1. 1 Considerations for the Use of Risk Minimization Action Plans FDA Draft Guidance and Experience Anne Trontell, M.D., M.P.H. CDER Office of Drug Safety February 15, 2005

2. 2 Outline Definitions of risk management and risk minimizationDefinitions of risk management and risk minimization Risk Minimization Action PlansRisk Minimization Action Plans –When are they needed –Design considerations and evaluation ExperienceExperience

3. 3 FDA Definition of Overall Process of ‘Risk Management’ An iterative processAn iterative process –Assessing benefit-risk balance –Use of tools to minimize risk and preserve benefits –Evaluation of tools, risks, and benefits –Reassessment of benefit-risk balance

4. 4 FDA Definition of Overall Process of ‘Risk Management An iterative processAn iterative process –Assessing benefit-risk balance –Use of tools to minimize risk and preserve benefits –Evaluation of tools, risks, and benefits –Reassessment of benefit-risk balance

5. 5 Risk Management Risk assessment + risk minimization efforts

6. 6 Risk Assessment and Risk Minimization Highly inter-related Occur both pre- and post-marketingOccur both pre- and post-marketing Best if both are evidence-basedBest if both are evidence-based Risk minimization efforts are based upon good risk assessment

7. 7 FDA Risk Management Guidances (Drafts) FDA Risk Management Guidances (Drafts) Development and Use of Risk Minimization Action PlansDevelopment and Use of Risk Minimization Action Plans Premarketing Risk AssessmentPremarketing Risk Assessment Good Pharmacovigilance and Pharmacoepidemiologic AssessmentGood Pharmacovigilance and Pharmacoepidemiologic Assessment

8. 8 FDA Risk Management Guidances (Drafts) FDA Risk Management Guidances (Drafts) Development and Use of Risk Minimization Action Plans Premarketing Risk AssessmentPremarketing Risk Assessment Good Pharmacovigilance and Pharmacoepidemiologic AssessmentGood Pharmacovigilance and Pharmacoepidemiologic Assessment

9. 9 Risk Minimization Action Plans Term used in draft FDA guidance to distinguish risk minimization interventions from overall process of risk management Risk Minimization Action Plan RiskMAP

10. 10 When is a RiskMAP Appropriate? It dependsIt dependsConsiderations: Nature and rate of known risks vs benefitsNature and rate of known risks vs benefits What are risks and are they preventable?What are risks and are they preventable? –Best if risks can be minimized or avoided by one or more preventive measures Probability of benefitProbability of benefit

11. 11 When is a RiskMAP Appropriate? No ready formula for comparing risks and benefits- decisions thus made on a case- by-case basis Employ RiskMAPs judiciously – –Expect only a limited number of products to need RiskMAPs – –For most products, risk minimization is accomplished via package insert (product labeling)

12. 12 The Package Insert FDA-approved professional product labeling (package insert or PI)FDA-approved professional product labeling (package insert or PI) –the cornerstone of routine risk communication and risk minimization/management efforts –updated to reflect new benefits or risk concerns –ongoing efforts to make clear, concise and focused Not a RiskMAP in and of itselfNot a RiskMAP in and of itself

13. 13 Risk Minimization Action Plan (RiskMAP) Definition A strategic safety program designed to meet specific goals and objectives in minimizing known risks of a product while preserving its benefits Uses one or more tools to accomplish these ends

14. 14 RiskMAP Definitions Goal – End result, expressed in terms of one or more health outcomes to be achieved (or avoided)Goal – End result, expressed in terms of one or more health outcomes to be achieved (or avoided) Objective – Intermediate step to achieving the goal(s)Objective – Intermediate step to achieving the goal(s) Tool – System or process other than product labelingTool – System or process other than product labeling

15. 15 Definitions Applied to a Fictional Example Goal: A dangerous drug-drug interaction should not occurGoal: A dangerous drug-drug interaction should not occur Possible Objectives:Possible Objectives: –Physicians won’t co-prescribe 2 drugs –Pharmacists won’t co-dispense –Patients won’t take 1 drug with the other Tools: Education, pharmacy alert screens, or restrictions on physicians or othersTools: Education, pharmacy alert screens, or restrictions on physicians or others

16. 16 Selecting RiskMAP Tools

17. 17 Risk Minimization Tools Risk Minimization Tools Specialized communication of information to minimize risksSpecialized communication of information to minimize risks –Do X –Don’t do Y Alter typical methods of prescribing, dispensing, using product viaAlter typical methods of prescribing, dispensing, using product via –reminders (voluntary) –restrictions (mandatory)

18. 18 Categories of RiskMAP Tools Targeted Education & Outreach Targeted Education & Outreach Reminder Systems Reminder Systems Performance-Linked Access Systems Performance-Linked Access Systems

19. 19 Categories of RiskMAP Tools Targeted Education & Outreach Targeted Education & Outreach –to inform Reminder Systems Reminder Systems –to nag or nudge Performance-Linked Access Systems Performance-Linked Access Systems –to impose limits

20. 20 Targeted Education and Outreach Consider when risks cannot be minimized with routine measures alone (such as the PI)Consider when risks cannot be minimized with routine measures alone (such as the PI) To increase knowledge of key stakeholders who have capacity to prevent or mitigate product risksTo increase knowledge of key stakeholders who have capacity to prevent or mitigate product risks

21. 21 Education and Outreach Health care practitioner (HCP) lettersHealth care practitioner (HCP) letters Professional or public notificationsProfessional or public notifications Training programs for HCP or patientsTraining programs for HCP or patients Continuing education for HCPContinuing education for HCP Focused or limited product promotionFocused or limited product promotion Patient labelingPatient labeling –Medication Guides (MG) –Patient Package Inserts (PPI)

22. 22 Medication Guides FDA approved patient labelingFDA approved patient labeling Regulated since 1999 (21 CFR Part 208)Regulated since 1999 (21 CFR Part 208) Required dispensing with each prescriptionRequired dispensing with each prescription Primarily for outpatient Rx products with serious & significant public health concernsPrimarily for outpatient Rx products with serious & significant public health concerns

23. 23 Medication Guides Three triggering criteriaThree triggering criteria At least one criterion must be met At least one criterion must be met –pt labeling could help prevent serious AEs –serious risks: could affect pt decision to use –pt adherence to directions crucial to effectiveness CFR 208.20 specifies format and contentCFR 208.20 specifies format and content

24. 24 Patient Package Insert (PPI) FDA approved patient labelingFDA approved patient labeling Not covered by regulation and not required to be dispensed with each prescriptionNot covered by regulation and not required to be dispensed with each prescription –Exception: Oral Contraceptives and Estrogens (21 CFR 310.501, 310.515)

25. 25 Patient Package Insert (PPI) FDA recommends Medication Guide format & content to promote consistency and patient recognition Unit-of-use packaging with PPIs can function similarly to Medication Guide

26. 26 Reminder Systems Use with targeted educationUse with targeted education –when education alone is insufficient to minimize risk(s) Prompt, remind, double-check or otherwise guide HCP or patientsPrompt, remind, double-check or otherwise guide HCP or patients –prescribing, dispensing, receiving Alternatively stated, make it difficult to forget important safety processesAlternatively stated, make it difficult to forget important safety processes

27. 27 Reminder Systems Patient agreement/acknowledgementPatient agreement/acknowledgement Practitioner attestation or certification programsPractitioner attestation or certification programs Special conditions of dispensingSpecial conditions of dispensing –special packaging that limits amount or misuse –limited supply / no refills –system of records that remind/attest appropriate safety measures are done (e.g. stickers)

28. 28 Performance-Linked Access Systems Use when targeted education and reminder systems are insufficient to minimize risk(s)Use when targeted education and reminder systems are insufficient to minimize risk(s) For products withFor products with –significant/unique benefits but –unusual risks, fatal or irreversible Links drug product access to compliance with plan conditionsLinks drug product access to compliance with plan conditions –e.g. documentation of safe use conditions (such as lab tests)

29. 29 Performance-Linked Access Systems “Involuntary” in the sense that access occurs only if compliant with procedures“Involuntary” in the sense that access occurs only if compliant with procedures ExamplesExamples –Clozapine –Thalidomide –Dofetilide

30. 30 Selecting and Developing Tools Consider: Seek to maintain appropriate product accessSeek to maintain appropriate product access Identify key stakeholder groups who have capacity to minimize risksIdentify key stakeholder groups who have capacity to minimize risks –healthcare providers, patients, insurers –seek input on feasibility of tool(s) –minimize stakeholder burdens

31. 31 Selecting and Developing Tools Consider: Current technologyCurrent technology Likely settings for product useLikely settings for product use –outpatient and inpatient –urban and rural Current evidence of effectivenessCurrent evidence of effectiveness –in other RiskMAPs –in related area Seek to avoid unintended consequencesSeek to avoid unintended consequences

32. 32 Evaluation Collection of information on RiskMAP and tool performance is essential To achieve health outcomes/goalsTo achieve health outcomes/goals –effectiveness & value-added of tools –ensure energy/resources being expended actually achieve desired goals –stakeholder acceptability –compliance with procedures To identify areas for improvementTo identify areas for improvement

33. 33 Experience/Lessons Learned

34. 34 Examples of Products Using RiskMAP Tool Categories Targeted education and outreachTargeted education and outreach –products with Medication guides, CME Reminder systemsReminder systems –alosetron, isotretinoin, lindane, abarelix PLASPLAS –bosentan*, clozapine*, dofetilide*, mifepristone, thalidomide*, xyrem * lab testing required

35. 35 Targeted Education and Outreach Tools Advantages/Disadvantages Advantages Acceptable to mostAcceptable to most FeasibleFeasible No effect on accessNo effect on access Disadvantages General effectiveness often unstudied or limited Poorly effective in pregnancy prevention for isotretinoin (APCC), troglitazone LFT monitoring

36. 36 Reminder Systems Advantages/Disadvantages Advantages Physician, pharmacist, patient autonomyPhysician, pharmacist, patient autonomy Ongoing education, reminders re risks and safe useOngoing education, reminders re risks and safe use Less intrusive than limited distributionLess intrusive than limited distribution Disadvantages Time and $ costs Evaluations limited to sticker programs SMART showed high process compliance, limited outcome effectiveness; Lotronex system the reverse!

37. 37 Performance-Linked Access Systems Advantages/Disadvantages Advantages Limits access to those adhering to critical risk minimization toolsLimits access to those adhering to critical risk minimization tools Mandatory participation  registration, better data for evaluationMandatory participation  registration, better data for evaluation System burdens alone likely to limit exposure to riskSystem burdens alone likely to limit exposure to risk Disadvantages Time and $ burdens Limits access to drug benefits May prompt illicit access without any safety measures Limited experience in large numbers of users

38. 38 Summary: RiskMAPs Apply to a small number of productsApply to a small number of products –PI still cornerstone of RM Have clear goals and objectivesHave clear goals and objectives Use tools thatUse tools that –are evidence-based –allow product access that is appropriate –consider stakeholder input, technology, use settings, other factors Are evaluable and monitoredAre evaluable and monitored

39. 39 Web References Premarketing guidancePremarketing guidancehttp://www.fda.gov/cder/guidance/5767dft.pdf Pharmacovigilance guidancePharmacovigilance guidancehttp://www.fda.gov/cder/guidance/5767dft.pdf RiskMAP guidanceRiskMAP guidance http://www.fda.gov/cder/guidance/5766dft.pdf