PAES e PASS: opportunità da cogliere?

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1 primo corso di aggiornamento NOVITÀ IN FARMACOVIGILANZA PAES e PASS: opportunità da cogliere? Fabrizio De Ponti Dipartimento di Scienze Mediche e Chirurgiche Alma Mater Studiorum Università di Bologna Good Vigilance Practice (GVP) 7 Moduli adottati (I, II, V, VI, VII, VIII, IX) I Title First published Pharmacovigilance systems and their quality systems 25/06/2012 II Pharmacovigilance system master file 25/06/2012 V Risk management systems 25/06/2012 VI Management and reporting of adverse reactions to medicinal products 25/06/2012 VII Periodic safety update report 25/06/2012 VIII Post-authorisation safety studies 25/06/2012 IX Signal management 25/06/2012 1

2 New Definition Any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures. [Past definition: A pharmacoepidemiological study or a clinical trial carried out within the terms of the marketing authorizations conducted with the aim of identifying or quantifying a safety hazard relating to an authorized medicinal product] Objectives PASS to quantify potential or identified risks to evaluate risks of a medicinal product used in patient populations for which safety information is limited or missing (eg pregnant women, specific age groups, patients with renal or hepatic impairment) to provide evidence about the absence of a risk to assess patterns of drug utilisation that add knowledge on the safety of the medicinal product (eg indications, dosage, co-medication, medication errors) to measure the effectiveness of a risk minimisation activity. Arrhythmogenic potential of drugs 2

3 THE POPULATION PERSPECTIVE POPULATION DRUG PHARMACOEPIDEMIOLOGY European exposure to ARITMO drugs with relevant risk level PASS: gli standard scientifici e di qualità Riferimento a linee guida scientifiche rilevanti per: lo sviluppo del protocollo di studio, la conduzione, la stesura dei reports, la valutazione dei protocolli e reports da parte del PRAC e NCAs. ENCePP Guide on Methodological Standards in Pharmacoepidemiology ENCePP Checklist for Study Protocols Guideline on Conduct of Pharmacovigilance for Medicines used by the paediatric population for studies conducted in children Guidelines for Good Pharmacoepidemiology Practices of the International Society of Pharmacoepidemiology (ISPE GPP) 3

4 PASS: Armonizzazione e procedure devono avere un protocollo scritto prima dell inizio della raccolta dati; (possibilità pre-sub meeting); Coinvolgimento del QPPV nella revisione e firma dei protocolli di studio condotti in EU; Richiesto uso di template per protocollo, abstract, rapporto finale; protocollo sottomesso al PRAC ; decisione del PRAC entro 60 giorni; studi possono cominciare solo dopo approvazione scritta e trasmissione del protocollo approvato a NCAs; ogni emendamento al protocollo deve essere sottoposto al PRAC; (anche progress report, final study report); registrazione dello studio in EU PAS PASS: trasparenza pubblicazione risultati studio: publication policy (casi in cui l investigatore è indipendente); fornire il manoscritto a AC entro 2 settimane dall accettazione per pubblicazione; Il titolare di AIC rende disponibili informazioni nel Registro elettronico degli studi autorizzativi (Registro EU PAS) gestito dall Agenzia ed accessibile attraverso il portale web europeo dei farmaci; Effettuare la registrazione per tutti i PASS. 4

5 EU PAS register transparency, exchange of information, peer review supports EMA to fulfil its obligation to make public protocols and results of PASS imposed as an obligation supports MS to ensure that the public is given important information on pharmacovigilance concerns repository of all non-interventional PAS conducted in the EU, irrespective of the source of funding and status of investigators (MAH, academia, regulatory or public health authorities, ) NOT to replace regulatory submission for imposed studies Accepted by MS as means for submitting information on studies conducted voluntarily (Annex 1 of GVP Module VIII) EU PAS Register to be developed as upgrade of ENCePP E-Register of studies and will include already registered studies, including ENCePP seal 5

6 Un esempio che dimostra la necessità dei PASS: Incretinomimetici e Pancreatite Nel 2006, emersero i primi case reports - Denker PS, Dimarco PE. Exenatide (exendin-4)-induced pancreatitis: a case report. Diabetes Care 2006;29:471 - Ahmad SR, Swann J. Exenatide and rare adverse events. N Engl J Med 2008;358:1970 La Ditta inserì l informazione nella RCP (ottobre 2006) L FDA pubblicò due warning (ottobre 2007 e agosto 2008) Gli studi analitici su database amministrativi o cartelle cliniche elettroniche non trovano un rischio significativo: Dore et al. A cohort study of acute pancreatitis in relation to exenatide use. Diabetes Obes Metab 2011; Garg et al. Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: a retrospective observational pharmacy claims analysis. Diabetes Care 2010;33: Gli studi di disproporzione sulle segnalazioni spontanee forniscono risultati discordanti: Hauben et al. The Importance of Reporting Negative Findings in Data Mining. The Example of Exenatide and Pancreatitis. Pharm Med 2008;22: Elashoff et al. Pancreatitis, Pancreatic and thyroid Cancer with Glucagon-Like Peptide-1-Based Therapies. Gastroenterology 2011 Jul;141(1): We downloaded the FDA AERS database for the period covering the first quarter of 2004 through third quarter of >6-fold increased reported adverse event rate for pancreatitis with [ ] exenatide 6

7 ROR cumulative No. of Reports 5 Weber effect Notoriety bias 5000 FDA approval (April 28, 2005) 4500 ROR cumulative with 95%CI New indication with TZD (December 22, 2006) FDA ALERT (October, 2007) FDA ALERT UPDATE (August 18, 2008) Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q4 No. of Reports Year-Quarter Raschi et al., Acta Diabetologica, in press (PMID: ) JAMA Intern Med Feb 25:1-6. Cancer? Class effect? 7

8 Safeguard (Safety Evaluation of Adverse Reactions in Diabetes) RCT SRS HCD Lit PAES: questioni aperte Guideline document by EMA Place in therapy as compared to the standard of care Superiority vs non-inferiority design subpopulations most likely to benefit from drug Unmet clinical needs vs drug policies (payment by results) Cooperation (drug companies academia regulators) 8

9 EMA EC PASS PAES ACADEMIA DRUG COMPANY 9