This document provides an overview of pharmacovigilance systems and regulations in the US and EU. It describes regulatory oversight bodies, key regulations governing pharmacovigilance, safety reporting requirements during pre-marketing and post-marketing periods, pediatric legislation differences, and risk management strategies between the regions.

1. Pharmacovigilance in the US & EU Angie Barfield, RN, BSN 20 January 2009

2. When the system fails…. Avandia ® (GSK) Chantix ® (Pfizer) Vioxx ® (Merck) Baycol ® (Bayer) Tysabri ® (Biogen Idec) Ketek ® (Sanofi-Aventis) Zelnorm ® (Novartis) Lotronex ® (GSK)

3. Overview of Pharmacovigilance Literature Reports Spontaneous Reports Clinical Trial Data Regulatory Reports Licensing Partners Data Review Submission Amend Prescribing Information Review marketing status Licensing Partners World-wide Regulatory Reports (expedited and periodic) Enquiry Response Signal Generation Collect… Collate… Analyze… Communicate…

4. Risk Management Across the Lifecycle Product Life Cycle Capabilities Provided Approval Ph IV FIM PhI Ph II Ph III Address any new emerging safety issues Post approval studies and epidemiology Signal Detection Studies to better understand population, risks, etc Promote high quality analysis Determine appropriate label Estimate potential benefit Predict potential candidates Disease and patient population Mechanism of Action Studies Post Marketing Pharmacovigilance Clinical Development Drug Discovery/ Preclinical

5. Regulatory Oversight National Authorities – each country’s CA is responsible for monitoring the safety profile of product in its territory and taking action when necessary European Commission – Responsible for overall Community System of PV and for legal framework (authorization) EMEA – evaluate and supervise medicinal products in the EU and provision of advice on measures to ensure safe and effective use. CHMP - (Committee for Medicinal Products for Human Use) prepares the EMEA opinions/recommendations concerning medicinal products for human use US-FDA EU

6. Key Regulations Governing Pharmacovigilance 2001/20/EC Clinical Trials Directive 2005/28/EC Good Clinical Practice Medicinal Products for human use in clinical trials – Volume 10-Clinical trials Volume 9A Pharmacovigilance US-IND Annual Reporting 21CFR 312.33 Post-marketing Reporting of ADRs 21CFR314.80 PDUFA Reenactment with U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007, FDAAA) FDA Guidance Documents Premarketing Risk Assessment Development and Use of Risk Minimization Action Plans (RiskMAPs) Good PVG Practices and Pharmacoepidemiologic Assessment Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting to IRBs — Improving Human Subject Protection

7. MAA Approval Procedures in the EU Centralized Procedure EMEA Marketing authorization granted that cover all EU Member States and the EEA. Mutual Recognition Procedure – National Agencies + Mutual Recognition Facilitation Group Reference Member State - RMS Concerned Member State(s) –CMS Pharmaceutical companies who already hold a marketing authorization in one EU Member State ask additional Member States to recognize the marketing authorization that has already been granted. National Procedure National Agencies Marketing authorizations on a country-by-country basis by the competent authorities in each Member State. Different Labeling Requirements & Different Expedited Reporting Requirements/Timelines

8. Pre-Marketing Safety Reporting (EU) Investigational medicinal product – not just study drug but also placebo and any active comparator Electronic Reporting Mandatory! Treatment un-blinding before SUSAR reporting to CA/EC Information to EC Expedited individual case reports may be limited to domestic cases only. All other foreign SUSARS may be provided in a bi-annual line listing Information to investigators Investigator Notifications on findings which might have implications to subject’s safety Can be aggregated in a line listing of SUSARs + concise summary of safety profile Blinded trials should have blinded treatment information of all SUSARs (placebo/comparator included) Investigator Reports all SAEs Sponsor Reports all SUSARs* CA EC EVCTM *S uspected U nexpected S erious A dverse R eaction

9. Pre-Marketing Safety Reporting (US) Not required to send just expedited cases for placebo or active comparators FDA does not currently support electronic reporting for expedited case reports for clinical trials Treatment un-blinding prior to sending expedited report NOT required Sending individual ESR reports to FDA and IRBs is the norm Investigator Reports all SAEs Sponsor Reports all ESRs* FDA IRB

10. Pre-marketing Periodic Reports Benefit-Risk Assessment Progress Report (focus on clinical development program) Purpose Concise global analysis Benefit-risk evaluation Implications for trial subjects Proposed measures to minimize risk Supporting results of non-clinical studies Tabular summary of most frequent and most serious AEs by body system List of completed non-clinical studies and result summary Summary of foreign marketing developments General Investigational Plan for next year Outstanding IND business Description of IB revisions, Significant Phase 1 protocol modifications Format SUSARs; serious, associated, +/- expected Listings of all SAEs, deaths, ESRs, and withdrawals due to AEs for the reporting period Adverse Events Included Benefit-risk assessment; supporting tables Study data and summary information Content EMEA, MS, EC FDA Recipients Annual Safety Report (EU) IND Annual Report (US)

11. Pediatric Legislation EU: Significant Therapeutic Benefit or Fulfilled Therapeutic need vs US Meaningful Therapeutic Benefit or Substantial number of pediatric patients. Europe has a “centralized” procedure. All appropriate applications are submitted for review by a Pediatric Committee which addresses the studies needed for the Pediatric Investigational Plan (PIP), waivers and deferrals. (Incentive linked to PIP) European filing of a product for an adult indication can be denied if it does not have the required pediatric plan, waiver or deferral; not possible in US European process is asking for more definitive information early in development process EU: If the product is not marketed for pediatrics the safety review is not obligatory US can ask for indication that does not exist in adults or not approved for marketing in adults US has 2 separate triggering processes (incentive and requirement) that are only partially coordinated by a pediatric committee while Europe has 1 pediatric law In the US only those studies in response to a Written Request are eligible for the incentive US has required pediatric focused PM safety reviews with public presentation US has mandated pediatric focused review of post marketing adverse events and a public review of the data, even if the product does not have a pediatric indication (not approved but labeled) EU US

12. Post-Marketing Safety Reporting AERS MedWatch Program (Voluntary and Mandatory) Optional Electronic Reporting NDA Annual Reports to FDA. Consumer Reports ‘ Dear HCP’ Letters Expedited Reporting of all Class Action lawsuits Clinicians are encouraged, but not required, to report drug-related adverse events either to drug manufacturers or directly to the FDA NDA Periodic Reports quarterly during the first 3 years after the medicine is approved, and annual reports thereafter . Eudravigilance Mandatory electronic reporting Only include Medically Confirmed Reports Require QPPV Rapid Alert System EU, there are no harmonized rules for post-marketing studies. In the United Kingdom, reports of such events are actively solicited through the Prescription-Event Monitoring system, which surveys prescribers regarding any adverse experiences among the first 10,000 people who use a given drug. The European Medicines Evaluation Agency (EMEA) requires PSURs every 6 months for 2 years, annually for the 3 following years, and then every 5 years (at the time of renewal of registration).

13. PADER vs. PSUR Summary and analysis of the 15-day reports submitted during the reporting period. Tables of frequency of occurrence of adverse events from the reporting period, organized by body system. A MedWatch form for each adverse event not previously submitted as a 15-day report. Actions taken for safety reasons since the last report. NDA periodic reports do not include adverse events occurring outside the U.S. or those obtained from the scientific literature or from post-approval studies, except for 15-day reports. Companies are also encouraged by FDA to seek a waiver to exclude MedWatch forms for non-serious listed adverse events from periodic reports. Worldwide approval status Update on regulatory agency or pharmaceutical company actions taken for safety reasons Changes to ref. safety information Data on patient exposure derived from an estimate of the number of patients exposed, along with the method used to calculate the estimate. Individual case histories (from literature, spontaneous reports, clinical studies, or other sources) Newly analyzed completed studies yielding safety data Serious unlisted reactions, placing cumulative reports into perspective Non-serious unlisted reactions Increased reporting frequency of listed reactions PADER PSUR

14. Risk Management Plans FDA may determine Risk Evaluation and Mitigation Strategy (REMS) but this is not a requirement (FDAAA) Risk Minimization Action Plans (RiskMAPs) not mandatory in US but strongly advised at the time of filing, especially for NCE Risk management plan is mandatory in the EU A valid EU-RMP must Section 1: Product Information Section 2: Safety Specifications Section 3: PVG Plan Section 4: Risk Minimisation Plan if needed

15. Pharmacovigilance Audits Focus on reporting of data to FDA Field investigators 0 to 3 days notice for domestic inspections No clear agenda/plan Document/data review 1-2 inspectors for 1-3 days Focus on Systems ( Summary of Pharmacovigilance Systems) Variable resources but includes PV inspectors 4 months notice Detailed agenda/plan in advance of the audit Interview driven 3-4 inspectors for 5 days

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