Public Workshop on Risk Management Day 2 – Risk Management Programs Washington DC, April 10

1. Public Workshop on Risk ManagementDay 2 – Risk Management ProgramsWashington DC, April 10 International Society for Pharmacoepidemiology S. Pérez-Gutthann, MD, MPD, PhD

2. ISPE Backgroundwww.pharmacoepi.org • Non-profit international professional membership organization • Mission: to foster the science of pharmacoepidemiology, applying epidemiologic approaches to studying the use, effectiveness, value and safety of therapeuticals. • International forum for sharing knowledge and scientific approaches • Over 700 members, 45 countries. • Working in academia, pharmaceutical industry, government agencies, non-profit and for-profit research organizations. • Background: epidemiology, biostatistics, medicine, nursing, pharmacology, pharmacy, law, health economics, and journalism. • Comments are based on the feedback provided by senior members

3. General • This concept paper is useful in the overview of the Agency’s views • initiating and designing a RMP • selection and development of tools, • evaluation of RMP • web based catalog of programs and tools • We have identified a number of suggestions and clarifications.

4. Section I - C & DWhat is Risk Management Planning, What is a Risk Management Program and what are its goals and objectives • The three concept papers suggest a fragmented view of Risk Management. • Danger of consolidating institutional divisions between those working in safety pre and post approval. • Integration of specialists in both areas from early development through post market is needed. • PVP and RMP definitions - overlap and partially contradict each other in concept papers II & III • RMP, Concept Paper III, line 65: a risk management program (RMP) would be a submission to FDA that comprehensively analyzes a product’s risk profile and proposes active interventions to minimize them. • RMP, Concept Paper II, line 62: FDA is defining a risk management program (RMP) as a strategic safety program designed to decrease product risk by using one or more interventions or tools beyond the package insert. • PVP, Concept Paper II, line 55. We envision a pharmacovigilance plan as being a plan proposed by a sponsor for the ongoing evaluation of identified safety signals through enhanced pharmacovigilance practices.

5. Section I - C & DWhat is Risk Management Planning, What is a Risk Management Program and what are its goals and objectives • Gaps in current RMP • Risk management prior to launch • Activities, timelines, interactions with Agency, relation to other development planning documents and meetings • Determination of background risks based on epidemiologic analysis of the patient population anticipated to be exposed to the therapeutic agent • Formal document to provide overall overview of risks and decisions about moving or not beyond risk communication in IB/PI • Guidance for therapeutic agents other than medications

6. Section I - C & DWhat is Risk Management Planning, What is a Risk Management Program and what are its goals and objectives • Proposal • A dynamic Risk Management Plan - broader sense that the targeted Risk Management Program in this concept paper – • Initiated at the moment of entry into humans, based on data from toxicology, etc. • Moving with the drug along development milestones • With a specific Pharmacovigilance Plan section prior to approval • Moving with the drug in the postapproval periodic safety review process • A specific Risk Management Program would be then initiated when moving beyond IB/PI for a specific issue (s).

7. Section IV – A, B, CIntervention or tools available • Assumptions for use of tools • Use of tools is based on the assumption that risk factors for the target adverse event have been identified and that there is some understanding of how the medication should be used to minimize this risk. • This point could be made clearer at the front of the document • Effectiveness of tools – wide range in results • Educational / academic detailing programs. • Flag warning systems in pharmacy computers • PI as risk communication/minimization tool • Content: E.g.: describing risks as crude percentages without specifying the exposure duration, balance common adverse events versus rarer serious adverse events • Target: prescribers, patients

8. IV – DChoice of tools and RMP Levels • Broad categorization helpful in providing overview of level of concern and action for specific agents and accross therapeutic class • Clarification: What are the views on guiding criteria to move from level 1 to level 2, etc. • Frequency of event, public health impact, effectiveness of tool… • Web catalog of programs & tools plus categorization in levels is very useful

9. Section VHow and when can risk management programs be evaluated • P 9, lines 304, 320: Evaluation of an RMP might involve a metric of reducing the occurrence of an adverse event • Goal of any program, but may be very difficult to measure. • Mention that for most drugs, the frequency of serious adverse events, which are usually the focus of RMPs, the evaluation of such events might be problematic because of sample size considerations. • For an event, which occurs at 1/1000, for example, it would take tens of thousands of patients to detect a halving of this frequency. • p.4, lines 119-120: No ready formula currently exists to determine when risks exceed benefits. • P 10, lines 368-372. Limitations of SR • Given above, a more prominent role of formal pharmacoepidemiologic studies in assessing risk and evaluating risk interventions is proposed

10. Special Considerations • Impact on health delivery systems • Impact on prescriber and pharmacist workload • Particularly if Level 2-4 RM programs are running simultaneously • Therapeutic class balance • Avoid that only new drugs within a TC with similar safety profile are focus of RMP   • International coordination • EMEA, ICH work in progress. Opportunity to coordinate internationally objectives, process and documents early on. • Collaboration among stakeholders • Guidelines should emphasize the important role of close collaboration between the Agency, Sponsor and Experts in the decision to move beyond Level 1 RM, choice of tools, evaluations, etc.

11. Next stepswww.pharmacoepi.org • ISPE is firmly committed to providing an unbiased scientific forum to the views of all parties with interests in the safety of therapeuticals, and as such is deeply committed to the advancement of Risk Management Sciences. • Welcome opportunity to work together with the Agency • Full membership to provide feedback on paper. • Annual conference will be focused on Risk Management. • Several workshops and sessions are being planned jointly with FDA staff. 1st International Conference on Therapeutic Risk Management and the 19th International Conference on PharmacoepidemiologyAugust 21-24 in Philadelphia. • Thank you