Hazard and Risk Management

1. Hazard and Risk Management E. Stewart Geary, M.D. Eisai Co., Ltd. National Regulatory Conference 2005 Subang Jaya, Selangor, Malaysia 6-7 September, 2005

2. Hazard & Risk Management • Principles of Risk Management • Risk Management: Clinical Safety of Medical Products • ICH: E2E Guideline • EU • FDA: 3 Guidances National Regulatory Conference 2005

3. Principles of Risk Management

4. Risk • “Risk can be defined as the combination of the probability of an event and its consequences” (ISO/IEC Guide 73) National Regulatory Conference 2005

5. Risk Management • Process by which organizations methodically address the risks associated with their activities • Requires identification and “treatment” of risks • Should be a continuous and developing process • Management of safety risks focuses on prevention and mitigation of harm National Regulatory Conference 2005

6. Types of Risks: External • Financial risks • Interest rates • Foreign exchange • Strategic Risks • Competition • Industry changes • Operational Risks • Regulations • Hazard Risks • Natural disasters • Contracts • Suppliers National Regulatory Conference 2005

7. Types of Risks: Internal • Financial risks • Liquidity & Cash Flow • Strategic Risks • Research & Development • Intellectual capital • Operational Risks • Accounting controls • Information systems • Hazard Risks • Employees • Properties National Regulatory Conference 2005

8. Risk Management • Cycle of Management • Risk Identification • Risk Assessment • Plan • Implement Risk Treatment • Assess the implemented plan • Report internally and externally on the identified risk and the progress of its management National Regulatory Conference 2005

9. Risk Management Cycle Identify Assess/ Analyze Track Report Report Mitigate/ Treat Plan National Regulatory Conference 2005

10. Risk Management: Clinical Safety of Medical Products

11. Background: E2E • E2E: Pharmacovigilance Plans • The Guideline was released for consultation, under Step 2 of the ICH process, on November 11, 2003. • EU : Adopted by CPMP, 20 November 2003, issued as CPMP/ICH/5716/03 • MHLW : Released for consultation on April 27, 2004, PFSB/ELD, Deadline for comments July 26, 2004 • FDA : Published in the Federal Register, Vol. 69, No 61, Tuesday, March 30, 2004, pages 16579-80.Comments due by May 19, 2004. National Regulatory Conference 2005

12. Background EU • “Action Plan to Further Progress the European Risk Management Strategy” published 4 May 2005 • Risk Detection • Risk Assessment • Risk Minimization • Risk Communication National Regulatory Conference 2005

13. Background: RiskMAP • PDUFA III approval June, 2002 included FDA promise to produce guidance for industry on risk management • 3 Concept Papers issued March 2003 • Public Workshop April 2003 • 3 Draft Guidance Documents issued May, 2004 • Development and Use of Risk Minimization Action Plans • Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment • Includes guidance on when to develop PVP • Premarketing Risk Assessment • 3 Guidances Finalized March 2005 National Regulatory Conference 2005

14. ICH: E2E Guideline Pharmacovigilance Planning

15. E2E • Pharmacovigilance Specification • Summary of the identified risks of the drug • Potential for important unidentified risks • Populations potentially at-risk • Situations that have not been adequately studied • Pharmacovigilance Plan • Annex of Pharmacovigilance Methods National Regulatory Conference 2005

16. Pharmacovigilance Specification • Summary of the identified risks of the drug • Potential for important unidentified risks • Populations potentially at-risk • Situations that have not been adequately studied • Can be stand-alone or incorporated in CTD National Regulatory Conference 2005

17. Elements of PV Specification • Non-clinical • Clinical • Limitations of human safety database • Extent of world-wide exposure • Any new or different safety issues identified • Regulatory actions related to safety • Populations not studied in pre-approval phase • Children, elderly, pregnancy & lactation, hepatic or renal disease, genetic polymorphisms, ethnic origin National Regulatory Conference 2005

18. Elements of PV Specification • Clinical • AE/ADR • Most important identified ADRs (by frequency or seriousness) • Potential risks (how will they be further identified?) • Food-drug and drug-drug interactions • Epidemiology of indication and associated AEs • Class effects • Summary - Ongoing safety issues National Regulatory Conference 2005

19. PV Plan • Summary of Ongoing Safety Issues • Important identified risks • Important potential risks • Important missing information • Routine PV Practices • Safety Action Plan for specific issues/missing information • Summary of actions to be done, milestones National Regulatory Conference 2005

20. Safety Action Plan for specific issues/missing information • Risk Issue/Information missing • Objective • Action proposed • Rationale for proposed action • Oversight within company for issue & action • Milestones for evaluation and reporting • Exposure to product reaching certain levels • Results of studies becoming available National Regulatory Conference 2005

21. E2E-Safety Action Plan • Safety Action Plan • The objective is to have a more structured and specific approach to examining pre-defined safety issues • Is the product safe for elderly patients? • Is there a risk for cardiac events? How great is that risk? • Analyses to be performed at each milestone National Regulatory Conference 2005

22. E2E-Safety Action Plan • If a Safety Action Plan results in specific actions there is a need to follow-up and see if those actions improved the risk profile • For instance: Did a Package insert change or specific education program result in a decrease in the adverse event of concern? National Regulatory Conference 2005

23. Summary: E2E-Safety Action Plan • Created on the basis of conscious assessment of current safety information • Targeted plan to address a specific question • Usually involves gathering more information to better define a specific risk • Requires re-assessment and modification at pre-determined milestones • Submitted to a regulatory authority for comment and approval National Regulatory Conference 2005

24. FDA

25. FDA: Premarketing Risk Assessment

26. Premarketing Risk Assessment • Depends on • Quantity of patients studied • Quality of data analysis • Size of database • Smaller for life-threatening diseases • Difficult to offer guidance for products used for short-term, acute use • Long-term treatment of non-life-threatening Dz (E1A) • 1500 patients exposed of which • 300-600 for 6 months • 100 for 1 year • Reasonable exposure to highest proposed dose National Regulatory Conference 2005

27. Premarketing Risk Assessment • Larger databases needed for • Safety concern from animal studies, pharmacological class, etc. • Small benefit • Preventive therapies (few of exposed benefit) • Uncertain magnitude of benefit • Use in healthy population • Safe and effective alternative already available National Regulatory Conference 2005

28. Premarketing Risk Assessment • Examine terminology, assessment methods, use of standard terms • MedDRA • Consider long-term controlled studies • Most extensions are single-arm or otherwise uncontrolled • For comparison group for evaluation of events common in that background population • Diverse population in safety database • Old, young, women, minorities, limit exclusion criteria • Multiple doses in phase III National Regulatory Conference 2005

29. Premarketing Risk Assessment • Detecting Unanticipated Interactions • Drug-drug interactions in addition to those predicted by metabolic pathway • For likely concomitant medications used in that population • Product-dietary supplement interactions • Comparative Safety Data • Especially when background rate of AEs is high or other drugs in class have same ADRs National Regulatory Conference 2005

30. Premarketing Risk Assessment: Data Analysis • Essentially the same tools currently used for the Integrated Safety Summary • Similar to E2E “PV Specification” National Regulatory Conference 2005

31. FDA: Risk Minimization Action Plans (RiskMAP)

32. Role of RiskMAPs • Necessary for only some products • “For most products routine risk management will be sufficient and a RiskMAP need not be considered.” • RiskMAP: a strategic safety program designed to meet specific goals and objectives in minimizing known risks while preserving benefits National Regulatory Conference 2005

33. RiskMAP • State a specific goal • “fetal exposure to drug X should not occur” • “lower incidence of liver failure on drug X” • Translate into pragmatic, specific and measurable objectives • Targeted education to physicians, patients • Reminder systems • Access systems National Regulatory Conference 2005

34. RiskMAP Tools • Targeted education & outreach • Health care practitioner letters • Training programs • Continuing education • Professional/public notifications • Medication guides • Patient package inserts • Focused or limited promotion techniques National Regulatory Conference 2005

35. RiskMAP Tools • Reminder systems • Patient agreement forms • Certification programs for practitioners • Limit amount in single prescription • Specialized product packaging • Systems to attest safety measures are satisfied (stickers, etc.) National Regulatory Conference 2005

36. RiskMAP Tools • Performance-linked access systems • Link product access to lab test results or other documentation • Compulsory reminder systems (no product without acknowledgment) • Prescription only by specified practitioners • Dispensing only by specially certified pharmacies National Regulatory Conference 2005

37. FDA’s Tools • Product recalls • Warning letters • Safety alerts • Guidance documents • Seizures and injunctions National Regulatory Conference 2005

38. RiskMAP • Every RiskMAP should contain a plan to periodically evaluate its effectiveness • Test tools before implementation if possible (e.g. during phase III) • RiskMAP plan should describe when periodic evaluation results will be sent to FDA • Eliminate ineffective tools • RiskMAP evaluations will involve analysis of observational/descriptive data rather than statistical hypothesis testing National Regulatory Conference 2005

39. RiskMAP • Select evidence-based performance measures • Number, percentage or rate of an outcome • Whenever possible use at least two different measures/methods for each goal • Submit RiskMAP to IND/NDA/BLA National Regulatory Conference 2005

40. RiskMAP Contents • Background • Goals & Objectives • Strategy & Tools • Evaluation Plan • Including potential unintended and untoward consequences of the RiskMAP National Regulatory Conference 2005

41. RiskMAP Progress Report • Summary of the RiskMAP • Methodology • Data • Results • Discussion & Conclusions National Regulatory Conference 2005

42. RiskMAP Data Analysis • Emphasis is on selecting a quantitative “performance measure” • Number, percentage or rate of outcome • Careful consideration at the time of choosing a performance measure • Adapting to increasing exposure to drug as use expands • New population exposures as new indications or new countries get marketing approval • Data analysis to demonstrate the performance measure is being met • If performance measure is not met, need to consider new actions/additions to RiskMAP National Regulatory Conference 2005

43. Summary: Safety Action Plan vs RiskMAP • Broadly defined, all products have always had a PVP • Package insert, CCDS, ADR collection & reporting • Some but not all products will require a PVP Safety Action Plan or RiskMAP • FDA’s RiskMAP is similar to the Safety Action Plan in E2E but is targeted to reduce a specific risk National Regulatory Conference 2005

44. Summary: Safety Action Plan vs RiskMAP • Both PVP and RiskMAP’s are marked by • Moving from a reactive to proactive model of PV • Moving from “one size fits all” PV to tailored programs specific for each drug • Setting measurable targets for drug safety and periodically assessing whether or not they have been met • RiskMAP takes a specific risk and creates a plan to minimize it • Pharmacovigilance Plan gathers more information to identify risks National Regulatory Conference 2005

45. Thank you for your kind attention!