1. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 Selecting Risk Management Tools: FDA Considerations and Experience Anne Trontell, M.D., M.P.H. Deputy Director, Office of Drug Safety Joint Advisory Committee of DSaRM and Dermatologic & Ophthalmic Drugs February 26, 2004 Anne Trontell, M.D., M.P.H. Deputy Director, Office of Drug Safety Joint Advisory Committee of DSaRM and Dermatologic & Ophthalmic Drugs February 26, 2004

2. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 2 OutlineOutline Definitions General considerations Concerns with current isotretinoin RMP Candidate tools to address concerns Related programs Advantages, disadvantages of tool options Definitions General considerations Concerns with current isotretinoin RMP Candidate tools to address concerns Related programs Advantages, disadvantages of tool options

3. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 3 Risk Management Program (RMP) Definitions Goals –ideal product use scenario/“vision” statement –tailored to product-specific risk concerns –may not be fully achievable in practical terms –example: No fetal exposures shall occur Goals –ideal product use scenario/“vision” statement –tailored to product-specific risk concerns –may not be fully achievable in practical terms –example: No fetal exposures shall occur

4. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 4 RMP Definitions Tools –processes or systems intended to enhance safe product use by reducing risk –Choice influenced by severity, reversibility and frequency of risk Tools –processes or systems intended to enhance safe product use by reducing risk –Choice influenced by severity, reversibility and frequency of risk

5. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 5 Considerations in Selecting RMP Tools Each tool should add value in attaining goals Seek: proven effectiveness, acceptability, low burden Avoid: unnecessary limitations on beneficial uses, multiple customized tools, unintended consequences Each tool should add value in attaining goals Seek: proven effectiveness, acceptability, low burden Avoid: unnecessary limitations on beneficial uses, multiple customized tools, unintended consequences

6. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 6 Broad Categories of Tools Product labeling for health professionals Education and outreach –educational materials for HCP and/or patients Reminder/Prompting systems –stickers, informed consent, limited supply Limited distribution –selected groups able to prescribe, dispense, use –often mandatory use of reminder-like systems Product labeling for health professionals Education and outreach –educational materials for HCP and/or patients Reminder/Prompting systems –stickers, informed consent, limited supply Limited distribution –selected groups able to prescribe, dispense, use –often mandatory use of reminder-like systems

7. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 7 Experience with Tool Categories Product labeling, education and outreach –extensive use; effectiveness limited/unknown Reminder systems –infrequent use; effectiveness largely untested Limited distribution –rarely used; typically small patient populations with limited therapeutic options; registration allows and has demonstrated effectiveness Product labeling, education and outreach –extensive use; effectiveness limited/unknown Reminder systems –infrequent use; effectiveness largely untested Limited distribution –rarely used; typically small patient populations with limited therapeutic options; registration allows and has demonstrated effectiveness

8. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 8 Experience: Tool Categories Reminder/prompting/limited supply –alosetron, isotretinoin, lindane Limited distribution –bosentan*, clozapine*, dofetilide*, mifepristone, thalidomide*, xyrem * lab testing required Reminder/prompting/limited supply –alosetron, isotretinoin, lindane Limited distribution –bosentan*, clozapine*, dofetilide*, mifepristone, thalidomide*, xyrem * lab testing required

9. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 9 Areas of Concern with Current Isotretinoin RMP Refills dispensed (2.4% of Rx) Prescriptions filled without stickers (5-9%) Stickers without pregnancy testing (9%) Patients pregnant at initiation of therapy (6% of reported pregnancies) –2 tests not done, timed incorrectly to menses, erroneous or misreported tests Refills dispensed (2.4% of Rx) Prescriptions filled without stickers (5-9%) Stickers without pregnancy testing (9%) Patients pregnant at initiation of therapy (6% of reported pregnancies) –2 tests not done, timed incorrectly to menses, erroneous or misreported tests

10. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 10 Areas of Concern with Current Isotretinoin RMP Pregnancy exposures occurring during therapy (94% of total) –Poor/no use of adequate contraception –Abstinent patients having unanticipated sexual activity without contraceptive use Use without medical supervision (?%) –Internet, borrowed, leftover pills Pregnancy exposures occurring during therapy (94% of total) –Poor/no use of adequate contraception –Abstinent patients having unanticipated sexual activity without contraceptive use Use without medical supervision (?%) –Internet, borrowed, leftover pills

11. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 11 Areas of Concern with Current Isotretinoin RMP Extent of pregnancy exposures unknown –only voluntary reports and patient surveys –potential duplication of patients across surveys Extent, duration of isotretinoin exposure among FCBP poorly estimated Extent of pregnancy exposures unknown –only voluntary reports and patient surveys –potential duplication of patients across surveys Extent, duration of isotretinoin exposure among FCBP poorly estimated

12. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 12 Prescribing/Dispensing with Stickers Tool Options Better education of pharmacists and physicians (  “good faith”) Increase number or types of reminders (~ disease management models) Limit prescribing, dispensing by HCPs –by training, certification, and/or registration –with systems that obligate compliance and/or allow monitoring Better education of pharmacists and physicians (  “good faith”) Increase number or types of reminders (~ disease management models) Limit prescribing, dispensing by HCPs –by training, certification, and/or registration –with systems that obligate compliance and/or allow monitoring

13. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 13 Pregnancy Testing Tool Options for HCP More and better education More or better reminders Limit prescribing, dispensing to selected HCPs Require documentation check of negative  -HCG at time of dispensing (e.g. Kaiser) More and better education More or better reminders Limit prescribing, dispensing to selected HCPs Require documentation check of negative  -HCG at time of dispensing (e.g. Kaiser)

14. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 14 Contraception: Challenges for Intervention Complex and private behavior, sensitive to discuss –with adolescents when parents are present –assumptions, misinformation common among all ages Behavior influenced but not necessarily controlled by knowledge Attitudinal and behavioral components Complex and private behavior, sensitive to discuss –with adolescents when parents are present –assumptions, misinformation common among all ages Behavior influenced but not necessarily controlled by knowledge Attitudinal and behavioral components

15. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 15 Contraception Tool Options Improved education and outreach to patients to increase knowledge –Need for 2 methods –Effective methods –Ineffective methods Improved education and outreach to patients to increase knowledge –Need for 2 methods –Effective methods –Ineffective methods

16. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 16 Contraception Tool Options Use reminders/prompts (such as counseling) –Reinforce knowledge –Address attitudes about contraceptive use, planned/unplanned sexual activity, partner cooperation/resistance to use –One time or periodic to reinforce behaviors –Methods could include technologies such as interactive voice response (IVR), moderated chat rooms, etc Use reminders/prompts (such as counseling) –Reinforce knowledge –Address attitudes about contraceptive use, planned/unplanned sexual activity, partner cooperation/resistance to use –One time or periodic to reinforce behaviors –Methods could include technologies such as interactive voice response (IVR), moderated chat rooms, etc

17. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 17 Contraception Tool Options Limit product to patients demonstrating appropriate knowledge, skills, and behaviors –Counselor certification of patient commitment, skills with chosen contraceptives –Periodic IVR or counselor screening for high risk behaviors –DOT for OCP or patches, pill counts, other models to track adherence Limit product to patients demonstrating appropriate knowledge, skills, and behaviors –Counselor certification of patient commitment, skills with chosen contraceptives –Periodic IVR or counselor screening for high risk behaviors –DOT for OCP or patches, pill counts, other models to track adherence

18. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 18 Contraceptive ‘Failures’ Contraceptive effectiveness in actual practice << efficacy Options to limit exposure of FCBP to only with the most severe cases of acne –require documentation, prior authorization, 2nd opinion, or other check mechanism for use by FCBP Contraceptive effectiveness in actual practice << efficacy Options to limit exposure of FCBP to only with the most severe cases of acne –require documentation, prior authorization, 2nd opinion, or other check mechanism for use by FCBP

19. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 19 Medically Unsupervised Use Tool Options Educate patients about risks Alter product packaging –note risks of unsupervised use, Internet purchase, sharing –limit supply dispensed << 30 days to decrease sharing Constrain Internet sales Educate patients about risks Alter product packaging –note risks of unsupervised use, Internet purchase, sharing –limit supply dispensed << 30 days to decrease sharing Constrain Internet sales

20. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 20 Relevant RMPs for Comparison Clozapine –multiple manufacturers –interrelated data systems –evaluation data used to relax requirements Thalidomide –teratogen with extensive and effective system –experience with FCBP limited (~5%) Clozapine –multiple manufacturers –interrelated data systems –evaluation data used to relax requirements Thalidomide –teratogen with extensive and effective system –experience with FCBP limited (~5%)

21. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 21 ClozapineClozapine Goal: No agranulocytosis Weekly to biweekly blood testing assures adequate WBC and prevents agran Pharmacist must see documented WBC to dispense Only registered patients, pharmacists, physicians can access drug Goal: No agranulocytosis Weekly to biweekly blood testing assures adequate WBC and prevents agran Pharmacist must see documented WBC to dispense Only registered patients, pharmacists, physicians can access drug

22. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 22 Clozapine Processes Central, shared non-rechallenge registry of those with history of low WBC Independent sponsor programs for weekly, biweekly testing No patient survey, education Central, shared non-rechallenge registry of those with history of low WBC Independent sponsor programs for weekly, biweekly testing No patient survey, education

23. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 23 ThalidomideThalidomide Goal: No fetal exposures Only registered patients, pharmacists, physicians can access drug Pregnancy testing done according to pregnancy risk category (gender, age, fertility) Physician reports negative pregnancy status to central authorization database Goal: No fetal exposures Only registered patients, pharmacists, physicians can access drug Pregnancy testing done according to pregnancy risk category (gender, age, fertility) Physician reports negative pregnancy status to central authorization database

24. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 24 ThalidomideThalidomide Patients must report via IVR module on risk factors for pregnancy exposure: high-risk routed directly to person for action Pharmacist dispenses product only if check of central database assures appropriate physician and patient responses System tracks pregnancy exposures not lost to f/u Extensive education, including medication guide, informed consent, video Patients must report via IVR module on risk factors for pregnancy exposure: high-risk routed directly to person for action Pharmacist dispenses product only if check of central database assures appropriate physician and patient responses System tracks pregnancy exposures not lost to f/u Extensive education, including medication guide, informed consent, video

25. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 25 Comparison of Programs: Isotretinoin, Thalidomide, Clozapine Warnings in labeling: All Patient education materials: I, T Medication guide:I, T Patient informed consent:I, T Warnings in labeling: All Patient education materials: I, T Medication guide:I, T Patient informed consent:I, T

26. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 26 Comparison of Programs: Isotretinoin, Thalidomide, Clozapine Lab testing –Documentation of results required:C –Physician report of results required:T –Physician uses sticker to attest to pregnancy test done and negative:I Lab testing –Documentation of results required:C –Physician report of results required:T –Physician uses sticker to attest to pregnancy test done and negative:I

27. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 27 Comparison of Programs: Isotretinoin, Thalidomide, Clozapine Patient Registration –All patients: T –Nonrechallenge only:C –None:I Physician registration –Required to prescribe:T, C –Voluntary to get stickers:I Patient Registration –All patients: T –Nonrechallenge only:C –None:I Physician registration –Required to prescribe:T, C –Voluntary to get stickers:I

28. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 28 Comparison of Programs: Isotretinoin, Thalidomide, Clozapine Pharmacist Registration –Required to dispense product: T, C –None:I Pharmacist Registration –Required to dispense product: T, C –None:I

29. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 29 Comparison of Programs: Isotretinoin, Thalidomide, Clozapine Tracking performance –patient behaviors:T (I) –patient exposures:T (C) –Direct tracking of outcomes: T, C –Voluntary outcomes, AEs:I Tracking performance –patient behaviors:T (I) –patient exposures:T (C) –Direct tracking of outcomes: T, C –Voluntary outcomes, AEs:I

30. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 30 Increasing Education and Outreach Tools Advantages/Disadvantages Advantages Acceptable to most Feasible No change in access More time to see if performance improves Advantages Acceptable to most Feasible No change in access More time to see if performance improves Disadvantages Effectiveness limited/unknown, particularly for changing behaviors such as contraception

31. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 31 Increasing Reminder/Prompting Systems Advantages/Disadvantages Advantages Physician, pharmacist, patient autonomy Ongoing education, reminders re risks and safe use Less intrusive than limited distribution Advantages Physician, pharmacist, patient autonomy Ongoing education, reminders re risks and safe use Less intrusive than limited distribution Disadvantages Limited experience Unknown effectiveness Time and $ costs for counseling, disease mgt

32. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 32 Limited Distribution Advantages/Disadvantages Advantages Limits access to those adhering to critical risk minimization tools Mandatory participation  registration, better data for evaluation Likely to limit exposure by FCBP Advantages Limits access to those adhering to critical risk minimization tools Mandatory participation  registration, better data for evaluation Likely to limit exposure by FCBP Disadvantages Unknown effectiveness in young, fertile women Time and $ burdens Limits access to drug benefits May increase illicit access without any safety measures

33. Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory Committee February 26 & 27, 2004 33 Considerations in Modifying or Selecting New RMP Tools Seek evidence for effectiveness and high likelihood of added value Stay close to familiar tools that work and are acceptable Avoid unnecessary limitations Anticipate time, cost, access impacts of constraints, including unintended consequences Seek evidence for effectiveness and high likelihood of added value Stay close to familiar tools that work and are acceptable Avoid unnecessary limitations Anticipate time, cost, access impacts of constraints, including unintended consequences