serves as an indicator of the number of hepatic progenitor cells and ductular reaction. Significantly higher caspase activity can be observed in patients with NASH (Neuman, Cohen and Nanau, 2014). Review of 15 studies in NASH patients shows that CK-18 fragments including M30 and M65 can be used to distinguish NASH from simple steatosis and assess disease progression. The levels of a liver-secret-hormone FGF-21 are significantly higher in patients with NAFLD, suggesting its potential value in the diagnosis of NAFLD/NASH. More data is needed to establish reference points and cut of values. These markers are not yet widely used in clinical practice due to technical and accuracy issues (He et al., 2017)

Cirrhosis

Patients with ALD or other chronic liver conditions often present only in final stages when they experience symptoms of bleeding and ascites. Identification of those at risk of fast progression can prevent and treat complications. Remodeling processes in cirrhotic liver lead to a release of a wide range of intracellular and extracellular proteins in the bloodstream. Neo-epitope based markers represent a unique fingerprint of this process and reflect the turnover of fibrotic tissue. Degradation products of type I collagen are used as indicators of bone resorption, multiple myeloma, and liver fibrosis. The diagnostic marker for liver fibrosis is PIIINP, a pro-peptide of type III collagen, which is cleaved off the pro-collagen during formation of mature collagen. PIIINP can be detected using monoclonal antibodies embedded into ELISA. A fragment of type III collagen (C3M) is a biomarker of inflammation-induced soft tissue turnover. Protein fingerprints have to be carefully interpreted in clinical context of full clinical picture (Karsdal et al., 2014).

Hepatocellular carcinoma (HCC)

High-risk factors for the development of HCC is chronic liver disease caused by HCV and HBV infection, chronic alcohol abuse, NAFLD/NASH, and progression to fibrosis, cirrhosis and eventually cancer. HCC tops the list of cancer-related mortality due to late diagnosis and limited treatment options for advanced stages of the disease. The most widely used biomarker for HCC is alphafetoprotein (AFP) that lacks the necessary sensitivity and specificity. Currently, advanced radiological surveillance methods are recommended for patients with chronic liver disease to detect HCC at time when tumor resection, ablation, transarterial chemoembolization and liver transplant are still possible (Kimhofer et al., 2015).

HCC biomarkers

Emerging biomarkers for HCC include the identification of proteins, peptides and metabolites in accessible bodily fluids, notably des-carboxy prothrombin, squamous cell carcinoma antigen–immunoglobulin M complexes, and chromogranin A. Bile acids (glycochenodeoxycholic acid, glycocholic acid, CA, and deoxycholic acid) are extensively studied as indicators of hepatic decompensation and a major source of oxidative stress.

Lysophosphatidylcholines (C16:0, LPC C18:0, and LPC C18:2) decrease in patients with HCC compared to cirrhosis. Metabolic changes affect also the synthesis and degradation of aminoacids, observable as a drop in branched chain aminoacids (leucine, isoleucine, and valine) and the increase in aromatic amino acids (tyrosine, phenylalanine, tryptophan and histidine). Creatinine and trimethylamine-N-oxide (TMAO) also drop in HCC patients. The best model appears to be scanning of the whole serum protein fraction using LC-MS (100% sensitivity and 100% specificity) and its reduced version based on scanning canavaninosuccinate and AFP (96.4% and 100%). Other promising biomarkers are propionylcarnitine and betaine, haptoglobin and fucosylated haemopexin. The full clinical picture has to be considered because biochemical markers of a minor tumor on extensively cirrhotic liver differ substantially from a large tumor on the background of mild cirrhosis (Kimhofer et al., 2015).

Validation of biomarkers

There is an increasing need for classification of biomarkers to facilitate their use and interpretation. Non-invasive markers of fibrosis are validated against the gold standard tool, which is a liver biopsy. However, equivocal results can be expected in about a third of biopsy specimens. (Duarte-Rojo, Altamirano and Feld, 2012). The osteoarthritis (OA) Biomarkers Network, funded by the US National Institutes of Health (NIH), proposed the BIPED approach to classification of biomarkers. The classification takes into account burden of disease, and investigative, prognostic and diagnostic attributes in addition to the efficacy of the intervention. Similarly, in liver fibrosis, an imprecise gold standard makes the validation of non-invasive markers challenging (Karsdal et al., 2014). Non-invasive biomarkers may, in fact, better reflect the true progression of the disease than a liver biopsy and must be assessed in longitudinal studies for predictive value in clinical outcomes (Duarte-Rojo, Altamirano and Feld, 2012).

Conclusion

Many critical gaps still exist for the evaluation of chronic liver disease and its progression. Non-invasive biomarkers are being developed to detect progression of liver damage, select appropriate treatment strategies, and measure response to treatment. Biomarkers also help avoid liver biopsy in patients in whom advanced stages of the liver disease can be excluded and who would not benefit from the additional information provided by the procedure. A reference library of normal values of various tests in different population subgroups, including ethnic groups and patients with comorbidities, needs to be developed to make these new tests useful in clinical practice. Validation of biomarkers remains a major challenge, making their utilization in establishing safety profiles of medications in patients with NAFLD/NASH especially challenging.

References

Caviglia, G., Touscoz, G., Smedile, A. and Pellicano, R. (2014). Noninvasive assessment of liver fibrosis: key messages for clinicians. Polish Archives of Internal Medicine, 124(6), pp.329-335.

Neuman, M., Cohen, L. and Nanau, R. (2014). Biomarkers in nonalcoholic fatty liver disease. Can J Gastroenterol Hepatol, [online] 28(11), pp.607-18.

Neuman, M., Voiculescu, M., Nanau, R., Maor, Y., Melzer, E., Cohen, L., Opris, M. and Malnick, S. (2016). Non-Alcoholic Steatohepatitis: Clinical and Translational Research. Journal of Pharmacy & Pharmaceutical Sciences, [online] 19(1), p.8.

Gao, B. and Bataller, R. (2011). Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets. Gastroenterology, 141(5), pp.1572-1585.

Karsdal, M., Krarup, H., Sand, J., Christensen, P., Gerstoft, J., Leeming, D., Weis, N., Schaffalitzky de Muckadell, O. and Krag, A. (2014). Review article: the efficacy of biomarkers in chronic fibroproliferative diseases - early diagnosis and prognosis, with liver fibrosis as an exemplar. Alimentary Pharmacology & Therapeutics, 40(3), pp.233-249.

Chrostek, L. (2014). Liver fibrosis markers in alcoholic liver disease. World Journal of Gastroenterology, 20(25), p.8018.

Schiavon, L. (2014). Non-invasive diagnosis of liver fibrosis in chronic hepatitis C. World Journal of Gastroenterology, 20(11), p.2854.

Zeng, D., Dong, J., Liu, Y., Jiang, J. and Zhu, Y. (2016). Noninvasive models for assessment of liver fibrosis in patients with chronic hepatitis B virus infection. World Journal of Gastroenterology, 22(29), p.6663.

Branchi, F. (2014). Non-invasive assessment of liver fibrosis in chronic hepatitis B. World Journal of Gastroenterology, 20(40), p.14568.

He, L., Deng, L., Zhang, Q., Guo, J., Zhou, J., Song, W. and Yuan, F. (2017). Diagnostic Value of CK-18, FGF-21, and Related Biomarker Panel in Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. BioMed Research International, 2017, pp.1-12.

Kimhofer, T., Fye, H., Taylor-Robinson, S., Thursz, M. and Holmes, E. (2015). Proteomic and metabonomic biomarkers for hepatocellular carcinoma: a comprehensive review. British Journal of Cancer, 112(7), pp.1141-1156.

Duarte-Rojo, A., Altamirano, J. and Feld, J. (2012). Noninvasive markers of fibrosis: key concepts for improving accuracy in daily clinical practice. Ann Hepatol, 11(4), pp.426-39.

The long way to clinically actionable pharmacogenomic biomarkers

Sat, 09 Nov 2019 20:36:15 GMT

The practical aspects of precision medicine

The impact of cytochromes P450 (CYP450) variability on drug metabolism and drug interactions is well known and long recognized in the community of medical and pharmaceutical professionals as a significant contributor to avoidable patient casualty (1). Many active pharmaceutical ingredients are known for being substrates, inducers, and inhibitors of CYP450 enzymes. Some CYP450s are highly polymorphic, namely CYP2C9, CYP2C19, and CYP2D6 (1). Three classes of drugs account for most adverse events: Anticoagulants, opioid analgesics, and antidiabetics (2, 3).

Well-documented concern, limited clinical use

Information about pharmacogenomic biomarkers is listed in U.S. drug labels. The labels describe drug interactions with germline or somatic gene variants (polymorphisms, mutations), functional deficiencies with a genetic etiology, gene expression differences, chromosomal abnormalities, and selected proteins used for treatment selection (4). Some healthcare facilities already offer PGX testing to their patients, e.g., CYP2C9 and VKORC1, to better predict response to warfarin and adjust dosing (5).

Institute of molecular biology and bioinformatics Charite, Berlin, published a comprehensive database of about 1.170 drugs, 2.785 cytochrome-drug interactions, and about 1.200 alleles (6, 7). For example, Plavix (clopidogrel) has a boxed warning that the drug should not be given to CYP2C19 poor metabolizers (8). Zocor (simvastatin) label contains information that the drug must not be taken concomitantly with CYP3A4 inhibitors (9).

However, the widespread and routine testing of patients for CYP450 polymorphism and other genetic biomarkers is still a matter of the future. Even for drugs where the drug-CYP interactions are well known, only a small minority of patients undergo testing before prescription (10). In some cases, a minor delay in treatment is not a concern (e.g., SLCO1B1 genotype and risk for myopathy with simvastatin).

In other instances, a delay would be highly problematic. A patient's ultra-rapid or extensive metabolism needs to be available in real-time to ensure the safe administration of clopidogrel for the acute coronary syndrome (11).

Two main approaches are employed in pharmacogenetics testing: preemptive testing upon enrollment in a plan or registration, or point-of-care testing. Studies that would compare adverse event incidence and severity in profiled and non-profiled groups would be necessary to prove cost-effectiveness in terms of patient outcome, prevented patient injury, illness severity scores, and other attributes.

Genomic and metabolomics data as a part of medication selection and treatment schedules are becoming increasingly relevant in emergency medicine as well. Conditions like sepsis, acute respiratory distress syndrome (ARDS), acute kidney injury, and delirium are inherently protean, and their manifestation in individual patients is very heterogeneous (12). There is no clinical guidance that would stratify patients into treatment bundles by their genetic makeup despite extensive research into genetic polymorphism in sepsis. Currently, most omics-based tests are too slow to guide clinical decision-making in the ICU (12).

Barriers and challenges

The current main barriers in PGX testing at point-of-care include limited physician knowledge, delays in care, incidental findings, ambiguous interpretation, and the inability to prove cost-effectiveness in terms of prevented drug-related injuries (11). Physician education is essential for the successful utilization of PGX in clinical practice. Physicians often dismiss direct-to-consumer testing obtained by patients as inaccurate or irrelevant (11). One of the limitations is that the predicted phenotype cannot always be established from the detected genotype. The relationship between genotype and phenotype is established for CYP2D6. For 2D6, the extensive, normal, poor, intermediate, and ultrarapid metabolizers are well-defined. The same is, however, not the case for e.g., CYP1A2, CYP3A4, and CYP3A5 (13).

Pharmacogenomic Biomarkers in U.S. drug labeling

Over 350 PGX biomarkers have been identified in FDA-approved drug labelling of which 112 are considered actionable and 16 informative (14).

Actionable PGX biomarkers where clinical guidelines exist ( CPIC, 2019 )

References

(1) Johansson I, Ingelman-Sundberg M. Genetic Polymorphism and Toxicology—With Emphasis on Cytochrome P450. Toxicological Sciences. 2010;120(1):1-13.

(2) U.S. Department of Health and Human Services, Office of Disease Prevention and Health Promotion. National Action Plan for Adverse Drug Event Prevention [Internet]. Washington, DC: U.S. Department of Health and Human Services, Office of Disease Prevention and Health Promotion; 2014 [cited 17 August 2017]. Available from: https://health.gov/hcq/pdfs/ade-action-plan-508c.pdf

(3) Health Research & Educational Trust. Adverse Drug Events Change Package: 2017 Update [Internet]. Chicago, IL: Health Research & Educational Trust (February 2017). Adverse Drug Events Change Package: 2017 Update. Chicago, IL: Health Research & Educational Trust. Accessed at www.hret-hiin.org.; 2017 [cited 17 August 2017]. Available from: http://www.hret-hiin.org/Resources/ade/17/ADE_ChangePackage-508.pdf

(4) FDA. Table of Pharmacogenomic Biomarkers in Drug Labeling [Internet]. Fda.gov. 2017 [cited 31 August 2017]. Available from: https://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm

(5) Mayo Clinic. CYP2C9 & VKORC1/warfarin Pharmacogenomic Lab Test - Mayo Clinic Center for Individualized Medicine [Internet]. Mayoresearch.mayo.edu. [cited 17 August 2017]. Available from: http://mayoresearch.mayo.edu/center-for-individualized-medicine/cyp2c9-vkorc1-warfarin.asp

(6) Institute of molecular biology and bioinformatics. SuperCYP [Internet]. Bioinformatics.charite.de. [cited 17 August 2017]. Available from: http://bioinformatics.charite.de/supercyp/index.php?site=home

(7) Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D et al. SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Research. 2009;38(suppl_1):D237-D243.

(8) BMS. PLAVIX® (clopidogrel bisulfate) tablets, for oral use, Initial U.S. Approval: 1997 [Internet]. BMS; 2016 [cited 17 August 2017]. Available from: http://packageinserts.bms.com/pi/pi_plavix.pdf

(9) Merck. ZOCOR (simvastatin) Tablets Initial U.S. Approval: 1991 [Internet]. Merck; 2015 [cited 17 August 2017]. Available from: https://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf

(10) Simoons M, Mulder H, Schoevers R, Ruhé H, van Roon E. Availability of CYP2D6 genotyping results in general practitioner and community pharmacy medical records. Pharmacogenomics. 2017;18(9):843-851.

(11) Haga, S., & Moaddeb, J. (2014). Comparison of delivery strategies for pharmacogenetic testing services. Pharmacogenetics And Genomics, 24(3), 139-145. http://dx.doi.org/10.1097/fpc.0000000000000028

(12) Maslove D, Lamontagne F, Marshall J, Heyland D. A path to precision in the ICU. Critical Care. 2017;21(1).

(13) Eum S, Lee A, Bishop J. Pharmacogenetic tests for antipsychotic medications: clinical implications and considerations. Dialogues in Clinical Neuroscience [Internet]. 2016 [cited 2 September 2017];18(3):323–337. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067149/

(14) FDA. Table of Pharmacogenomic Biomarkers in Drug Labeling [Internet]. Fda.gov. 2017 [cited 31 August 2017]. Available from: https://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm

(15) Genes-Drugs [Internet]. Cpicpgx.org. 2017 [cited 2 September 2017]. Available from: https://cpicpgx.org/genes-drugs/

Redesigning Post-Market Drug Safety Surveillance

Sat, 09 Nov 2019 19:08:43 GMT

Existing pharmacovigilance post-market surveillance system relies on reporting of adverse drug reactions to national databases in real-time and post-marketing safety studies. Quantitative evaluation of incidence, prevalence trends, and patterns of use from reporting data is problematic due to under-reporting and missing data on exposure. The absence of rates of occurrence is especially problematic if drugs are used off-label, in populations they were not intended for, or in combination with other medications.

The access rights to EudraVigilance reports differ for individual stakeholders. The publicly accessible part of the database allows access to summaries by product and active substance. Adverse effect reporting in the U.S. is mandatory for manufacturers and distributors but voluntary for medical personnel and consumers. In Europe, a detailed description of the pharmacovigilance system, including a risk management plan where appropriate, is part of every application for market authorization. Since the passage of the FDA Amendments Act of 2007 (FDAAA), the FDA has the authority to mandate Risk Evaluation and Mitigation Strategies (REMS), post-approval studies, and post-market surveillance studies under the Section 522 to evaluate known and emerging serious risks of approved drugs. Penalties for delays can include fines, warning letters, and withdrawal of a product deemed misbranded.

Market Authorization Holders are now encouraged to implement multi-regional PASS as part of post-market surveillance activities. The objective of conducting post-authorization safety studies (PASS) is to gather additional safety information, assess patterns of drug utilization, to measure the effectiveness of a risk minimization activity. The responsibility for the evaluation of post-market drug safety surveillance belongs to the Center for Drug Evaluation & Research (CDER). The main limitations of pre-approval clinical trials are population size, short duration, inclusion and exclusion criteria, narrow scope, and the use of concomitant medications.

Patients with complex conditions are typically not enrolled. The objective of post-market surveillance is to detect less frequent adverse drug experiences. The system should also define patient populations that are at higher risk of developing Adverse Drug Events and determine safety during long-term use. Additional objectives include the detection of drug-drug and drug-food interactions, increased severity or frequency of known Adverse Drug Events, issues with misuse and abuse, and medication errors.

The main limitations of the current reporting system are under-reporting (estimated 1-10%), reporting bias, and varying quality of reports and duplication of case reports. The system does not collect information on incidence and prevalence because the numerator is uncertain, and the denominator can only be projected from drug utilization data.

Signal detection methods in pharmacovigilance

PMS – post-market surveillance, ICSR – individual case safety report, PSUR – periodic safety update report, NI studies – non-interventional studies, PASS – post-authorization safety studies

Signal detection in drug safety relies heavily on the review of individual case reports and case series and disproportionality analysis of data reported ADR databases. The creation of other signal detection methods besides disproportionality statistics is a matter for ongoing research. The foundational concept for many disproportionality methods is the proportional reporting ratio (PRR), which means the degree of disproportionate reporting of an adverse event for a product of interest compared to this same event for all other products in the database. The statistical association does not imply causality. Change-point analysis (CPA) detects changes in either the slope or variability in a time series or sequence in vast databases. Text mining is used to analyze unstructured data.

Post-market safety events as a public health challenge

The difference between pharmacovigilance and quality management systems in inpatient and outpatient healthcare settings is the nature and purpose of the information collected. While pharmacovigilance systems are designed to collect data on adverse drug reactions, the quality management systems were developed to collect information that measures the quality of care, which is all adverse experiences relating to drugs, including transcribing and dispensing errors. The highest number of adverse drug events in inpatient settings are attributed to insulins, anticoagulants, and opioid analgesics.

Adverse Drug Events: "All harms that occur during medical care directly caused by the drug including medication errors, ADRs, allergic reactions, and overdoses"

Adverse Drug Reaction: "Harm directly caused by a drug at normal doses."

Medication Error: "Inappropriate use of a drug that may or may not result in harm."

System responsiveness: safety withdrawals

In the period from 2001 to 2010, the FDA approved 183 novel pharmaceuticals and 39 biologics. One-third of the newly approved therapeutics was affected by at least one post-market safety event: 3 withdrawals, 61 boxed warnings, and 59 safety communications. The most affected groups were psychiatric medications and biologics.

Onakpoya and colleagues identified 462 products that were withdrawn for safety reasons in the period from 1950 to 2014 in at least one country. The team also evaluated the quality of evidence that led to these withdrawals. In 72% of cases, the supporting evidence that led to market withdrawal consisted of anecdotal reports (level 4). Less than 10% of the identified products were withdrawn worldwide, and 39% in one country only. The authors argue that there is insufficient research into the evidence that leads to market withdrawals. The interval between first detection and authorization withdrawal did not significantly shorten since 1953.

Level 4 evidence is routinely used to make high-impact decisions, including product withdrawals. The average time from the detection of a safety signal to eventual product withdrawal on safety grounds is six years. This time lag did not substantially improve since the 1950s.

Post-authorization safety studies

The FDA may require a post-approval study as a condition of a premarket approval (PMA), humanitarian device exception (HDE), or product development protocol (PDP) application. The objective of such a study is to ensure continued safety and efficacy of marketed drugs, biologics, and devices. Post-marketing commitments (PMCs) are studies or clinical trials that a sponsor has agreed to conduct after the product launch. Post-marketing requirements (PMRs) are studies that are required under the law. These studies can be mandated under FDAAA can be required to assess a known serious relating to the use of the drug, assess signals of serious risk, and identify unexpected serious risks.

Post-marketing studies/clinical trials of drugs approved under the accelerated approval program (Accelerated approval requirements: 21 CFR 314.510 and 21 CFR 601.41)
Deferred pediatric studies required under the Pediatric Research Equity Act (21 CFR 314.55(b); 601.27(b)
Studies/clinical trials under the Animal Efficacy Rule (21 CFR 314.610(b)(1) and 601.91(b)(1))
Drugs: Database of post-approval drug studies lists 306 ongoing PMC and PMR studies
Devices: Database of post-approval studies of medical devices contains 248 studies

As of December 20, 2017, 874 Phase IV, Observational studies were listed in the ClinicalTrial.gov registry. Results are available in a mere 69 of the 626 completed studies and for 11 of the 61 terminated studies. The situation is very similar for interventional studies. Of the more than 23.000 phase IV interventional studies found in the database, only less than 4000 have results available to the public. The majority of post-marketing studies do not have published results at all, or the results come long after completion of the study.

Real-World Evidence (RWE) that is of sufficient quality will enhance the information environment in the post-authorization phase of the drug life cycle and augment understanding of the benefit-risk profile of marketed drugs.

References

Cochrane Training. GRADE approach to evaluating the quality of evidence: a pathway | Cochrane Training. Trainingcochraneorg. 2017. Available at: http://training.cochrane.org/path/grade-approach-evaluating-quality-evidence-pathway. Accessed December 21, 2017.

Oxford Centre for Evidence-based Medicine. Oxford Centre for Evidence-based Medicine - Levels of Evidence (March 2009) - CEBM. CEBM. 2017. Available at: http://www.cebm.net/blog/2009/06/11/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/. Accessed December 20, 2017.

Food and Drug Administration. Postmarketing Requirements and Commitments: Introduction. Fdagov. 2017. Available at: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/. Accessed December 21, 2017.

Food and Drug Administration. Post-Approval Studies. Fdagov. 2017. Available at: https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/PostApprovaStudies/default.htm. Accessed December 21, 2017.

Food and Drug Administration. Postmarket Requirements and Commitments. Accessdatafdagov. 2017. Available at: https://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm. Accessed December 21, 2017.

Food and Drug Administration. Post-Approval Studies (PAS). Accessdatafdagov. 2017. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma_pas.cfm. Accessed December 21, 2017.

NIH U.S. National Library of Medicine. Search of: Observational Studies | Phase 4 - List Results - ClinicalTrials.gov. Clinicaltrialsgov. 2017. Available at: https://clinicaltrials.gov/ct2/results?age_v=&gndr=&type=Obsr&rslt=&phase=3&Search=Apply. Accessed December 20, 2017.

NIH U.S. National Library of Medicine. Search of: Interventional Studies | Phase 4 - List Results - ClinicalTrials.gov. Clinicaltrialsgov. 2017. Available at: https://clinicaltrials.gov/ct2/results?age_v=&gndr=&type=Intr&rslt=&phase=3&Search=Apply. Accessed December 20, 2017.

Downing N, Shah N, Aminawung J et al. Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010. JAMA. 2017;317(18):1854. doi:10.1001/jama.2017.5150.

Onakpoya I, Heneghan C, Aronson J. Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature. BMC Medicine. 2016;14(1). doi:10.1186/s12916-016-0553-2.

Health Research & Educational Trust. Adverse Drug Events Change Package: 2017 Update. Chicago, IL: Health Research & Educational Trust; 2017. Available at: http://www.hret-hiin.org/Resources/ade/17/ADE_ChangePackage-508.pdf. Accessed December 21, 2017.

U.S. Department of Health and Human Services, Office of Disease Prevention and Health Promotion. National Action Plan For Adverse Drug Event Prevention. Washington, D.C.: U.S. Department of Health and Human Services, Office of Disease Prevention and Health Promotion.; 2014. Available at: https://health.gov/hcq/pdfs/ADE-Action-Plan-508c.pdf. Accessed December 21, 2017.

European Medicines Agency. Pharmacovigilance - Signal management. Emaeuropaeu. 2017. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000587.jsp. Accessed December 18, 2017.

European Medicines Agency. EMA/849944/2016 Screening For Adverse Reactions In Eudravigilance. European Medicines Agency; 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/12/WC500218606.pdf. Accessed December 18, 2017.

Duggirala H. Data Mining at FDA. Fdagov. 2017. Available at: https://www.fda.gov/ScienceResearch/DataMiningatFDA/ucm446239.htm#textmining. Accessed December 18, 2017.

Food and Drug Administration. Questions and Answers on FDA's Adverse Event Reporting System (FAERS). Fda.gov. 2017. Available at: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/. Accessed December 17, 2017.

European Medicines Agency. European Medicines Agency - EudraVigilance - EudraVigilance system overview. Emaeuropaeu. 2017. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000166.jsp. Accessed December 17, 2017.

World Health Organization. Open Access to the WHO Global Pharmacovigilance Data base. World Health Organization. 2017. Available at: http://www.who.int/medicines/news/glob_pharmvig_database_qa/en/. Accessed December 17, 2017.

World Health Organization. Minimum Requirements For A Functional Pharmacovigilance System. World Health Organization; 2010. Available at: http://www.who.int/medicines/areas/quality_safety/safety_efficacy/PV_Minimum_Requirements_2010_2.pdf. Accessed December 17, 2017.

World Health Organization. WHO Pharmacovigilance Indicators A Practical Manual For The Assessment Of Pharmacovigilance Systems. Geneva, Switzerland: World Health Organization; 2015. Available at: http://apps.who.int/medicinedocs/documents/s21970en/s21970en.pdf. Accessed December 17, 2017.

World Health Organization. VigiAccess. Vigiaccessorg. 2017. Available at: http://www.vigiaccess.org/. Accessed December 17, 2017.

Food and Drug Administration. FDA Adverse Event Reporting System (FAERS): Latest Quarterly Data Files. Fdagov. 2017. Available at: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm082193.htm. Accessed December 17, 2017.

Food and Drug Administration. FDA Adverse Events Reporting System (FAERS) Public Dashboard. Fdagov. 2017. Available at: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm070093.htm. Accessed December 17, 2017.

European Medicines Agency. European Medicines Agency - EudraVigilance - Access to EudraVigilance data. Emaeuropaeu. 2017. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000674.jsp&mid=WC0b01ac0580a69390. Accessed December 17, 2017.

European Medicines Agency. European database of suspected adverse drug reaction reports - Search. Adrreportseu. 2017. Available at: http://www.adrreports.eu/en/search_subst.html#. Accessed December 17, 2017.

Food and Drug Administration. Reporting Serious Problems to FDA. Fdagov. 2017. Available at: https://www.fda.gov/Safety/MedWatch/HowToReport/default.htm. Accessed December 17, 2017.

European Medicines Agency. European Medicines Agency - Post-authorisation - Pharmacovigilance: post-authorisation. Emaeuropaeu. 2017. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001819.jsp&mid=WC0b01ac05800241de. Accessed December 17, 2017.

Food and Drug Administration. FDA Basics Webinar: A Brief Overview of Risk Evaluation and Mitigation Strategies (REMS). Fdagov. 2017. Available at: https://www.fda.gov/AboutFDA/Transparency/Basics/ucm325201.htm. Accessed December 17, 2017.

Food and Drug Administration. Post-Approval Studies (PAS). FDAgov. 2017. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma_pas.cfm. Accessed December 17, 2017.

Food and Drug Administration. 522 Postmarket Surveillance Studies. Accessdatafdagov. 2017. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pss.cfm. Accessed December 17, 2017.

Food and Drug Administration. CFR - Code of Federal Regulations Title 21. Accessdatafdagov. 2017. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm. Accessed December 17, 2017.

Food and Drug Administration. Notice to Industry: Postmarketing Requirements - Postmarket studies and clinical trials. Fdagov. 2017. Available at: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm292758.htm. Accessed December 18, 2017.

Food and Drug Administration. FDA's Sentinel Initiative. Fdagov. 2017. Available at: https://www.fda.gov/Safety/FDAsSentinelInitiative/ucm2007250.htm. Accessed December 21, 2017.

Nevo N. FDA Post-Marketing Drug Safety Surveillance. 2017.

Cómo responder a los cambios en un mundo en constante evolución

Sat, 09 Nov 2019 18:13:10 GMT

Los procesos en la empresa del descubrimiento, desarrollo y comercialización de drogas están en constante evolución, para adecuarse a las nuevas exigencias reglamentarias, cambiar las prioridades del negocio y a nuevas tecnologías.

Fusiones, adquisiciones, reorganizaciones

Productividad de I&D Farmacéutica

La flexibilidad del personal y la reducción de costos se encuentran entre las ventajas más comúnmente citadas de la tercerización. Las desventajas, sin embargo, pueden ser devastadoras a largo plazo, debido a la disolución de equipos especializados y al debilitamiento de la comunidad nacional de investigación. La experiencia compleja de multi-especialidad, requerida para perseguir con éxito una carrera en el desarrollo de fármacos tarda décadas en construirse. Las complejidades de la gestión y las limitaciones geográficas pueden eclipsar fácilmente las ventajas de la tercerización de la I&D. (Ebnesajjad in Chemical Manufacturing Excellence, 2017).

Uno de los principales problemas es la validez predictiva de las tecnologías de tamizaje y los modelos predictivos de enfermedades, incluyendo los modelos animales. Desafortunadamente, en la realidad la toma de decisiones organizacionales a menudo prioriza los datos que muestran resultados medibles y concretos sobre aquellos datos que son cualitativos pero poco claros y más complejos de presentar y comprender, aunque sean más importantes en su efecto final (Scannell and Bosley, 2016).

Source: Scannell JW, Bosley J (2016) When Quality Beats Quantity: Decision Theory, Drug Discovery, and the Reproducibility Crisis. PLoS ONE 11(2): e0147215. https://doi.org/10.1371/journal.pone.0147215

La toma de decisiones en el largo y complejo proceso del desarrollo de fármacos depende de la exactitud, fiabilidad y reproducibilidad de la información científica que se suministra a los responsables de la toma de decisiones, junto con los datos sobre el costo de "unidad de conocimiento". De hecho, los actuales fármacos-candidatos tienen más probabilidades de fracasar en los ensayos clínicos que los fármacos probados en los años setenta. Los fracasos tardíos con alto costo (por ejemplo, en Alzheimer) son en gran parte los culpables de esta tendencia. Derek Lowe argumenta que la crisis en la reproducibilidad no es fácil de superar y las ganancias y eficiencias del actual modelo industrial del descubrimiento de fármacos son ilusorias (In the Pipeline, 2016).

La industria también se enfrenta a una crisis en el acceso al talento científico, tanto local como global. La escasez de mano de obra calificada abarca todas las fases del desarrollo de fármacos, desde la ciencia básica y el descubrimiento de fármacos hasta el monitoreo de los ensayos clínicos.

La división geográfica entre las partes individuales del proceso, la sobre-especialización y la difícil transición entre las funciones dentro de la misma empresa contribuyen a la escasez de personal calificado y de proveedores. La incapacidad para atraer, entrenar al estándar, y retener talento en funciones críticas es uno de los desafíos clave que la industria está enfrentando hoy en día (Morgan, goBalto, Inc., 2016 and Ed Miseta, Clinical Leader, 2016)

Las nuevas tecnologías como la bioinformática, la utilización de la inteligencia artificial en la seguridad de los fármacos, la fármaco-genómica clínica, la selección de bio-marcadores o la utilización de datos del mundo real en la investigación para nombrar unos pocos, están transformando la cara de la medicina y del desarrollo de fármacos de maneras que eran inimaginables hace una década. Se requiere un cambio en la adquisición y retención del talento para asegurar la fluidez funcional operacional de la actual gestión del ciclo de vida de las farmacéuticas, y para aumentar la capacidad de explorar las posibilidades traídas por las nuevas tecnologías e incorporarlas con éxito en su función empresarial.

La respuesta lógica e intuitiva a la actual crisis de I&D es un muy necesario cambio en la manera como la industria busca, adquiere, retiene, entrena y desarrolla a personal talentoso y capacitado.

Continuará.

References:

Visnji, M. (2019). Pharma Industry Merger And Acquisition Analysis 1995 To 2015. Retrieved 9 November 2019, from https://revenuesandprofits.com/pharma-industry-merger-and-acquisition-analysis-1995-to-2015/

Haucap, J., & Stiebale, J. (2016). Research: Innovation Suffers When Drug Companies Merge. Retrieved 9 November 2019, from https://hbr.org/2016/08/research-innovation-suffers-when-drug-companies-merge

European Commission. (2000). Case No COMP/M.1846 - GLAXO WELLCOME / SMITHKLINE BEECHAM. REGULATION (EEC) No 4064/89 MERGER PROCEDURE. Luxembourg: Official Publications of the European Communities. Retrieved from https://ec.europa.eu/competition/mergers/cases/decisions/m1846_en.pdf

Ebnesajjad, S. (2017). Outsourcing Pharmaceutical Research and Development – pros and cons. Retrieved 9 November 2019, from https://chemical-materials.elsevier.com/chemical-manufacturing-excellence/outsourcing-pharmaceutical-research-development-pros-cons/

Scannell, J., & Bosley, J. (2016). When Quality Beats Quantity: Decision Theory, Drug Discovery, and the Reproducibility Crisis. PLOS ONE, 11(2), e0147215. doi: 10.1371/journal.pone.0147215

Lowe, D. (2016). A Terrific Paper on the Problems in Drug Discovery. Retrieved 9 November 2019, from https://blogs.sciencemag.org/pipeline/archives/2016/02/18/a-terrific-paper-on-the-problems-in-drug-discovery

Morgan, C. (2016). Are Delays in Clinical Trials Due to a Lack of Experienced CRAs? - Drug Discovery and Development. Retrieved 9 November 2019, from https://www.drugdiscoverytrends.com/are-delays-in-clinical-trials-due-to-a-lack-of-experienced-cras/

Miseta, E. (2019). Clinical Staff Shortage “Growing Plague” For Pharma CROs. Retrieved 9 November 2019, from https://www.clinicalleader.com/doc/clinical-staff-shortage-growing-plague-for-pharma-cros-0001

The time has come to develop pharmacogenomic guideline for oxycodone.

Mon, 04 Nov 2019 01:20:16 GMT

CYP2D6 interaction with oxycodone is well established and should be considered as a likely contributing factor in overdose deaths.

Adverse drug events account for an estimated one-third of hospital adverse events and approximately 280,000 hospital admissions annually. Three types of Adverse drug events were selected as high-priority targets as common, clinically significant, preventable, and measurable: Anticoagulants (primary concern: bleeding), diabetes agents (primary concern: hypoglycemia) and opioids (primary concern: accidental overdoses, oversedation, and respiratory depression) [1],[2]. Anticoagulants, antidiabetic agents, and opioid analgesics are responsible for ~60% of emergency department visits for adverse drug events among older adults [3].

According to the Center for Disease Control and Prevention, the most common drugs involved in prescription opioid overdose deaths were Methadone, Oxycodone, and Hydrocodone [4]. Of more than 63,000 overdose deaths that occurred in the U.S. in 2016, two thirds (42,249) involved an opioid. This number includes prescription opioids, illicit opioids or both. It is often difficult to distinguish between prescription opioids taken as prescribed, prescription opioids that were diverted or abused, and illicit opioids [5]. Because of the risk of abuse, misuse, addiction and potentially lethal overdose, opioid analgesics are subject to Risk Evaluation and Mitigation Strategy (REMS) . Key components of the REMS program are prescriber training and providing educational materials for patients [6].

The role of Cytochrome P450 in drug metabolism

The cytochrome P450 monooxygenase enzymes (P450s, CYP450s) are important catalysts in a diverse array of chemical reactions, namely oxidations and CH bond cleavage. Cytochrome P450s are essential in the metabolism of many medications. The group consists of more than 50 enzymes, but only 6 of them are responsible for the metabolism of about 90% of all drugs. The two most significant P450s are CYP3A4 and CYP2D6. Besides, P450s can be the source of clinically relevant drug-drug interactions, due to inhibition or induction by other drugs [7]. Typical substrates for CYP2D6 are lipophylic bases. CYP2D6 metabolizes approximately 25% of current drugs, including antidepressants, antipsychotics, antiarrhythmics, antiemetics, beta-blockers, and opioids [10].

Genetic variability influences individual response to treatment. While poor metabolizers may accumulate the drug's byproducts and experience unexpected toxicity, fast metabolizers are more likely to find the same drug at the same dose ineffective. Specific genotype testing can determine specific alleles and corresponding metabolic activity of individual P450 enzymes, however, there is little evidence of how pharmacogenomic testing improves clinical outcomes. To answer the question of how genotype translates to blood levels of active metabolites of drugs, the combination of pharmacogenomic profile, laboratory readings of drug concentrations, and clinical outcomes would have to be obtained [8]. Drug metabolism is described in detail on drug labels in the section clinical pharmacology, pharmacokinetics and metabolism. The Flockhart Table provides basic guidance to drug interactions based on CYP450 metabolism.

Opioid metabolism

Opioids and their formulations differ in ways in which they are metabolized by the body. In addition, individuals have varying amount and activity of enzymes that metabolize opioids, depending on their genetics, meaning that the speed of breaking down the drugs varies from one individual to another. Whilst in ultra-rapid metabolizers the drug level never reaches its therapeutic threshold, in individuals whose opioid metabolism is too slow the active metabolites stay in the system too long, producing toxic effects. To make things even more complicated, the same enzymes are used in the metabolism of other drugs and xenobiotics, not just opioids, so different compounds compete for the same enzyme.

Most opioids are extensively metabolized in the liver upon absorption from the gut. This first-pass metabolism reduces the drug bioavailability by subjecting it to dealkylation, hydroxylation, sulfoxidation, deamination, dehalogenation, oxidation or hydrolysis. Metabolism of opioids mainly involves the CYP3A4 and CYP2D6 enzymes. The second phase of drug metabolism, that also takes place in the liver, is conjugation with glucuronic acid, sulfate, glycin or glutathione. Glucuronidation produces highly hydrophilic compounds that are eventually excreted in the urine [9].

Actionable pharmacogenomic biomarkers

CYP2D6. There are currently 74 know allelic variants and subvariants of the CYP2D6 gene and the number of alleles is still growing, ranging from no function to ultrarapid metabolism. The consequence of altered metabolism can be either toxicity, an adverse drug reaction, or suboptimal therapeutic response. Because CYP2D6 is largely non-inducible, higher doses taken by addicts do not result in faster metabolism of opioids. Interindividual variation in CYP2D6 activity varies considerably and ranges from ultrarapid metabolizers (UMs), extensive metabolizers (EMs), intermediate metabolizers (IMs) to poor metabolizers (PMs) [10].

CYP3A4. Cytochrome P450 3A4, along with CYP3A5, is the dominant cytochrome P450 expressed in human liver. CYP3A4 is absent in newborns but reaches levels comparable to adults at about 1 year of age. It is most active in the liver and small intestine. Intestinal CYP3A4 is responsible for food-drug interactions, namely grapefruit and St. John's Wort [11]. Cytochrome P450 3A4 is involved in the metabolism of more than 50-60% of all drugs, including opioids [12].

There are several other enzymes involved in the metabolism of opioids. Efforts are ongoing to include pharmacogenomic profile in clinical decision-making to make opioid therapy safer, more effective and more predictable [13].

Actionable PGX biomarkers & existing clinical guidelines

The Clinical Pharmacogenetics Implementation Consortium (CPIC) published 44 guidelines how to interpret and apply pharmacogenomic information in clinical practice, including, codeine, phenytoin, warfarin, citalopram, allopurinol, abacavir and others. For opioids, clinically relevant drug-gene interactions exist for alfentanil (OPRM1), fentanyl (ABCB1, OPRM1), morphine (ABCB1, OPRM1), codeine (CYP2D6), oxycodone (ABCB1, CYP2D6) and tramadol (ABCB1, CYP2D6, OPRM1). The level of evidence for alfentanil, fentanyl, and morphine is rather weak (CPIC: C/D, PharmGKB: 2B). The only opioid analgesic guideline is available for CYP2D6 interaction with codeine [14].

Tramadol

Tramadol interaction with CYP2D6 is well documented. CPIC assessed the level of evidence as "A" (i.e. Preponderance of evidence is high or moderate in favor of changing prescribing) [15]. In a clinical context, this means that "genetic information should be used to change prescribing of affected drug". PharmGKB evaluated the level of evidence for this interaction as "1B" (i.e. Annotation for a variant-drug combination where the preponderance of evidence shows an association. The association must be replicated in more than one cohort with significant p-values, and preferably will have a strong effect size) [16]. The interaction is also clearly described in the drug label, including a warning about drug level differences in poor metabolizers and a potentially life-threatening interaction with CYP2D6 inhibitors, specifically serotonin syndrome following concurrent administration with SSRIs [17].

Oxycodone

The level of evidence for the interaction between CYP2D6 and oxycodone is assessed as "A" by CPIC and 2A by PharmGKB (i.e. "annotation for a variant-drug combination that qualifies for level 2B where the variant is within a VIP (Very Important Pharmacogene) as defined by PharmGKB . The variants in level 2A are in known pharmacogenes, so functional significance is more likely") [18]. The interactions with CYP2D6 and CYP3A4 are mentioned on oxycodone labels, however, without specific warnings about poor metabolizers:

"Oxycodone is metabolized in part to oxymorphone via the cytochrome P450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent" [19].

What is next?

The Risk Evaluation and Mitigation Strategy for opioid analgesics relies on physician education to curb abuse, misuse, addiction and overdose. There is just one pharmacogenomic guideline for an opioid analgesic, for codeine. However, the existing evidence would support more than just that. The time has come to develop pharmacogenomic guidelines for opioid analgesics. CYP2D6 and oxycodone should be the one to begin with.

References:

[1] U.S. Department of Health and Human Services, Office of Disease Prevention and Health Promotion.

(2014). National Action Plan for Adverse Drug Event Prevention. Washington, DC

[2] AHRQ: National Action Plan for Adverse Drug Event Prevention

[3] Health Research & Educational Trust (February 2017). Adverse Drug Events Change Package: 2017 Update. Chicago, IL: Health Research & Educational Trust.

[4] CDC: Prescription opioid data.

[5] Seth, P., Rudd, R., Noonan, R., & Haegerich, T. (2018). Quantifying the Epidemic of Prescription Opioid Overdose Deaths. American Journal Of Public Health, 108(4), 500-502. doi: 10.2105/ajph.2017.304265

[6] FDA: Opioid Analgesic Risk Evaluation and Mitigation Strategy (2018)

[7] Jeffreys, L., Girvan, H., McLean, K., & Munro, A. (2018). Characterization of Cytochrome P450 Enzymes and Their Applications in Synthetic Biology. Methods In Enzymology, 189-261. doi: 10.1016/bs.mie.2018.06.013

[8] McDonnell, A. M., & Dang, C. H. (2013). Basic review of the cytochrome p450 system. Journal of the advanced practitioner in oncology, 4(4), 263–268.

[9] Smith H. S. (2009). Opioid metabolism. Mayo Clinic proceedings, 84(7), 613–624. doi:10.1016/S0025-6196(11)60750-7

[10] Zhou, S. (2009). Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance. Clinical Pharmacokinetics, 48(11), 689-723. doi: 10.2165/11318030-000000000-00000

[11] Eum, S., Lee, A. M., & Bishop, J. R. (2016). Pharmacogenetic tests for antipsychotic medications: clinical implications and considerations. Dialogues in clinical neuroscience, 18(3), 323–337.

[12] Medsafe (2014). Drug Metabolism - The Importance of Cytochrome P450 3A4.

[13] Pergolizzi JV, Taylor R, LeQuang JA, et al. Towards personalized opioid dosing: A concise overview of CYP polymorphisms. Anaesthesiol Clin Sci Res. 2018;2(1):11-19

[14] Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Cytochrome P450 2D6 (CYP2D6) Genotype and Codeine Therapy: 2014 Update (April 2014)

[15] CPIC: Prioritization.

[16] PharmGKB: Clinical Annotation Level of Evidence.

[17] Tramadol ER

[18] Clinical Pharmacogenomics Implementation Consortium: Gene-Drug

[19] Oxycodone hydrochloride

The value of curiosity

Fri, 01 Nov 2019 17:23:34 GMT

In October 2016, Merck KGAA (Darmstadt) published a fascinating study that appears to address lagging performance in innovation in the industry by including personal characteristics in hiring decisions. The company scrutinizes its new hires for curiosity.

Merck Publishes First International Curiosity Study

Merck's Curiosity Study examined the extent to which staff can make the most of their curiosity at work, and if they are encouraged to do so.

"73% of respondents do not feel comfortable asking more questions at work. Nearly 45% workers surveyed in Germany believe that they are discouraged by their employer from challenging the status quo. 35 % of German employees cited self-directed work as the most critical factor."

Pharmaceutical innovation has been suffering from problematic performance for years. And the core problems are primarily organizational and cultural.

Bruce Booth, in his article “Culture as a culprit of the Pharma R&D crisis?” (Forbes, 2012), highlights factors such as “tyranny of the committee”, “stagnation through risk avoidance”, and “negative impact of organizational entropy”. The article stirred a debate in the industry about cultural factors that affect human behavior within the system, namely the willingness of individuals to present new ideas that may or may not succeed. Instead, natural social preference is "playing it safe" and stick with projects that have approved budgets to avoid layoffs during acquisitions and mergers.

In 2012, Derek Lowe, in his article E-room’s Law (In the Pipeline, 2012) commented on the long-term trend in the cost of developing a new drug:

Now, the companies (and CEOs) involved in this generally talk about how they are going to turn things around, how cutting their research will put things on a better footing, how doing external deals will more than compensate for it, and so on. But it is getting increasingly hard to believe that.

Richard Wobbe, in the discussion below the article, posted a link to his article Project Management and Drug Discovery Productivity (page 8, figure 3) in which he presents the same problem in a differently designed graph (1960-1998), showing the same problem from a different angle. Combined diagram showing R&D spending and number of approved drugs/year:

The Big Pharma culture has been homogenised, purified, sterilised, whipped, stirred, filtered, etc. and lost its ability to ferment the good stuff required to innovate. This isn’t covered in most reviews of the productivity challenge facing our industry, because it’s nearly impossible to quantify, but it’s well known and a huge issue". ‘ From Vision to Decision Pharma 2020’

Sayle in his article Creating a Culture of Trust & Breakthrough Innovation in Pharma (EyeForPharma, 2015) dissected several analytical works such as PWC’s Report ‘From Vision to Decision Pharma 2020’ and ‘The Corporate Reputation of Pharma – The Patient Perspective’ and discussed the role of culture in pharmaceutical innovation. Sayle highlights the role of trust:

“So what can the industry’s senior figures do to rebuild public trust and build healthy, high-performing companies to successfully meet pharma’s fundamental challenges of the future?”

I wholeheartedly agree: public trust is essential for the industry to thrive. Without trust, no business is possible. Loss of public trust has the power to force major industry reform, such as the changes implemented in nuclear industry following the Three Mile Island accident. In extreme circumstances, as seen after the Chernobyl disaster in Soviet Union in 1986, failure to reform can trigger a regime change.

Recently a new trend emerged to offer half-a-century old drugs for a premium price: Innovators vs. exploiters (Forbes, 2016) comment on Mylan’s EpiPen, Citron’s last word on Valeant’s business model, or the price hike of daraprim by Turing Pharmaceuticals, just to name a few.

So why is drug development becoming so expensive, then?

Series of mergers and mega-mergers in the industry significantly affects the drug development pipeline, and the culture within which people, including scientists, operate. Recent research published by HRB (August 2016) shows that mergers do indeed stall innovation:

Research: Innovation Suffers When Drug Companies Merge

“Acquirers often target firms that have a relatively similar patent portfolio. That means there’s less competition for discovering and developing new therapies. If a non-merging rival is also researching similar therapies, that outside firm also now has one less competitor. It experiences a similar reduction in competition as the acquiring firm.”

With all due respect, this practice closely resembles behavior of sand tiger shark embryos in the womb: they cannibalize each other.

As pointed out by FiercePharma, McKinsey & Co. analysts in their 2014 report emphasized the “shareholder value” effects of megamergers.

The value of curiosity

The role of organizational culture in pharmaceutical innovation is hard to overestimate. No man is an island. People function within an organization, not independently of it, thoroughly immersed in its culture. They have to respect its reporting structure, encouraged (and more often than not discouraged) to undergo training that is relevant to their (current) job, with endorsed (or not) excursions into other areas of interest. Promotion issues and career ladder, mobility within the enterprise, and choices presented to internal talent all affect whether or not people communicate their preferences, develop the skills and abilities they have, and pursue their dreams.

Handling a high-risk HIPAA breach

Thu, 31 Oct 2019 21:17:21 GMT

Published October 31, 2019

Part of scenarios for patient privacy crisis management

Every hospital encounters patients, who for the reason of their social circumstances, dependent status, personal characteristics, or the nature of their condition, are more vulnerable than the general population. While compliance with HIPAA is indeed important, because of the potential to inflict significant liability on the hospital resulting from compliance failure, it should not be the only consideration when caring for vulnerable patients. Mere compliance with the minimum requirements of HIPAA does not guarantee the safety of vulnerable patients. In the case study scenario, the hospital emergency department in a small town admitted a 15-year-old female with emergency labor. After delivery in the emergency room, the mother and the baby were moved to Obstetrics and Neonate. Despite appropriate care, the infant presented with multiple medical problems, which may or may not be resolved in the future. A nurse, who took care of the young mother, inadvertently disclosed the patient’s identity and condition to her young daughter, who found her mother's phone and managed to spread the news in all high schools in the area by the following day. The 15-year-old managed to hide her pregnancy from her family. To complicate matters, the young mother’s mother and aunt work in the same hospital.

HIPAA assessment

The Health Insurance Portability and Accountability Act of 1996 (HIPAA) required the Secretary of the U.S. Department of Health and Human Services (HHS) to develop regulations protecting the privacy and security of certain health information. The HIPAA Privacy Rule sets national standards for the protection of personal health information against unauthorized disclosure. The Privacy Rule can be found at 45 CFR Part 160, and 45 CFR Part 164, Subparts A and E. The standards, requirements, and implementation specifications apply to health plans, healthcare clearinghouses, and healthcare providers and their business associates. The Security Rule sets standards for protecting electronic health information. Enforcement of the regulation is the responsibility of the Office for Civil Rights (OCR) that is part of HHS. In this case study, the nurse disclosed personal health information, including the full identifier and the patient’s medical condition to an unauthorized individual. A nurse, as an employee of a covered entity, would indeed be subject to obligations under HIPAA. The Site Privacy Officer’s concerns should be the facilitation of an investigation and risk of harm assessment. If a Breach is substantiated and notification is required, the Site Privacy Officer shall notify each individual whose PHI has been accessed, acquired, used, or disclosed as a result of the Breach. In cooperation with other hospital functions, the Site Privacy Officer shall determine what additional external notifications should be made. In this case, it may be necessary to notify local law enforcement if there is a reason to believe the minor’s pregnancy was the result of abuse, neglect, or domestic violence.

A breach or not?

Breach means the acquisition, access, use, or disclosure of protected health information in a manner not permitted under subpart E, which compromises the security or privacy of PHI. To prevent unauthorized access to text messages that contain patient health information, the messages must use encryption for data at rest and in motion. Encryption makes the information inaccessible to users who are not authorized to access the information, especially when the device is borrowed, lost, or stolen ( providertech , 2020). Breach excludes unintentional acquisition, access, or use of PHI by a person acting under the authority of a covered entity, or inadvertent disclosure between employees of the same covered entity, as long as this information does not spread any further. Breach also excludes disclosures made to unauthorized persons who would not be reasonably able to retain such information. Any other acquisition, access, use, or disclosure of PHI not permitted under subpart E is considered a breach [45 CFR 164.402]. Based on this definition, the incident indeed constitutes a breach of personal health information that does not fall under any of the exclusions. In the event of an impermissible use or disclosure of unsecured PHI, the covered entity is obligated to conduct a risk assessment. Breach notification is necessary for all situations where PIH has been compromised. Breach notification is not required if the covered entity demonstrates that there is a low probability that PHI has been compromised. In this particular case, there is no doubt PHI has been compromised since the information reached all four high schools in the area by the following day.

Breach notification

The HIPAA Breach notification rule [45 CFR 164.400-414] requires covered entities to report breaches of health information that have not been rendered unusable, unreadable, or indecipherable. Notification of the Breach has to be provided to the affected individuals, the Secretary, and in certain circumstances, to the media. In this instance, the hospital would have to report the Breach to the patient and to the Secretary within 60 days following the discovery of the Breach. The notification must include a description of the Breach and the information involved, and steps the individuals should take to protect themselves from potential harm. Besides, the hospital should include a brief description of what it is doing to investigate the breach, mitigate the harm, and prevent further breaches, as well as contact information such as a toll-free number. To notify the Secretary, the hospital shall submit the information via an electronic form that is available on the OCR website.

Risk of Harm Assessment

In January 2013, the Risk of Harm standard was dropped from the final HIPAA Omnibus Rule. The initial rule stated that a breach does not occur unless the access, use or disclosure poses "a significant risk of financial, reputational, or other harm to an individual." It was up to the covered entities to decide whether the harm standard applies or not. The new rule assumes that all impermissible PHI disclosures are reportable (HHS, 2013). However, risk assessment conducted by the hospital shall not be limited to HIPAA compliance obligations. Risk is the probability that a vulnerability will be threatened, resulting in an adverse consequence. The hospital has to consider the potential harm to the affected patient as well as liabilities for the hospital and potential disruption of its own business operations.

The patient

The case study represents a myriad of ethical and legal problems, in addition to HIPAA compliance. These concerns include the fact that the patient is an unemancipated minor, that her parents were unaware of her condition until birth, and that the pregnancy may have been the result of rape or incest. The consequences of such disclosure in a small town are easy to imagine. Whilst the general acceptance of unwed and underage mothers and offspring conceived out of traditional boundaries of formal marriage depends on location, time, and culture, some patterns are universal in nature and only vary in extent. A teenage mother and a child of uncertain parentage, especially if ill or disabled, are likely to face severe repercussions and lifelong shunning even in the most benign environments. Young mothers may be forced to give up their newborn babies and become themselves subject to retaliation from angry relatives, including the risk of violent death. According to RAINN, the overwhelming majority of victims of sexual abuse know the perpetrator. Even more disturbingly, in 80% of perpetrators were a parent (RAINN, 2013).

Josephson (2016), in her book “Rethinking sexual citizenship” (Josephson, 2016) discusses in detail the causes and consequences of early motherhood, including various societal ills connected to the phenomenon of teenage motherhood, both real and perceived. Teenage sexual activity is considered a deviancy and a threat to public order, and as such, it is subject to widespread public shaming (pp. 82-84). The experiences of teenage mothers can be extremely distressing due to public shaming, shunning, rejection by the community and the family, and absence of elementary support. Even worse, children are often deprived of many opportunities later in their lives because of biases and prejudices; they have to grow up with (Odyssey, 2016).

According to “Report on Exploratory Study into Honor Violence Measurement Methods”, honor violence seems to be rare in the United States and apparently limited to ethnic minorities mainly from South East Asia. These cultures do not view honor violence as a crime, and the victims or potential victims are unlikely to report victimization because of fear of repercussions from their own family. These cultures defend honor violence as a means to maintain or regain the reputation and social standing of a family by female members who violate the community’s traditions and norms, should it be sexually inappropriate behavior or disobedience (Helba, Bernstein, Leonard and Bauer, 2014). Other cultures find it appropriate to murder the infant whilst preserving the life of the female. Hungary, a country in Eastern Europe, is an example of a culture where infanticide is generally acceptable, although not legal, mechanism of restoring family honor (Journeyman’s Pictures, 2016). The risks to the mother and the infant following such disclosure are grave, and depending on circumstances, and cultural and ethnic background can include retaliation, infanticide, and honor violence.

The Infant

Genetic testing of the infant may be warranted to confirm paternity and exclude or confirm the pregnancy was the result of an incestuous relationship. Whether such a test would or would not be permissible and what authorization is required to conduct such tests is a delicate question that requires careful professional judgment, both medical and legal. Genetic screening without parental consent is subject to much controversy, and New Act Newborn Screening Saves Lives Reauthorization Act of 2014 includes the requirement of parental consent for the screening of newborn babies with deadly yet treatable conditions (National Institutes of Health, 2015). The quality and speed of newborn screening programs vary from state to state (Gabler, 2013). Whelan (2013) argues that the main concern of privacy advocates and patient advocacy groups was not the initial screening itself but indefinite retention of genetic material for undisclosed uses, potentially resulting in tangible harms in the future such as employment discrimination and insurance coverage (Whelan, 2013).

The American Society of Human Genetics (ASHG, 2015) published a position statement in which it clarified its stance on genome-scale, carrier, and newborn results, and covered a variety of conditions and circumstances including incest. While parental consent is required under most circumstances, clinician’s judgment can override the lack of parental consent "when there is strong evidence that a secondary finding has urgent and serious implications for a child's health or welfare, and effective action can be taken to mitigate that threat". In this instance, the healthcare provider should be able to perform genetic testing even without parents’ consent.

Mitigation of adverse consequences

Steps relating to the protection of the young mother and the infant shall be taken with full consideration of the benefits and risks of available options and possible solutions.

Personal representative

With respect to use or disclosure, 45 CFR Part 160 does not preempt State Law in regards to disclosure of protected health information about a minor to a parent [45 CFR 160.202(2)]. However, in this particular instance, the disclosure of the minor’s condition may not be in the best interest of the young mother and her newborn child. First, the minor’s parents or legal representatives were supposedly unaware of their daughter’s pregnancy. This fact itself should trigger hospital procedures for care for vulnerable minors, including potential victims of rape, incest, sexual abuse, parental neglect, domestic violence or human trafficking. A minor does not become an adult by virtue of becoming pregnant and giving birth. Regardless of the potential Breach, determining who is the patient’s legal representative, and making sure, that she does have an appropriate one, would be the most important first step.

A covered entity may elect not to treat a person as the personal representative of an individual if the reason to believe that the individual may be subjected to domestic violence, abuse or neglect by such person, or treating such person as the personal representative could endanger the individual [45 CFR 164.502 (g)(5)(i)(A)-(B)]. The hospital has the option to exercise its professional judgment and decide not to treat the person as the individual’s personal representative [45 CFR 164.502 (g)(ii)]. The rules for the emancipation of a minor vary from state to state. Whilst in most cases court decision is required, in cases where the evidence shows that censurable parental conduct had occurred implied emancipation may apply (Legal Information Institute, n.d.).

Protection of disclosure within the hospital

Permitted uses and disclosures include the use of the individual’s name, location, and condition described in general terms to maintain the hospital’s directory and to be able to locate the individual in the facility. The patient should have the opportunity to agree or object to such disclosure [45 CFR 164.510(a)(1)(i)(A)-(C)]. In emergency circumstances, the health care provider shall act in the individual’s best interest as determined by the covered health care provider, in the exercise of professional judgment [45 CFR 164.510 (3)(B)].

Law enforcement disclosures

The Fourth Amendment to the U.S. Constitution states: “The right of the people to be secure in their persons, houses, papers, and effects, against unreasonable searches and seizures, shall not be violated, and no warrants shall issue, but upon probable cause, supported by oath or affirmation, and particularly describing the place to be searched, and the persons or things to be seized” (U.S. Constitution, Amendment IV). Medical records contain very sensitive information about individual patients. Law enforcement searches are authorized as reasonable under very specific circumstances and only to a specific extent. Whilst the pregnancy could have been the result of a relationship between two sexually experimenting minors, the possibility that an adult was involved deserves an appropriate investigation. Successfully hiding a pregnancy from an immediate family is not an easy thing to achieve. Near-complete ignorance and willful blindness are required not to notice that a teen living in the same household is pregnant and about to give birth. Awareness of the pregnancy, in combination with the failure to provide appropriate support, could indicate the intent not to allow the infant to live. In some cultures, infants born from unapproved relationships are at risk of infanticide.

The Site Privacy Officer shall make appropriate disclosures to staff in functions designated to coordinate high-risk cases of this nature with other appropriate departments and services, in addition to the investigation of the Breach. To this end, additional external disclosures may be necessary. A covered entity may use or disclose protected health information without the written consent or authorization of the individual if there is a reason to believe that the individual is a victim of abuse, neglect, or domestic violence. Such disclosure shall be limited in nature to comply with relevant laws if the individual agrees, or to the extent expressly authorized by statute or regulation [45 CFR 164.512 (c) (i) – (iii)]. Any attempts to mitigate the damage caused by the Breach shall be appropriately documented for the Office of Civil Rights (OCR).

Obligations after impermissible disclosures

Once an impermissible disclosure has been made, covered entities should take steps to mitigate the potential damage. Covered entities have a duty to identify and document security incidents and privacy violations, including an impermissible disclosure. Appropriate safeguards include administrative, technical, and physical safeguards that protect PHI from any intentional or unintentional use or disclosure [45 CFR 164.530]. In response to the incident, the hospital should examine the events that led to the disclosure. This primarily includes the review of the history of impermissible uses and breach logs, training materials, and training records. Gap analysis and holistic vulnerability assessment to prevent future breaches would be beneficial to prevent future breaches. Examination and review of the hiring process and critical assessment of organizational culture would facilitate the change in the ways people think about patient privacy and the implications of privacy breaches.

Personal accountability

The hospital shall have in place written policies and procedures regarding breach notification and must train their workforce appropriately. The organization also has to apply appropriate sanctions against staff members who fail to comply with HIPAA law as relevant to them. A breach of this kind would warrant the review of the appropriateness of policies and procedures, the record of previous breaches, and certainly a revision of training including a reminder of the implications of such disclosures for the patients and for the hospital.

When hiring new people, the focus on technical skills shall not overshadow the importance of character, trustworthiness, and ethical conduct. Although most organizations perform background checks prior to hiring them, these do not typically reveal elements such as trust. Workforce retention is a major problem in healthcare. Recent estimates placed the cost of staff turnover at $40,000 to $80,000 per nurse, including the investment required to find a permanent replacement, ensure staffing of shifts and provide onboarding training (Cohen, 2013).

A departing nurse can cause significant damage to the hospital, especially if hurt feelings are involved or the dismissal is perceived as unjust. Experience from the University of Rochester Medical Center (Shaw, 2016), shows how much damage a nurse can inflict on the hospital before leaving if she decides to take advantage of access to patient records that would give her the necessary leverage to either move to a new position or start a practice on her own (Shaw, 2016).

Whether the nurse who caused the Breach should be dismissed is a decision, the Human Resources department would have to make. Considering the potential damage caused both to the patient and to the hospital, and the need for extensive resources dedicated to mitigation of the disclosure, immediate dismissal seems appropriate. The incident does violate not only HIPAA but also represents a breach of the professional code of conduct and hospital policies. Most importantly, it shows a lack of sound judgment, which may be critical in many other situations. However, any action taken by the hospital should be proportionate and fair to avoid scapegoating of a single individual for conduct that may, in fact, be a widespread cultural problem observable across the enterprise, especially when it is clear this was the result of a mishap rather than malicious intent. A careful review of past incidents, policies, and procedures and quality of training and training records should provide better guidance about what is appropriate. The hospital should also look into the use of personal devices for work and the use of encryption for short communications within the hospital. At the very least, the nurse should be placed on administrative leave until the investigation is closed.

HIPAA v. the hospital

The risks to the hospital include a liability relating to HIPAA compliance failure and tort claims, including negligence. HIPAA breaches and the implications resulting from compliance failure is not the only liability the hospital’s leadership could face.

In 2012, in R.K. v. St. Mary’s Medical Center, the West Virginia Supreme Court of Appeals ruled that HIPAA did not preempt state law, and provided the standard of care for tort claims. The hospital shared R.K.’s medical information relating to his psychiatric hospitalization with his estranged wife, despite the patient’s request not to. R.K’s cause of action included negligence (R.K. v. . St. Mary’s Medical Center, 2012).

In Byrne v. Avery Center for Obstetrics and Gynecology, the Connecticut Supreme Court ruled that HIPAA does not preempt negligent claims for a breach of patient privacy. In this particular case, Emily Byrne’s medical information was shared with her partner against her wish. The healthcare provider received a subpoena from her partner’s attorney in a paternity suit and complied with the request, disclosing Byrne’s medical information to her significant other. Byrne then successfully sued the hospital for negligence (Byrne v. Avery Center for Obstetrics and Gynecology, 2014). Lewis in The National Law Review (2014) stressed that the fact that HIPAA does not give patients a right of private action does not mean that remedies for questionable disclosures do not exist. Remedial measures include namely state health laws and common law torts (Lewis, 2014).

Conclusion

Disclosure of protected health information in circumstances that would make the individual subject to serious repercussions is a major concern for the affected individual and for the hospital. The incident represents a complex set of medical, legal and ethical concerns in addition to HIPAA violations. Professional judgment is required to decide whether or not there is a reason to believe the teen may have been the victim of abuse, neglect or domestic violence, whether the hospital can deny disclosure of the patient’s PHI to her parents, and whether implied emancipation applies in this case. Hospital’s post-incident assessment shall address the risk of harm to the affected patient and her infant child, review previous instances of improper disclosures and breaches, implement corrective and preventative action to ensure HIPAA compliance, and address other risks, such as the risk of litigation for negligence. The Human Resources Department shall make the decision about the nurse’s future employment, and place her on administrative leave until the completion of the investigation. Gap analysis and critical assessment of organizational culture would be beneficial to identify vulnerabilities in the hospital’s operations and address them appropriately. Policies and procedures have to be implemented with fidelity to be effective. Review of training materials, procedures, methodologies, and training effectiveness has to follow to prevent inadvertent disclosures in the future. Dismissal of a single employee does not solve the problem of systemic issues and organizational culture that need to be addressed separately to be effective.

References

ASHG. (2015). ASHG Position Statement Provides Guidance for Genetic Testing in Children and Adolescents. Retrieved April 04, 2017, from https://www.genomeweb.com/molecular-diagnostics/ashg-position-statement-provides-guidance-genetic-testing-children-and

Cohen, S. (2013). Recruitment and retention. OR Nurse,7(3), 8-10. doi:10.1097/01.orn.0000429410.21897.75

Gabler , E. (2013). Delays at hospitals across the country undermine newborn screening programs, putting babies at risk of disability and death. Retrieved April 04, 2017, from http://archive.jsonline.com/watchdog/watchdogreports/Deadly-Delays-Watchdog-Report-Delays-at-hospitals-across-the-country-undermine-newborn-screening-programs-putting-babies-at-risk-of-disability-and-death-228832111.html

Helba, C., Bernstein, M., Leonard, M., & Bauer, E. (2014). Report on Exploratory Study into Honor Violence Measurement Methods (Rep. No. 248879). Westat.

HIPAA Privacy Rule Requirements Overview. (2003). The Practical Guide to HIPAA Privacy and Security Compliance. doi:10.1201/9780203507353.ch5

Josephson , J. J. (2016). Rethinking sexual citizenship. Albany: State University of New York Press .

The Damaging Effects Of Shaming Teen Mothers. (2016, May 31). Retrieved April 04, 2017, from https://www.theodysseyonline.com/damaging-effects-shaming-teen-mothers

Journeyman Pictures. (2016). Infanticide in Eastern Europe (1999) Retrieved April 04, 2017, from https://www.youtube.com/watch?v=ZjSC1xiQd-Q

Legal Information Institute. (2007). Emancipation of Minors. Retrieved April 04, 2017, from https://www.law.cornell.edu/wex/emancipation_of_minors

Lewis, J. (2014). Negligence Claims for Breach of Patient Privacy Not Preempted by HIPAA, Connecticut Supreme Court Holds. Retrieved April 04, 2017, from http://www.natlawreview.com/article/negligence-claims-breach-patient-privacy-not-preempted-hipaa-connecticut-supreme-cou

National Institutes of Health. (2015). Preliminary Guidance Related to Informed Consent for Research on Dried Blood Spots Obtained Through Newborn Screening. Retrieved April 04, 2017, from https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-127.html

Providertech (2020): 5 HIPAA Rules Regarding Text Messaging. ProviderTech. Retrieved Sep 28, 2020, from https://www.providertech.com/5-hipaa-rules-regarding-text-messaging/ .

RAINN. (n.d.). Children and Teens: Statistics . Retrieved April 04, 2017, from https://www.rainn.org/statistics/children-and-teens

R.K. v. St. Mary's Medical Center, 735 S.E.2d 715 (2012) 229 W.Va. 712 (November 15, 2012).

Secretary, H. O. (2013). Breach Notification Rule. Retrieved April 04, 2017, from https://www.hhs.gov/hipaa/for-professionals/breach-notification/index.html?language=es

Whelan, A. M. (2013). That's My Baby: Why the State's Interest in Promoting Public Health Does Not Justify Residual Newborn Blood Spot Research Without Parental Consent. Minnesota Law Review ,98, 419-453. doi:10.2139/ssrn.2590100

Secretary, H. O. (2015, November 05). Privacy Rule Introduction. Retrieved March 25, 2017, from https://www.hhs.gov/hipaa/for-professionals/privacy/guidance/introduction/index.html

Shaw, G. (2016). Departing Nurseʼs HIPAA Breach Spurs New Privacy Policies at URMC — A Case In Point for Reviewing and Tightening Practices. Neurology Today,16(3), 11-12. doi:10.1097/01.nt.0000480943.34345.44

Warren, Z. (2014). Connecticut Supreme Court rules that HIPAA does not preempt negligence claim. Retrieved April 04, 2017, from http://www.insidecounsel.com/2014/11/11/connecticut-supreme-court-rules-that-hipaa-does-no?slreturn=1491315877

Why plan when you can react?

Thu, 24 Oct 2019 23:28:40 GMT

Can we confidently achieve operational success?

Procedures are established to deal with probable occurrences. The key discriminator is expectation. There are generic challenges that any organization should prepare for. Procedures are intended to enable internal leadership to retain control, establish acceptable efficiencies, and to detect and refer threats to the appropriate jurisdictional authority. This category of activity is euphemistically referred to as “Business as Usual”. Additionally, procedures are less affected by personnel turbulence because organizations can easily assimilate new members without loss of effectiveness through mentoring and experience reinforced by routine duties.

Plans are established to deal with anticipated but unlikely occurrences. Often these contingencies are not unique but similar to situations with existing procedures however they are associated with severely escalated consequences. The intent is to minimize adverse effects from extraordinary events ranging from temporary operational confusion to an unrepairable loss of capacity. Multi-echelon training is essential. Conceptual communication and physical rehearsals will transform non-standard intuition and inconsistent conventional wisdom into common sense.

The demarcation between procedures and plans is actual performance. Regardless of how well an organization has rehearsed, all preparations are plans until validated during an actual occurrence, which transforms them into procedures. Once experienced, the organization gains confidence in its ability to develop and conclude a similar situation successfully. This effectively reduces vulnerability by removing operational ambiguity present within the best of plans. This is where organizational maturation occurs and is represented as the area bordered by red/blue dotted lines . However, the benefits of experience are negated by personnel turbulence that reduces the qualified experience of the organization leaving it unaware of actual vulnerabilities by assuming that it has adequate procedures and experience when effectively it should return to a deliberate planning process built upon candid introspect and assessment.

As an organization is forced beyond its comfort zone of high frequency low risk activity, its foundation of procedures and the quality of its planning will determine recoverability. When situations reach catastrophic, emergency management procedures are in effect. During these conditions the objective is survival over prosperity and a deliberate transition of control to an incident command organization should be anticipated.

The emergency management threshold is often the point of entry for discussions of disaster preparedness and consequence management. Although, the frequency of occurrence ranges from unlikely to highly improbable, the consequence increases exponentially and has been witnessed in recorded events. Therefore, participation in emergency management activities is accepted as an obligation demonstrating responsible leadership, if not a regulated requirement.

When taken out of context with the operations continuum, emergency management preparedness is often viewed as requiring specialized staff or hedged resources to guarantee success. This perception causes small commercial entities and economically disadvantaged municipalities to view true preparedness as a luxury they can’t afford. However, successful operations under any conditions depend entirely on the quality of decisions. Ideal control of risk is accomplished through situational awareness (SA) supporting understanding and decision-making. SA is measured by how completely it considers all aspects of the organization’s internal functions and relates them to the influences of the crisis situation. At this time more than any other the quality of preparedness is determined by the resiliency gained through routine procedures and complimentary plans which establish the only foundation providing viable emergency management and continuity of operations.

Routine to extreme, effective risk and consequence management starts with “Business as Usual”. Visualizing routine daily management data in new ways enables organizational agility and innovative solutions for extraordinary situations.

I originally built the continuum graphic and presentation in 1993 as a program component addressing emerging Homeland Security imperatives for commercial and municipal entities. The world has only gotten smaller and although Risk Management (RM), as a specialty, has developed to more appropriately encompass the enterprise, it has grown into an over specialized self-sustaining esoteric ecosystem within business management. Understanding for All-hazard preparedness benefit to Business Resiliency has not progressed to be internalized by subsequent generations of operational management.

All organizational dysfunctions track directly to Leadership failures is not an indictment, rather an observation that the increasing complexities of business management necessitate specialization that generally remains unknown outside of a particular department or office within an organization. There is a missing level of collaboration and cross-training that facilitates integration of disparate specialties into a Common Operational Picture (COP) that directly enhances decision support for operational resiliency. However, this is not an intuitive process until it has been experienced.

Administrative constructs will vary but, this graphic illustrates principal enterprise functions that all businesses evolve through, starting informally with a couple folks and a good idea, incrementally formalizing functions into a mature enterprise, which will be inevitably riddled with exploitable vulnerabilities. From any point of individual perspective within this dynamic; what is the meaningful contribution to risk assessment for the enterprise as a whole? Any individual only knows what they are responsible for or required to do, the resources and authorities provided, and their challenges or frustrations in meeting expectations. However, this does not equate to a valid opinion on Enterprise Risk until those duties and responsibilities are related to the strategic goal of the enterprise. Not all functions generate revenue but may be necessary simply to qualify the legal legitimacy of the enterprise to conduct business. So all things being connected, what effect does a distraction or disruption at any point cause across the enterprise to affect revenue?

The fallacy in all analytical approaches is data interpretation and that simplified charts mislead because they legitimize subjective determinations. Somewhere there must be a trace to a Performance Measure of Effectiveness (PME) in an operational blue print directly supporting mission achievement. Any forced deviation equates to consequence. Any aspect susceptible to influence or damage is a point of vulnerability. Does the operation have the ability to adjust and recover to meet obligations within available resources? If not, the consequence becomes more significant, necessitating intervention beyond published procedural controls and possible implementation of a contingency plan.

RM exist to qualify the aspirations and ambitions of an enterprise for the investors by identifying circumstances that necessitate a prudent adjustment to intentions, timing, or reallocation of resources relative to the strategic goal. Ambiguity is ever present and there is latency to some seemingly insignificant occurrences that manifest significant consequence in combination with others as a “perfect storm”. Risk managers must apply methods/principals appropriate for answering the fundamental question, which should be asked by all leaders: Can we confidently achieve operational success?

"Why plan when you can react" is a ludicrous statement but it got you to open the article :-)

All organizational dysfunctions track directly to leadership failings (Part 3)

Thu, 24 Oct 2019 23:07:46 GMT

Threat spectrum revised: Violence is a distraction

The greatest differentiation for leadership quality and organizational effectiveness is approach to enterprise risk management. For optimal business resiliency it is necessarily an all-consequence effort. Any operational confusion poses distraction, ranging from minimum consequence and escalating to threaten enterprise viability. However, what do the seeming insignificant distractions mean? Is there more than simply the nuisance of noise and confusion for a “Day in the life…”?

For assessment and mitigation of hostile threats, expectations are for specific information of sponsor, method, and targets; absence of such is often used to delay or reject security related initiatives and limit funding. However, for virtual threats, emphasis is on identifying and reducing opportunities for intrusion with indifference to sponsor or motive. Network monitoring emphasizes detection and countering illicit access, including abuse of authorized-access. For external virtual threats, tactics/methods are necessarily shared across industry sectors because threat agility and incident volumes equate to a state of universal siege on information systems. Conversely, traditional physical security consulting often includes threat assessments extrapolated from collateral crime statistics, which are abstract and more obviously represent fear mongering for persuasion, relating to local personal safety and potential liabilities rather than coherent risk to an enterprise. Consequently, the essential significance and implication of these statistics is often unrealized. Three primary aspects of relevance apply: 1.Probability that a random incident may occur. 2. Any directly intentional threat may remain masked in the background noise, minimizing potential for detection and avoidance. 3. External emergency response capabilities may be limited and delayed as a result of collateral engagement, which extends necessity of self-reliance and increases due diligence liability.

The typical threat attribute that drives physical security investment is violence and its prevention at established operating locations. This begins with a spillover of domestic violence into the workplace, to active shooter, and because of international events, jumps to the severity of a coordinated terrorist attack, inclusive of various Improvised Explosive Devices (IEDs). The after-effect of a violent incident is psychologically persistent and undermines staff productivity long after the event. Additionally, it infers significant liability upon the organization for safety and security due diligence. However, legitimate concerns for safety of staff and guests from potential violence within controlled spaces, eclipses significant vulnerabilities to enterprise viability from intentional exploitation of persons, while away, because of their corporate affiliation and specific knowledge.

Rethinking the threat spectrum, by including accidental and non-violent categories for balanced all-consequence mitigation, facilitates comprehensive review and assessment of human factors, as a contributor to enterprise vulnerability. Personnel performance is naturally variable but is also susceptible to influence. Social-Justice emphasis and advocacy for tolerance and accommodation of human frailties shifts the burden of personal choice and discretionary behavior consequences from the individual to the community and within business can create Collective Bargaining contention and sympathetic conflict with Human Resource management, which undermine essential discipline for adherence to policies and procedures. The factor that misleads perceptions for necessity is, in a stable public-safety/rule-of-law environment, an enterprise can be commercially competitive with mediocre effectiveness as an organization.

No criminals or terrorist were injured in the making of these images. However, the severity of direct and extended costs and consequence should be obvious. The associated confusion and distraction from unintentional human-factor incidents because of neglected incompetence or corruption, provides conditional vulnerability from increased exploitation opportunities that attract malicious threats.

Optimal business resiliency requires enlightened, empathetic, leadership that inspires individuals to dissociate personal distractions by establishing an organizational environment where policies evolve for relevance, comprehensive process/procedures are implemented with fidelity, and performance is motivated by satisfaction rather than job fear or duress.

SCHOFIELD'S DEFINITION OF DISCIPLINE. “The discipline which makes the soldiers of a free country reliable in battle is not to be gained by harsh or tyrannical treatment. On the contrary, such treatment is far more likely to destroy than to make an army”.

I am not suggesting that commercial organizations emulate military culture, which is more stereotype than reality. Discipline, in contrast to dogmatic contractual obedience, is a result that any organization or activity would benefit from because it is intrinsically self-aware and collaborative. Time, place, and purpose add legitimacy where non-conforming activity attracts scrutiny. However, as everyone pitches in to keep things in motion there is seldom time to scrutinize something out of place because lean operations and just-in-time supply chain management places emphasis on tight production schedules relative to staffing capacity. When success metrics default to fixate exclusively on production quotas, distractions become immediately corrected nuisances, rather than realized as indicators of potential threat.

Vulnerability is compounded by typical administrative constructs that segregate security into specialized physical and information technology categories. Physical intrusions and violence are traditionally actions managed by physical security specialists, with virtual network intrusions and data security aligned to information technology departments. Separation reduces coherence, creating blind-spots in vigilance and gaps in procedural controls. Additionally, countermeasures for unauthorized access, physical and virtual, emphasize external threats as most obviously consequential, however statistical data indicates higher incident rates and severity from internal access abuses. The segregation of physical security and information systems security is problematic as they are two dimensions of the same challenge and function optimally when synchronized, in a holistic design, around preserving critical functions and information essential to enterprise viability. It is important to realize that critical risk to the enterprise correlates to confident information controls. However, such programs traditionally focus on physical and virtual security for handling documents, media, electronic data archives, and associated networks in their principal location, but do not fully account for vulnerabilities when exploitation of persons occur outside the physical security perimeter of their primary workplace.

Risk evaluation is appropriately applied to all employees and associated entities with access to information and controlled space, but must also account for them as guest at external facilities or sponsored events. The global nature of commerce has staff routinely participating in activities and events away from their primary location and its associated security foot print. During these occasions they potentially expose their knowledge of corporate affairs and impose vulnerability upon the enterprise. The cumulative amount and significance of the information present within a group or at a particular event defines its attractiveness for exploitation. Again multiple independent threats may coincidentally target the same event for different motives. A day in the life of… may not be as thrilling as cinema but it is far noisier and challenging to sort out. For any event, threat attraction can be inferred by estimating value/consequence from direct loss of attendees and the information they possess as well as the liability implications to not provide for safety and security of staff and guests, as a host/sponsor. Understand that exploitation does not necessarily mean violent disruption of the event but the event creates a convenient consolidation for potential targeting of participants, individually or collectively, because it fixes their presence in an unfamiliar location where they may not recognize surveillance or threat indicators, unless specifically trained.

It is reasonable to expect that any course of action taken by a belligerent would be intentionally innocuous as it builds to culmination. This creates a challenge to situation awareness because threat actions, if suspected, may be confused with random criminal activity or social activism. Likewise, legitimate activities of labor, environmental, or human rights organizations may be unwittingly exploited to compliment or divert attention from a more divisive scheme that remains unrealized by civil authorities or security staff. This vulnerability, when assessed and viewed with a local or tactical perspective, ensures the tendency to over secure a site by creating and defending a strong point. As indicators support the conclusion of hostile interest, the immediate objective should be to inventory staff and information then modify security in a manner that prevents or restricts further collection of information so that attack opportunities are denied or delayed until counter-measures can be employed. However, is elevated security effectively extended beyond the formal venue and are personal behaviors undermining security efforts by wandering away from secure settings or by not communicating changes in location or coordinated itinerary? This is where procedural controls and personal discipline are essential to protecting both the individual and the enterprise.

Executive staff is routinely protected however, certain non-executive staff positions or incidental groupings of individuals achieve a special level of significance because the cumulative information they possess deserves special security consideration as an essential asset. Enterprise risk programs should proactively track and manage these exposures.

Consequence Criteria:

Sensitive information , if disclosed would damage corporate operations within a state or province through the potential loss of product or staff and diminish corporate prestige at the local level.

Protected information , if disclosed would cause serious damage to corporate operations across a country or geographic sub-region from the potential loss of infrastructure or capability and diminish corporate prestige at a national level.

Guarded information , if disclosed would cause exceptional damage to the design and intentions of the corporation through the potential loss of pending litigation, market share, technology, or competitive advantage. Additionally, disclosure will diminish both the prestige and economic viability of the enterprise by providing cause for class action litigation or government action.

Target Susceptibility/Selection Criteria:

Who/Why: The significance and consequently attractiveness of any individual, group, or event as a target must be continuously evaluated because it will change with the circumstances and dynamics of both business and regional politics. However, why can be more confidently determined and used to define a scope for program development.

Knowledge

Business Plans
Mergers and acquisitions
Production details, partnerships, and modernizations
Market analysis supporting operational decisions

Litigation/legal

On-going liability (Corporate Defendant)
Proposed (Corporate Plaintiff)
Patent Applications

Technology

Intellectual Property
Access to corporate internal systems and spaces
Access to corporate services subscriber/client information

Prominence

Wealth

Affiliation

How/Where: Discerning the methods of how a threat may take action depends on a clear recognition of who is the threat and what is their intent. However, where can be more confidently anticipated because facilitated introspection will expose opportunities that enable threats to gain access and influence over persons that meet the criteria for an attractive target. This has implications for the selection and preparation of an event venue or rejecting a meeting or its suggested location as unsuitable because safety for personnel and control of information cannot be confidently established.

Typical defensive thought predisposes everyone to assume they are the intended target. Consequently emphasis is on countering direct threat actions. Additionally, discussions typically address singular events or one threat at a time, assuming emergency services are exclusively available. However, different threat motives will be attracted to different facets of an operation or activity and expectations should include that multiple threats may develop independently but manifest collaterally.

These inclinations represent the biggest fallacy in traditional security/risk planning and preparedness because an exploitation or attack may be motivated by the potential to indirectly gain access or influence over a third party. Appreciating the potential for indirect cause and effect will likewise enable a better appreciation of critical vulnerabilities that result from functional interdependencies.

The political and commercial significance of corporate activities within many countries routinely has prominent persons from outside of the organization present. This condition may attract and inadvertently introduce their uniquely associated threats into the situation to gain an exploitation opportunity. Detection signatures for third party threats may not conform to monitoring parameters, remaining unnoticed until post incident investigation makes them obvious.

Inevitably threat and target will meet. In some instances, threat proximity must be achieved for individuals, in others a device. Additionally, does threat intention or success require recovery/removal of an individual, device, or data? Concerns for operational simplicity will cause potential threats to first assess the static security profile for gaps/lapses. If necessary, a more sophisticated, coordinated action, incorporating cover and diversion will be considered; defensive actions drive threat evolution. An observable elevation in security profile may deter lesser threat actions but is seldom prepared for the level of sophistication it has inadvertently stimulated from a more determined threat. Additionally, violence potential is a distraction that generates alarmist tendencies, which must be managed so that an overzealous security profile or response escalation does not excessively restrict the essential activity it intends to protect?

Threat Spectrum, reevaluated:

Espionage has the lowest probability for violence but the greatest potential for adverse impacts. Information advantages enable competitors to outpace targeted program objectives as well as disruption by provoking negative publicity or litigation. These activities are intentionally clandestine and seek long term financial benefits. They may range from a onetime elicitation opportunity during a conference to persistent leaks that continue because of monetary inducements and because the absence of overt violence keeps them beyond the attention of security or law enforcement (LE). The corporate identity is the reason for the attack and at the worst; consequences intend to adversely affect the entire enterprise. There is a wide range of motives for acquisition and exploitation of information, which include:

Entities that want to out maneuver a competitor in order to win a service contract with the targeted entity.
Entities that want to increase their position/value anticipating acquisition.
Separating Employees seeking advantage in the job market.
Information brokers that acquire and sell information of strategic business value about the targeted enterprise and its clients.
Direct targeting by commercial business sector competitors.
Direct targeting by nation state sponsored commercial competitors.
Activism supporting a public or legal attack that may delay or undo business planning.

Studies have indicated that employees anticipating separation are inclined to abscond with information that they believe may be of value in securing their next employment. Pilfering information is seen as clean or benign and not easily proven or prosecutable, so there is reduced psychological deterrence than for traditional larceny. Additionally, there is still knowledge in their heads that is impossible to account for and control. Non-disclosures agreements are seldom enforced until after damage is done.

Crime (Petty and Organized) increases the probability that localized violence will be a factor because expediency and intimidation are employed to prevent victims from taking effective action. These activities are typically covert and seek immediate or near term financial benefits by absconding with something of marketable value. This category of threat will target individuals for both the value of their personal assets as well as their corporate affiliation. Therefore, it is important for the corporation to internally determine the extent of their liability and obligation to pay for the safe return of any employee while on official travel as one factor in determining what ways and means are appropriate for establishing security in the first place.

Terrorism is violence first. The political motives of terrorist often take resolution out of the hands of corporate leaders. The emotional nature of kidnappings, hostage killings, and potential use of explosives and mass effect weapons, means that any person or entity may be directly or indirectly affected. Sensational consequences intend to be undeniable. Attacks may have consequential spill over or compounded effects and force evacuation of nearby facilities or communities and delay resumption of operations within the affected area. This leads directly to a correlation between security preparedness and feasibility for business continuity of operations when one operation is disrupted by an attack against a neighbor. Recorded events for large industrial accidents best approximate what a terrorist attack may intend to create. However, unlike an accident, the determined nature of a politicized threat means that once committed to action something will occur. Currently it is the political /national affiliation of the corporate identity that determines attractiveness as a target and although, an attack may be devastating (loss of staff and facilities) within a local context, the long term effects are likewise localized to the area of the attack unless the corporate identity becomes the target motivating a systematic campaign directed across the enterprise.

Natural Events are significant in the extent and duration that they may disrupt infrastructure and prevent resumption of operations in addition to the direct threat to personnel safety. The scale of some natural disasters, including pandemics, takes recovery out of the hands of corporate leaders and challenges the appropriateness of planning assumptions/provisions for business continuity. Terrorist hope to achieve the level of devastation witnessed during natural disasters but until that potential is reality, the review of these events is still the best way to evaluate scalable businesses resiliency and the potential success of business continuity preparedness for all hazards.

Threat Categories:

For optimal Enterprise Risk Management, another order of magnitude for analysis and planning integration is necessary. Deliberately expanding the scope of traditionally realized threats to include all consequences makes planning for mitigation and response more inclusive across enterprise leadership because it compliments operational efficiency studies and performance goals. Getting safety and security into routine, multi-echelon/multi-discipline management, discourse will be a significant improvement for most organizations.

Threat Categories:

1. Compliance Failure ; is the most obvious category of threat, which is the basis for ubiquitous procedural controls. Consequence could be a fine or curtailment of operations resulting from an audit. Compliance standardization intends to establish a baseline practice that instead is often implemented as an achievement goal, which ultimately limits both investment and thoughts on the matter.

2. Accident ; threats do not need to be malicious to impose significant consequence. Incidents are often linked to compliance violations compounding consequence. Therefore, accident prevention often becomes an item in managerial performance evaluations. However, accidental incidents are seldom reviewed for conditions which may be intentionally contrived.

3. Incompetence and Corruption ; internal and external, here is where leadership is most critically influential; reducing undesirable human factors that impose both physical and psychological consequence on the enterprise. Internally, developing performance measures of effectiveness (PME) for critical tasks helps maintain efficiency and highlights priorities for staff training programs.

4. Business Sector Competitors ; as a category includes both intentional actions by known entities and unintentional market turbulence that may cause key contractor/vendor businesses to fail, imposing consequence. Vendors and contractors may not be fully realized as essential and their business viability may fail independently of your contracted relationship.

5. Organized Crime ; as a category is inclusive of all illicit maliciousness, from petty larceny to politicized hostilities (terrorism).

6. Civil Disruption ; as a category is inclusive of labor strikes, targeted boycotts, and unrelated civil disruptions.

7. Severe Weather and Natural Disaster ; as a category includes pandemic.

Any assessment or survey determining exploitable vulnerability must consider, first and foremost, the susceptibility of the facility or activity to information collection. This includes information from direct observation as well as information disclosure resulting from the subject's operational practices. Additionally, every facility as well as the staff has identities in a local community. How much information is either in the public domain or filed and available through contractors or vendors? Consideration must also include casual discussions by employees away from work. Regardless of the sensitivity or location of a facility, it is erroneous to assume that information is not available or that it can be absolutely controlled. Therefore, the most significant realization available to security planners is to understand and accept the amount and nature of information available to anyone interested in investigating their site/operation.

Every task may be important to the person it is assigned to, because of personal performance evaluation, but not all routines are essential to enterprise viability. For differentiation, tasks that have a direct and immediate impact on internal productivity are considered essential; tasks that impose consequence on an external entity are critical. i.e customs declarations may be perceived as a simple clerical task but when values for quantity or country of origin are incorrect, the delay can have significant impact on downstream entities depending on delivery. All actions associated with the data entry on a customs form should be deliberately scrutinized and controls implemented to correct errors before the port of entry.

It does not matter how secure your network is if you can not retain talent and sensitive information walks out the door. An outstanding technician, in at start-up, may not have the skills or demeanor to effectively supervise persons as the organization grows, just because of seniority. Inappropriate lead or manager selection, often has a detrimental impact on an entire section, which compounds vulnerability because of reduced production and talent retention. Retaining talent must address multiple aspects of personal expectation and satisfaction. Do Performance Improvement Plans (PIP) as implemented, effectively remediate performance or is it a mechanism to avert termination recourse? Does the write-up on a PIP actually reveal a supervisor inadequacy? "At will" contract provisions reduce scrutiny of managerial competency.

Optimal risk reduction, especially for human factors, comes from diligent preparedness with relevant policies, comprehensive procedures, and disciplined behaviors. Redundant checks and balances for essential and critical tasks with responsive feedback loops for non-conforming activity are paramount. Know what is vital, be sure of your capabilities, strive to increase self-reliance, but know when and whom to ask for assistance then facilitate transition of incident control. Only enlightened leadership can move an enterprise beyond mediocre management effectiveness. When the full extent and potential of the organization is consistently accessed, vigilance need not be exhaustive nor preparedness burdensome and return on effort is resiliency providing agility, competitiveness, and profitability

All organizational dysfunctions track directly to leadership failings. (Part 2)

Thu, 24 Oct 2019 22:45:04 GMT

Situational Analysis: Ambiguous Threat and Operational Environment

Much has been written about the visceral similarities between war/conflict and business enterprise. The correlation is more than artful metaphor. We have Captains of Industry and military units identified as companies. Politics, commerce, and armed conflict are inextricably intertwined because they are societal manifestations of individual human nature and interpersonal relations. This may seem to stray from the topic but some philosophical introspection is important to set the context for discussion. Most attempts to transfer terms or process from one side to the other are often clumsy and ineffective. I will try to bridge some gaps from an “art of war” perspective, which derives from military campaign planning where complex operations are associated with immediate and severe consequences.

What ultimately determines success? Simplistically, some folks may quip, crossing the finish-line first and others, in our emoting, politically correct, self-esteem oriented times, may say, just crossing the finish-line is success. This is important because success is relative and in principal both are correct because success is accomplishing what you intended to do. However, are your aspirations feasible and is your ambition a vulnerability?

Ambiguity imposes risk, so how to proceed? Everyone constantly, and generally subconsciously, manages ambiguity. Individual experience and personality establish confidence and a personal comfort zone for accepting uncertainty. Audacity in some is offset by other’s hesitancy. Averseness generally comes from knowledge or perception of direct consequences or concern for unintended consequences and desire to avoid regret. Regardless, self-interests/preservation predisposes choice and although caution can lead to “analysis paralysis”, conversely, it takes a keen edge to separate daring from reckless.

We each introduce our individual perspectives into any group effort and attempt to imprint onto the collective demeanor. This alchemy of personality blending can be synchronous or dissonant. Acceptance of any proposition depends upon the effective organization of relevant information and reasoning used to persuade others that risk is manageable and consequences can be avoided or will be tolerable. So, how best to support that argument? Most importantly, once you gain consent, how do you maneuver through ambiguity to accomplish your goal while maintaining stakeholder confidence?

I suggest orienting on developing information collection and intelligence production that corresponds to the planning, decision, and execution activities within the enterprise life cycle. Information requirements supporting decision‐making are specific and change with the phase of evolution from concept, to creation, through growth, to sustainment. However, regardless of complexity or context there are three key questions that can be used to bring order to the most chaotic and ambiguous situations and will reduce risk by differentiating relevant from distraction.

Of course these three questions must relate to an accurate understanding of the strategic goal for friend and/or foe. Internally this may be a competently articulated mission statement or an unpublished but commonly acknowledged intent. When used to correlate with a competitor, specific information collection must corroborate published positions or intelligence should be used as the basis to redefine it. This provides clarity of purpose and intent that all associated activities can align with and enables effective sifting through the datascape of any situation to visualize the essential scope and sequence of operational development, also revealing where critical risk may exist.

Used as a template, it adds value to either macro analysis or micro scrutiny correlating to the strategic goal/terminal objective/end-state of a proposed campaign i.e. increased market share, new product acceptance, expanded operational area, merger/acquisition, amicable separation, or regime change. Likewise, when applied to a competitor or adversary it can be used to aid predictive analysis because subconsciously humans process information in the same way, but thankfully with a wide range of effectiveness. There may be nurtured differences between individuals or groups because of industry or social culture and experiential influences, however the reasoning process or nature, remains the same. It is important to assess individual influence before making a conclusion or prediction about collective persona.

Regardless if it is a start-up or a new initiative in a mature enterprise, it all starts with what seems to be a good idea, which must be converted into a feasible proposition that can be successfully executed. This must begin by formulating a mission statement inclusive of purpose, method, and end-state. Once you have Who, What, When, Where, and Why, the concept of operation or How becomes more intuitively obvious.

Although any plan must proceed on assumptions, it is essential to develop an information collection plan that replaces assumptions with facts and monitors for situational changes that will affect planning conclusions. These are indicators of consequence and potential risks should be tracked with Priority Information Requirements (PIR). PIR may be further emphasized for correlation with essential decision points by leadership as Critical Information Requirements (CIR). CIR focuses information collection and differentiates actionable PIR from trivial pursuit and statistical aggregation that often distracts Competitive Intelligence (CI) schemes. CIR validates operational planning assumptions and indicates a prudent adjustment to intentions, timing, or reallocation of resources relative to the strategic goal. Also, restraint is imperative so that assumptions are minimized to only what is essential to move the concept forward and protect vulnerabilities.

As answers/data for these questions populate, it will become obvious where there are shortfalls and what essential resources or capability must be acquired, spawning nested actions and supporting plans, essential to overall feasibility. These tangential requirements are developed into planning branches and sequels that must be confidently completed to meet intermediate, conditional milestones. This incremental approach avoids consequence from over commitment of resources by matching investment and effort to ongoing feasibility determinations. Additionally, this process enhances operational agility by providing proactive recognition to circumvent or mitigate emerging technical or political obstacles. Natural compartmentation and parallel planning opportunities from branches, provides intrinsic security potential when managed intentionally; otherwise it represents a significant vulnerability that will compromise the outcome from accidental disclosures or easy exploitation. This systems perspective is critical and why an optimal safety and security profile should not fixate on monitoring people, places, or things but be designed to preserve essential functions and sensitive information critical to enterprise viability, which, of course, is comprised of people, places, and things. The subtle shift in rhyme and reason is significant.

Effective decision-support requires accurate information and competent analysis that values multi-source corroboration and understands that annual reports are, to a certain extent, marketing propaganda and may not reveal all significant intentions. Convenient information should be suspect as should CI vendor products. Once there is confidence for understanding of the Strategic Goal, the remainder falls into place with the three key questions.

These questions merge perspective for what is often segregated as strategic, operational, or tactical. This facilitates a concise introspection deriving an essential scope and direction for operational development and intuitively identifies where safeguards should be emplaced.

When extended, these three questions accommodate a broad range of analysis and planning approaches and terminologies. The most important observation is that where some organizations differentiate planning teams by Strategic or Tactical orientation, it is essential that each focus group understands its relationship to others and the overall strategic goal so that within their respective spheres of responsibility, operations can be paced to complement the system as a whole i.e. if a regional transportation slowdown is expected, can stockpiles be created by a temporary production surge to keep assembly rates at the requisite level to satisfy contract terms or can redundant transportation arrangements be made? If political obstacles are anticipated at a specific port of entry, what alternate routing options can be arranged? If a key contractor is lost to merger/buyout by a competitor what arrangement will reduce the impact? What affect will product diversion or counterfeiting have on timelines and relationships?

Planning dynamics are fairly unique within the scope of each question. However, associated operating locations will be engaged in a myriad of local routines, which could, accidentally or intentionally, adversely affect throughput and subsequently disrupt the whole system. Holistic, vulnerability assessment is imperative.

When applying these questions for predictive analysis of potential illicit threats, evaluation of their public rhetoric or past actions will provide a reasonable assessment of their strategic goal. Differentiating but processing threats, across the spectrum, in a similar manner will enable a comprehensive correlation of probable actions against system vulnerabilities so that countermeasures can be justified and implemented.

It takes a keen edge to separate daring from reckless and three key questions to manage the significant risk that ambiguity represents. This is the initial entry point for application of mature processes of intelligence and operational planning created, refined, and proven in the high threat ambiguities of war, which are relevant to business and competitive intelligence. Embrace daring, resist reckless, Business is war!

All organizational dysfunctions track directly to leadership failings (Part 1)

Thu, 24 Oct 2019 22:29:11 GMT

Do not base your safety and security on a LIE.

It is often, critically, said that the military prepares to fight the last war. Then how is a civilian/commercial organization expected to prepare for circumstances they have never experienced?

All organizational dysfunctions track directly to leadership failures. This may seem a dramatically provocative statement however; it is precisely that optimal organizational effectiveness is not quantifiable because, an organization cannot manage its way to excellence. Yes, good management technique is essential but effectiveness is ultimately determined by how thoroughly and consistently enlightened leadership accesses team potential, relative to situational circumstances. Does performance equal or exceed the sum of the parts?

The first aspect of differentiation is framing the operational situation in a mission statement inclusive of purpose, method, and end-state. Without an effective mission statement that provides an external strategic objective to synchronize constituent components within the organization, personality driven self-interest begets politics and internal competition imposes operational myopia on the organization as a whole. These are predictable human factors that exist regardless of accent, complexion, or cuisine. Additionally, the two biggest, collectively self-imposed, organizational vulnerabilities are over-specialization and just-in-time supply chain management, which reduces systemic resiliency and situational awareness.

These inclinations persist because they represent quantifiable economies that in a profit and loss perspective seem sensible. However, they are sensible only to the extent that operational realities have been included in planning. The assumption of stability in external, sector and social, context of operating locations or accountability for functional interdependencies, beyond the Org Chart and parcel boundary, is where the variation in organizational effectiveness originates.

Organizational planning for competition of market share, product diversification, or access to new market regions are traditionally obvious priorities, which correlate to profit and loss projections emphasized for shareholders. However, the consistent vulnerability and source of all risk is not adequately securing the return on investment with contingency plans that have conditional branches and sequels tracking to the strategic objective. Sure, traditional risk management will obtain insurance coverage for potential loss but that is not as effective as avoiding crisis and consequence through situational understanding and operational agility. There are shelves of documents with Plan in the title that are simply a compendium of procedural statements without resourcing or authorities and therefore, are not executable during crisis. This is usually because they have never been rehearsed for validity, even in a limited table top exercise.

LIE or Last Incident Experienced is too often the rationale for safety and security investment when regulatory compliance is not applicable. This is not a revelation but rather a predictable condition of subjective adequacy with the challenge of quantifying cost/benefit. In situations where regulated compliance establishes standardization, it inevitably becomes the limiting factor although intended as a baseline. Compliance only guarantees avoidance of consequence from audit, not resistance to a determined threat. What reasoning can be used to establish how far performance and preparedness should extend beyond operational routines? What level of staff, training, equipment, and technology are prudent for hypothetical situations that may not occur?

Direct quantifiable correlation is a traditional business management expectation. In contrast, themes of Business Resiliency or Operational Assurance evoke astute but less obvious leadership choices and advocacy that without elaboration, conflicts with conventional wisdom defined by ledger performance. This dynamic, invariably results in a compromised outcome unique to each organization and propagates across an industry when bench-marking is used to model safety and security practices.

Safety and security budgeting may be conveniently managed when segregated as specialized services but functional alignment within an organization has significant influence on attitude of how those services relate to the operation as a whole. Traditionally, viewed as a cost center, there is constant pressure to limit expenditures through staffing reduction, delayed systems extensions and upgrades, or denied training and equipment investments. These predicable management inclinations impose significant vulnerability that any malicious threat expects and seeks to exploit.

The Leadership counterpoise resists bench-marking by orienting introspectively to deliberately construct a safety and security profile, which preserves critical operational functions by insulating them from distraction or disruption. This proactive operational alignment and approach accepts safety and security as essential underpinnings that will advance enterprise agility, competitiveness and profitability. Additionally, fusion of safety and security vigilance with core operational and asset management transforms situational awareness into situational understanding, which provides both optimal effectiveness and economy while increasing confidence and productivity by extending the threshold for transition to crisis management. Within military units, Force Protection is an operational function establishing priorities and policy although it is implemented and executed across multiple elements. This functional task-organization is independent from location or administrative organization but this flexibility is seldom approximated in civilian/commercial organizational constructs.

Semantics is the consistent weak point in Risk Consulting. Threat, Vulnerability, Risk, Consequence are often mixed or interchanged and further misunderstanding is compounded because typical context for Risk in commercial corporations are workmen’s’ compensation claims and insurance coverage to minimize exposures primarily from accidents. These synchronize with OSHA compliance regulations, which is the default scope for familiarity of these terms. However, the essential connotation of Risk is probability of action by a known Threat entity. For an intentional man-made Threat to be viable it must include three elements: Presence, Capability, Intent, without any one of these elements there cannot be any quantifiable probability, only conjecture for possibility, which is popularly acceptable in academic discourse but remains operationally ambiguous and generally inadequate for justifying resource allocation in a constrained and competitive corporate environment.

So, short of an unambiguous Threat, preparedness can proceed by facilitating introspection to reveal operational frailties as Vulnerabilities. Then hypothetical accidental and intentional actions affecting those Vulnerabilities are built into illustrative scenarios for how damage might occur. This enables development of indicators for monitoring the disposition of any Vulnerability to detect potential emerging Threats. Therefore, Vulnerability becomes the most significant assessment to be made. With Consequences quantified for each Vulnerability, priorities for safeguards and precautions become self-evident, requiring less convincing than when consequential action is hypothetically attributed to a specific Threat entity, as an abstract possibility.

Once critical/essential functions have been inventoried, the range of potential events or incidents for consequence management is intuitively categorized as Man-made or Natural, then within Man-made as Accidental or Intentional then sequenced according to frequency within those categories.

Hospitality has become a desirable attribute to increase employee happiness and visitor satisfaction. As an aspect of branding/image, positive public perception is emphasized, which often means an inclination to handle incidents quietly without external intervention or publicity. However, safety and security incidents do not only affect perception but also have physical consequence and legal liabilities. After an incident, investment avoids repeating the experience but in actuality the organization remains reactive and unprepared because it has not correlated safeguarding of critical functions against the full spectrum of potential threats. Violence is a distraction to be aware of!

A determined threat will adapt to overcome any security profile presented. In any case the threat intends to get as close to the objective as possible without detection and then decisively overwhelm any defense. This will predictably incorporate a guise of legitimacy to cover preliminary surveillance of the target in order to determine optimal timing and location for an attack. Any threat will first determine opportunities then qualify them for probability of success before hostile action occurs. Consequently, achievable proximity is the single most significant factor for predicting threat presentation. However, different motives will target different aspects of an operation. Expectations should include that multiple threats may develop independently but manifest collaterally. The common denominator is ACCESS, physical or virtual. Therefore, security measures are validated by how thoroughly they reduce access vulnerabilities, discern suspicious activity, accurately differentiate potential threats, and enable timely response or appropriate countermeasures that directly prevent or mitigate the severity of consequences.

In order to achieve a Return on Investment (ROI), all security staffing, training, policies, procedures, and technology must be relevant to these attributes and valuated using a formalized “Risk Assessment” methodology. Do not base your safety and security on a LIE.