1. 1 Concept Paper on Risk Management Programs CDER/CBER PDUFA3 Risk Management Working Group Anne Trontell, M.D., M.P.H.

2. 2 Risk Management Working Group Chair: Anne TrontellChair: Anne Trontell CDER lead: Florence HounCDER lead: Florence Houn CBER lead: Mark WeinsteinCBER lead: Mark Weinstein OTCOM supportOTCOM support –Nancy Smith –Colleen Pritchard ORP supportORP support –Aileen Ciampa Project ManagerProject Manager –Chris Bechtel CDER –Susan Allen –Jonca Bull –Yuan-Yuan Chiu –Toni Piazza Hepp –Deborah Leiderman –Claudia Karwoski –Denise Toyer –Kathleen Uhl CBER –Richard Diamond –Theresa Finn –Brian Harvey –Toni Stifano –Robert Wise

3. 3 Overall Context: PDUFA3 Guidances PDUFA3 calls for three interrelated guidances on risk managementPDUFA3 calls for three interrelated guidances on risk management Yesterday’s and tomorrow’s concept papers focus on risk assessment components of risk managementYesterday’s and tomorrow’s concept papers focus on risk assessment components of risk management –Premarketing Risk Assessment –Pharmacovigilance/pharmacoepidemiology

4. 4 Context: Today’s Concept Paper Focuses on actions taken to reduce risks in drug product useFocuses on actions taken to reduce risks in drug product use –based on assessments described in other two concept papers Distinguishes itself from overall efforts by using the term Risk Management ProgramsDistinguishes itself from overall efforts by using the term Risk Management Programs Calls overall process RM planningCalls overall process RM planning

5. 5 Process Highlights CommentsComments --> solicited today and through April 30, 2003 --> solicited today and through April 30, 2003 Draft guidancesDraft guidances --> Fall 2003 Public comment period on draft guidancesPublic comment period on draft guidances Final guidancesFinal guidances --> September 30, 2004

6. 6 Format of Today’s Meeting No external panelNo external panel –Workgroup and Steering Committee only Two half-day sessions each including:Two half-day sessions each including: –Two key sections of concept paper –Presentation of highlights by WG members –Clarifying questions on presentations –Presentations by registered public speakers –Qs & As, discussion Afternoon concludes with brief wrap-upAfternoon concludes with brief wrap-up

7. 7 Scope of Concept Paper Considerations for initiating and designing a risk management program - definitions and when appropriateConsiderations for initiating and designing a risk management program - definitions and when appropriate Selection of tools and levelsSelection of tools and levels Evaluation processes and methodsEvaluation processes and methods Elements of submissions to FDAElements of submissions to FDA

8. 8 Agenda Morning Workgroup Speakers: Concepts, Definitions & When RMPs are Appropriate Dr. Robert Wise, CBER Tools and Levels of RM Programs Dr. Toni Piazza-Hepp, CDER

9. 9 Agenda Afternoon Workgroup Speakers: Evaluation Processes and Methods Dr. Richard Diamond, CBER Submission Elements Dr. Claudia Karwoski, CDER

10. 10 Morning Session: Commentary Invited Definition of an RM Program (RMP)Definition of an RM Program (RMP) Clarity of RMP goals, objectivesClarity of RMP goals, objectives Determining when an RMP is needed and Sponsor/FDA roles in decision-makingDetermining when an RMP is needed and Sponsor/FDA roles in decision-making Best ways for tools to be in guidanceBest ways for tools to be in guidance Classification of RMP tools into LevelsClassification of RMP tools into Levels

11. 11 Afternoon: Invited Commentary Pretesting of RMP toolsPretesting of RMP tools Recommended evaluation of all RMPsRecommended evaluation of all RMPs Recommendation for 2 independent methods to evaluate key RMP goal(s)Recommendation for 2 independent methods to evaluate key RMP goal(s) Role of qualitative data in evaluationRole of qualitative data in evaluation Elements of RMP submissions & reportsElements of RMP submissions & reports

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13. 13 RISK MANAGEMENT PROGRAM CONCEPTS Robert P. Wise MD, MPH CBER

14. 14 OVERVIEW DefinitionsDefinitions Risk Management Program (RMP)Risk Management Program (RMP) –component goals and objectives –when appropriate

15. 15 Definitions Product: drug or biological regulated by CDER or CBERProduct: drug or biological regulated by CDER or CBER –Includes vaccines and plasma derivatives –Excludes other blood products FDA approval (or licensure) means a product is :FDA approval (or licensure) means a product is : –safe and effective –for labeled indications –under labeled conditions of use Safe means that beneficial actions:Safe means that beneficial actions: –outweigh harmful or undesirable side effects; –does not suggest absence of risk.

16. 16 Definition: Risk Management (RM) Methods used throughout a product’s lifecycle to: minimize risksminimize risks optimize benefit/risk balanceoptimize benefit/risk balance

17. 17 What is Risk Management? Use of risk information from investigational and marketing phasesUse of risk information from investigational and marketing phases Identification and interpretation of risks and benefits in actual useIdentification and interpretation of risks and benefits in actual use Interventions to minimize risks as necessaryInterventions to minimize risks as necessary Intervention phases:Intervention phases: –Design –Implementation –Evaluation –Revision as appropriate

18. 18 Risk Management Planning All sponsor efforts to minimize product risks:All sponsor efforts to minimize product risks: –Risk assessment –Pharmacovigilance/pharmacoepidemiology –Special studies or interventions –Professional product labeling (PI) All products have risk management planningAll products have risk management planning –Traditional: PI and postmarketing surveillance (PMS) –Risk management program when PI and PMS are not sufficient to minimize risks

19. 19 Risk Management Program (RMP) Strategic safety effort to reduce risk:Strategic safety effort to reduce risk: > 1 risk reduction goal > 1 intervention (tool) in addition to PI Tool examples: education, forms, processes, and other methods to influence or control a product’s:Tool examples: education, forms, processes, and other methods to influence or control a product’s: –prescribing –dispensing –use Note: the package insert (PI) is that portion of the approved product labeling described in 21 CFR 201.57, that is directed primarily to health professionals. The PI should not be confused with approved product labeling which my incorporate RMP materials such as Medication Guides and patient agreements in addition to the PI.

20. 20 Definition: RMP Goal(s) Tailored to specific risk concernsTailored to specific risk concerns Describe desired end result of RMPDescribe desired end result of RMP Include “Vision statement” of optimal drug use scenario, e.g:Include “Vision statement” of optimal drug use scenario, e.g: “No patient with condition A (e.g. pregnancy) should receive product B (e.g. teratogen).” should receive product B (e.g. teratogen).”

21. 21 Definition: RM Program Objectives Intermediate steps to an RMP goalIntermediate steps to an RMP goal Affect processes, behaviors, or outcomesAffect processes, behaviors, or outcomes Multiple objectives can serve one goal (e.g. MD training, pharmacy practice)Multiple objectives can serve one goal (e.g. MD training, pharmacy practice)

22. 22 When is an RM Program Appropriate? Whenever risk reduction needs emerge (throughout product lifecycle)Whenever risk reduction needs emerge (throughout product lifecycle) Sponsor may volunteer or FDA proposeSponsor may volunteer or FDA propose “When the number or severity of a product’s risks appears to undermine the magnitude of benefits in an important segment of actual or potential users.”“When the number or severity of a product’s risks appears to undermine the magnitude of benefits in an important segment of actual or potential users.”

23. 23 How to Assess Whether Risks Undermine Benefits? No simple formula compares risks to benefitsNo simple formula compares risks to benefits Risk and benefit numbers, types, measures varyRisk and benefit numbers, types, measures vary Case-by-case judgments required by sponsor and/or FDA on whether to develop, submit, and implement an RMPCase-by-case judgments required by sponsor and/or FDA on whether to develop, submit, and implement an RMP FDA expects:FDA expects: –Most products will be handled by PI. –PI revision will not automatically imply a need for RMP

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25. 25 Risk Management Tools Toni Piazza-Hepp, Pharm. D. CDER

26. 26 Definitions Risk management intervention (tool): a process or system intended to enhance safe product use by reducing riskRisk management intervention (tool): a process or system intended to enhance safe product use by reducing risk Risk management programs use one or more toolsRisk management programs use one or more tools Choice of tools influenced by severity, reversibility, and rate of riskChoice of tools influenced by severity, reversibility, and rate of risk

27. 27 Types of Tools in Current Programs

28. 28 Education and Outreach Beyond professional labeling (“package insert”, PI)Beyond professional labeling (“package insert”, PI) HCP letters and other public noticesHCP letters and other public notices Training programs and CE for creditTraining programs and CE for credit Patient-oriented labelingPatient-oriented labeling –Medication Guides (MG) –Patient Package Inserts (PPI)

29. 29 Systems Guiding Prescribing, Dispensing, Use Patient agreements/informed consentPatient agreements/informed consent Enrollment of one or more stakeholders in special programEnrollment of one or more stakeholders in special program Practitioner certification programsPractitioner certification programs Special conditions of dispensingSpecial conditions of dispensing –special packaging –limited supply / no refill –check mechanisms to assure appropriate prescribing

30. 30 Restricted Access Systems Designed to enforce compliance with program elementsDesigned to enforce compliance with program elements May include registration/enrollment of physicians/pharmacists/patientsMay include registration/enrollment of physicians/pharmacists/patients May include documentation of safe use conditions (such as lab tests) before dispensing to patientsMay include documentation of safe use conditions (such as lab tests) before dispensing to patients

31. 31 Suspension of Marketing With or without application withdrawal

32. 32 Selecting and Developing Tools Consider: Stakeholder input: feasibility, acceptanceStakeholder input: feasibility, acceptance Consistency: with existing/accepted toolsConsistency: with existing/accepted tools Evidence of success in achieving desired objective based on other RMPEvidence of success in achieving desired objective based on other RMP Evidence of success in ability of novel tool to achieve desired objectivesEvidence of success in ability of novel tool to achieve desired objectives –based on application in non-RMP settings Variability, validity, reproducibilityVariability, validity, reproducibility

33. 33 Proposed “Levels” for RMP Classification Proposed “Levels” for RMP Classification Broad categorization; a continuumBroad categorization; a continuum Risk management planning considers all levels; basis is product riskRisk management planning considers all levels; basis is product risk Risk management program (RMP)Risk management program (RMP) –begins at Level 2 –beyond the “package insert” Increased level - increased divergence from conventional prescribing and dispensingIncreased level - increased divergence from conventional prescribing and dispensing

34. 34 Proposed “Levels” for RMP Classification Level 1: Package insert only Level 2: Adds education and outreach tools Level 3: Level 2 plus systems guiding prescribing, dispensing and/or use Level 4: Access to product requires adherence to specific program elements

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36. 36 Morning Session: Commentary Invited Definition of an RM Program (RMP)Definition of an RM Program (RMP) Clarity of RMP goals, objectivesClarity of RMP goals, objectives Determining when an RMP is needed and Sponsor/FDA roles in decision-makingDetermining when an RMP is needed and Sponsor/FDA roles in decision-making Best ways for tools to be in guidanceBest ways for tools to be in guidance Classification of RMP tools into LevelsClassification of RMP tools into Levels