Bergamo, 20 settembre 2012

1. SERVIZIO FARMACEUTICO TERRITORIALE ESPERIENZEDI FARMACOVIGILANZA IN PROVINCIA DI BERGAMO L’evoluzione della Farmacovigilanza e i suoi nuovi orizzonti Achille P. Caputi Dipartimento Clinico e Sperimentale di Medicina e FarmacologiaUniversità degli Studi di Messina Bergamo, 20 settembre 2012

2. Disclosure I have received consultant and speaker fees from: AstraZeneca, Bayer, BMS, Chiesi, DOC-generici, Eli Lilly, Grunenthal, MSD, NovoNordisk, Pfizer, Rathiopharm, Rottafarm, Sanofi-Aventis, Schering-Plough, Servier, Theva Assogenerici, ANIFA I have received grant support for investigator-initiated research from: AIFA European Commission, FP6 and FP7 Programmes SIMG-HSD Roche

3. My talk today

4. “Primum non nocere” Ippocrate di Coo o Kos (Coo, 460 a.C. circa – Larissa, 377 a.C. terminus ante quem)

5. 1814: Uno dei primi case-report di farmacovigilanza N Engl J Med Surg 1814; 3:120-126

6. 1848: Death from Chloroform anaesthesia On JANUARY 28, 1848, only 3 months after James Young Simpson introduced chloroform in clinical anaesthesia, the first fatal case due to the inhalation of chloroform occurred in the British Isles. Thereafter, a number of deaths caused by chloroform inhalation occurred in succession. Lyman stated that between 1848 and 1881, 393 fatal casesoccurred during and following the inhalation of chloroform.

7. 1893: Report of the Lancetcommission on Anaesthetics “The Lancet set up a commission, which invited doctors in Britain and its colonies to report anaesthesia-related deaths. Thus, the forerunner of a spontaneous reporting system for suspected ADRs was established, at least for a time.”

8. 1937 - Elixir sulfanilamide 107 decessi negli USA a causa del dietilen glicole usato come solvente nell’elisir di sulfanilamide JAMA 1938; 111: 919-26]

9. “Regolamentazione in materia di farmaci”Origini della FDA 1906: US Pure Food and Drugs Act, 1° atto legislativo, – proibiva il trasporto fra gli stati di alimenti e farmaci adulterati o contraffatti (non esisteva ancora l’obbligo di stabilire l’efficacia e la sicurezza dei farmaci) 1938: US Food, Drug and Cosmetic Act • Test tossicologici per i farmaci prima della registrazione • Obbligo di dichiarazione della composizione e del metodo di preparazione dei farmaci • FDA autorizzata ad approvare o sospendere i farmaci

10. 1959 -1961: Disastro Talidomide

11. BillInman in 1960 Frances Kelsey Tempestività del segnale Va contro la certezza

12. l’affidabilità dei test sugli animali il comportamento dell’industria farmaceutica la necessità di sorvegliare i farmaci dopo la loro commercializzazione La tragedia della talidomide: pietra miliare della Farmacovigilanza

13. 1980: Prescription-Event Monitoring (PEM) “provides proactive post-marketing surveillance on a national scale”

14. History of drug safety: after thalidomide era • 1962: USA Kefauver-Harrise amendment to the law (requirement to prove safety and efficacy before issuing MA) • 1963: resolution WHA 16.36 reaffirmed the need for early action in regard to adverse drug reactions • 1964: UK started “yellow cards” system • 1965: European Union issued EC Directive 65/65 • 1968: start of WHO Programme for International Drug Monitoring • 1969: start of FDA-AERS system

15. 1941-1971:Dietilstilbestrolo (DES)

16. 1970-1976:Practololo e sindrome oculo-mucoso-cutanea • 1970: entra in commercio • 1972: primi casi di dermatite • 1974: cheratocongiuntivite in pazienti che avevano precedentemente sviluppato dermatite • 1974: primi casi di peritonite sclerosante • 1975: definizione della sindrome oculo-mucoso-cutanea • 1976: ritiro dal commercio Nel corso della sperimentazione clinica pre-marketing era stata registrata, ma giudicata irrilevante, una maggiore incidenza (20%) di disturbi oculari nel gruppo trattato vs il gruppo controllo (6%)

17. NON SISTEMATICA • SISTEMATICA • Organizzata • Sollecitata • Regolamentata • Non organizzata • Non sollecitata • Non regolamentata Dopo la tragedia della talidomide, la segnalazione spontanea da: • Inizio della segnalazione spontanea sistematica • Spontaneous Reporting Systems, SRS

18. Spontaneous Reporting System

19. 1968: nascita “WHO International DrugMonitoringProgramme”

20. My talk today

21. Some post-marketing withdrawals for ADRs RCTs (some withthousandspatients) hadfailedtodetectADRs; Safetyprofileof some drugswasreported = thatof placebo

22. NO I trial clinici pre-marketing sono capaci di prevedere che un farmaco, al momento dell’ AIC,abbia un profilo rischio beneficio accettabile?

23. International Conference of Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH E2E: Pharmacovigilance Planning. 2004; http://www.ich.org (accessed 1/12/2009) The decision to approve a drug is based on having a satisfactory balance of benefits and risks within the conditions specified in the product labeling. This decision is based on the information available at the time of approval. The knowledge related to the safety profile of the product can change over time through expanded use in terms of patient characteristics and the number of patients exposed. In particular, during the early post-marketing period, the product might be used in settings different from clinical trials and a much larger population might be exposed in a relatively short timeframe. Benefits and risk

24. Requiring that drugs on the market be completely safe is an impossible goal. The real question is whether a drug’s dangers are in some acceptable proportion to the good it does. Jerry Avorn

25. The rapidly widespread and often prolonged use of drugs could mean that even a small increase in the risk of a serious adverse event could be very significant in population health terms “Every new drug should enter the population of patients in a slow, monitored, and— importantly— an aselect and noninterventional way, maximising the accumulation of experience and minimising risk exposure”. Meyboom RHB, Edwards IR. Rosuvastatin and the statin wars—the way to peace. Lancet 2004; 364: 1997-9.

26. Evoluzione della percezione del rischio (e beneficio) e comunicazione del rischio Vecchi farmaci e nuove

27. It should be noted that in 2009, the number of new or updated boxed warnings (n=31) exceeded first-in-class new prescription drugs (n=26) approved by the FDA. Number of new boxed warnings per year a2004, All antidepressant medications received a boxed warning this year. b2005, All NSAIDs received a boxed warning this year. c2008, All antipsychotics, conventional and atypical, and all fluoroquinolone antibiotics received a boxed warning this year. Matlock A et al. Clinical Toxicology 2011; DOI: 10.3109/15563650.2011.564585

28.  Common Drug Classes with Boxed Warnings O’Connor NR. FDA Boxed Warnings: How to Prescribe Drugs Safely. Am FamPhysician 2010; 81: 298-303, 304.

29. Recommendations Against Use in Patient Subpopulation(Dusetzina SB et al., Impact of FDA Drug Risk Communications on Health Care Utilization and Health Behaviors. A Systematic Review. Med Care 2012; 50: 466–78) Communications cautioning use of a medicine or therapeutic class among a patient subpopulation, Telithromycin among patients with myasthenia gravis ACE-inhibitors among pregnant women Antipsychotics among the elderly with dementia or those with or high risk of diabetes or metabolic syndrome Antidepressants among children and adolescents, . Examples Between January 2006 and February 2007 the FDA issued a series of communications contraindicating telithromycin use in patients with myasthenia gravis, and removing indications for bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis. The proportion of all telithromycin prescribed for revoked indications was similar before and after the label change. A nationally representative physician audit identified substantial decreases in atypical antipsychotic use among elderly with dementia after an April 2005 black box warning that were accompanied by more modest decreases in use among those without dementia and for FDA-approved indications. ACE-inhibitor exposure among pregnant women in Medicaid from 1986–2003appeared to increase 4-fold, with no decrease after thewarning of FDA. A series of FDA communications about antidepressant use among children and adolescents were issued between June 2003 and October 2004. Most evidence suggests that there were substantial decreases inprescribing among children with more modest decreases among adults. The antidepressant advisories also had a variety of other effects, such as shifts in the market share accounted for by paroxetine, fluoxetine, and escitalopram; a shift away from diagnoses from primary care physicians; and a lack of non-antidepressant drug substitution.

30. Proactive Pharmacovigilance

31. National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance Project (NEISS-AIP) A partire dal 2004 63 ospedali degli USA ADR che inducono accesso ai dipartimenti di emergenza ed eventuale successivo ricovero Budnitz DS et al. JAMA 2006;296: 1858-66 Budnitz DS et al. Ann Inter Med 2007; 147: 755-65 Budnitz DS et al, NEJM 2011;365:2002-12 Cohen AL. et al. J Pediatr 2008; 152: 416–21 Schaefer MK et al, Pediatrics 2008;121;783-7;

32. Budnitz DS et al. National Surveillance of Emergency Department Visits for Outpatient Adverse Drug Events JAMA, 296:1858-66; 2006 warfarin, insulina, e digossina, con basso indice terapeutico ed alto rischio di tossicità sono causa di circa 1/3 delle ADE nei pazienti > 65 anni: dato importante per la prevenzione

33. National estimates of the numbers, population rates, and severity (measured by hospitalization) of individuals with ADEs treated in ED Active surveillance (1.1.2004-31.12 2005) through the National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance project (63 EDs) ED visit per ADEs = 21,298 annual estimate: 701,547 individuals (509.642-893.452) 2.4 (1.7-3.0) individuals per 1000 population, >65y: annual estimate, 4.9 vs 2.0 per 1000; RR= 2.4 (1.8-3.0) ADEs induced hospitalization = 3,487 individuals annual estimate: 117,318 [16.7% (13.1%-20.3%)]. >65y: annual estimate, 1.6 vs 0.23 per 1000; RR= 6.8 (4.3-9.2). Budnitz DS et al. JAMA 2006;296:1858-66

34. Drugindustry and safety(the inverse benefit law)

35. Recent highly publicized withdrawals of drugs from the market because of safety concerns raise the question of whether these events are random failures or part of a recurring pattern. The inverse benefit law, inspired by Hart’s inverse care law, states that the ratio of benefits to harms among patients taking new drugs tends to vary inversely with how extensively the drugs are marketed. • The law is manifested through 6 basic marketing strategies: • reducing thresholds for diagnosing disease, • relying on surrogate endpoints, • exaggerating safety claims, • exaggerating efficacy claims, • creating new diseases, • encouraging unapproved uses. Brody H, Light DW. Am J Public Health. 2011;101: 399–404.

36. Brody H, Light DW. Am J Public Health. 2011;101: 399–404.

37. Eudravigilance

38. My talk today

39. Proactive Pharmacovigilance ELECTRONIC MEDICAL RECORDS (EHR) DATABASES

40. 2008: FDA SENTINEL INITIATIVE A national electronic system launched in May 2008 by FDA, the Sentinel Initiative aims to develop and implement a proactive system that will complement existing systems that the Agency has in place to track reports of adverse events linked to the use of its regulated products. The Sentinel System enables FDA to actively query diverse automated healthcare data holders—like electronic health record systems, administrative and insurance claims databases, and registries—to evaluate possible medical product safety issues quickly and securely.

41. 2009: OMOP (Observational Medical Outcomesm Partnership) In partnership with PhRMA and the FDA, the Foundation for the National Institutes of Health launched the OMOP, a public-private partnership. This interdisciplinary research group has tackled a surprisingly difficult task that is critical to the research community’s broader aims: identifying the most reliable methods for analyzing huge volumes of data drawn from heterogeneous sources.

42. Objective To design, develop and validate a computerized system that exploits data from electronic healthcare records and biomedical databases for the early detection of adverse drug reactions

43. Data mining on electronic health record databases for signal detection in pharmacovigilance Data mining on electronic health records (EHRs) has emerged as a promising complementary method for post-marketing drug safety surveillance. The EU-ADR project, funded by the European Commission, is developing techniques that allow mining of EHRs for adverse drug events across different countries in Europe

44. Examples of pharmacoepidemiology databases • GPRD – GP research database in UK • HSD - GP research database in Italy • MEMO – Scottish record linkage data • Saskatchewan Health Services - Canada • Kaiser Permanente – US • Odense database- Denmark • PHARMO – Netherlands

45. Signal substantiation why? Once a signal is detected, has to be substantiated and validated Dramatic impact of true negative signals Prioritize the potentially true positive signals for further investigation Time- and energy-consuming process for signal validation how? Experts’ knowledge Epidemiologic evidence Biologic evidence Information about drug safety evolves over tim

46. Altre recenti iniziative

48. Grazie per l’attenzione Achille P. Caputi