1. Postmarketing Pharmacovigilance English D. Willis, MD Clinical Risk Management Merck Research Laboratories June 1, 2012

2. 2 Definition of Pharmacovigilance (PV) The study of the safety of marketed drugs under practical conditions of clinical use in large communities. A clinical science whose objectives are the surveillance, evaluation, and signaling of the undesirable effects of pharmaceutical products used for medical therapy and whose major sources of new information are spontaneous notification and reporting of such effects. It also includes the diffusion of this information and the regulatory measures taken to prevent future adverse drug reactions, to ensure safer use of drug products as well as improvement in the risk/benefit ratio. Ref: Mann R D, Andrews E B (2007) Pharmacovigilance 2 nd ed. John Wiley and Sons, Ltd, England Cobert BL, Biron P (2002) Pharmacovigilance from A to Z Adverse Drug Event Surveillance. Blackwell Science, Michigan

3. 3 Postmarketing PV Activities Designed to monitor the safety profile throughout the life-cycle of the product Adverse Event Reporting System (AERS) For the identification and assessment of previously unrecognized (unlabeled) AEs Worldwide, passive, spontaneous and voluntary AE reporting system Reports received from healthcare professionals (HCP), consumers, literature and serious reports from study environment Periodic Safety Update Reports (PSURs) Provides an update of the worldwide safety experiences of a medicinal product to Competent Authorities at defined points post-authorization. It includes succinct summary information with a critical evaluation of the risk-benefit balance of the product in the light of new or changing information. The evaluation helps to determine if further investigation or changes to the Company Core Data Sheet (CCDS) or company label are needed. Included is a comprehensive review of regulatory and exposure data, risk information and reports of AE temporally associated with use of a product Risk Management Systems Risk management ≠ risk elimination Risk management is intended to optimize the benefit risk balance, by minimizing risks while preserving the benefits Basic activities include: Risk identification Risk evaluation and characterization Risk communication Risk minimization

4. 4 Key International Organizations in the Development of Safety Regulations International Conference on Harmonization (ICH) of Technical Requirements of Registration of Pharmaceuticals of Human Use Topic areas of focus: Safety: relating to in vitro and in vivo preclinical studies Efficacy: relating to clinical studies in human subjects Quality: relating to chemical and pharmaceutical quality assurance Participants: EU: CHMP/EMEA US: FDA and PhRMA Japan: WHLW and JPMA Regulatory observers from WHO, Therapeutic Products Programme (Health Canada) and European Free Trade Assoc. Several ICH Documents to include: E2C-PSUR for marketed products E2D-Postapproval Safety Drug Management: Definitions and Standards for Expedited Reporting E2E-Pharmacovigilance Planning

5. 5 Key International Organizations in the Development of Safety Regulations (con’t) Council of International Organizations of Medical Sciences (CIOMS) Established by the WHO and UNESCO as an international, non- governmental, non-profit organization Regulatory and industry working group or “think tanks” Primary objectives: To facilitate and promote international activities in the field of biomedical sciences To maintain collaborative relations with UN and specialized agencies To serve the scientific interest of the international biomedical community in general

6. 6 Safety Profile at Approval This is why PV is necessary Safety data at time of drug/vaccine approval Randomized controlled clinical trials are rigorous in design but they have limitations Limited numbers of patients studied (range is 1500 to 10,000 for a new drug; vaccine trials ~ 20,000 or more) Select patient population intended to limit variability to be able to demonstrate efficacy without confounders Duration of exposure to the drug or vaccine is limited In summary, clinical trials are not “real world” use Post-approval data expands the understanding of the safety profile Detects rare events Monitor for and encourage safe use of the product

7. 7 Spontaneous Reports of Adverse Drug Events HCPs role in the continuous monitoring for safety and risk identification is crucial Medically confirmed reports from HCPs are preferred by industry Regulatory guidelines for reporting of AEs to agencies; company shares all AE reports with agencies; companies and agencies each have their own database. Several limitations inherent in postmarketing AE reports

8. 8 Signal Detection For the purpose of identifying: New unlabeled AEs An observed increase in a labeled event in its severity or specificity New drug, vaccine or food interaction Newly identified at-risk population Of consideration are: Disease occurrence in expected time Absence of symptoms prior to exposure Positive dechallenge and/or rechallenge Consistent with pharmacological effects or biological plausibility Consistent with known effects in the class Event identified in clinical trials Absence of alternative explanations (co-morbidities or co- medications/vaccine)

9. 9 Risk Management System Process for identifying, characterizing, evaluating, monitoring, communicating and mitigating risks that may arise from the normal conditions of use of a medical product. To ensure a positive benefit/risk balance

10. 10 EU Risk Management Plan (RMP) Submitted with each NDA filed; when requested by an agency; or with a significant change in the product “Living document” that is updated throughout the product life cycle Part I Safety specification Describes what is known and not known about the product, the epidemiology of the condition the drug/vaccine is intended to treat or prevent and the indicated population Includes important identified risk, potential risk and missing information Forms the bases of the PV plan and the evaluation of the need for risk- minimization activities Pharmacovigilance plan Describes how the risk will be identified and further characterized Activities may include: routine PV (AER with reporting), active surveillance (registries, sentinel sites), pharmacoepidemiology studies (PASS), clinical trials with safety as an end point, and/or preclinical studies to elucidate the mechanism of an observed risk

11. 11 EU Risk Management Plan (RMP) (con’t) Part II Evaluation of the need for risk-minimization activities Risk minimization activities are needed if warranted by the particular nature and/or seriousness of the risk. These are non-routine and beyond the PV plans and local labeling  Additional activities (non-routine)  Educational programs for HCP and consumers  Patient monitoring programs  Controlled distribution of the product  Restricted access programmes If RMP includes additional activities, a risk minimization plan is needed Details the activities for risk reduction of a safety concern Specific for the safety concern

12. 12 RMP - Safety Specification Important Identified Risk Adverse reaction (AR) suggestive of an association with product Important Potential Risk AR with some basis for suspicion of an association with product but not yet confirmed Important Missing Information Safety information not available at the time of submission and representing a limitation of the safety data with respect to predicting safety of the marketed product

13. 13 RMP - Pharmacovigilance Plan PV plan specific for each safety concern (identified and potential risk and missing information) Routine PV for those with no special concerns Additional PV activities for real and potential risks Example - registries Formal action plan for each safety concerns Objective of proposed action Rationale for proposed action Milestones for evaluation and reporting Further measures on the basis of findings

14. 14 RMP - Risk Minimization Product labeling is a standard risk minimization tool for risk communications Sections of Product Circular i.e. product label Indications Dosage and Administration Contraindications Warnings/Precautions Adverse reactions DD interactions Use in special populations Patient Product Information i.e. consumer information Additional activities to reduce the probability of an AR occurring or its severity if it occurs Examples: DHCP letter, prescribing or dispensing guides, laboratory monitoring, specific training programs

15. 15 Risk Evaluation and Mitigation Strategy (REMS) U.S. FDA specific regulation that describes the use of risk minimization actions for drugs in the U.S. Overall goal of REMS Allow safe access to drugs with serious risks for the patients who need them While minimizing the burden to patients and the healthcare system Most medication guides are no longer part of a REMS May Include: Communication Plan to Health Care Providers Dear HCP Letters Information dissemination to HCP through Professional Societies Examples of elements to ensure safe use Training or certification for HCPs Certification of dispensing sites (e.g. pharmacies) Dispensing only in certain settings (e.g. hospitals) Dispensing drug is conditional on documentation of safe use conditions 9i.e. lab results) Patients enrolled in Registry

16. 16 Risk Communication on Safety Issues Continuous updating of product and patient information labels Safety-related label changes may include additions to: Adverse Reaction section describing clinical findings from newly completed studies Postmarketing Experience sub-section describing new AEs identified from postmarketing surveillance Warnings and Precautions section describing safety concerns that affect decisions about prescribing the drug, recommendations for monitoring to ensure safe use and measure to be taken to prevent or mitigate harm. Contraindication section describing situations in which the drug should not be used because the risk clearly outweighs any possible therapeutic benefit