Selecting Risk Management Tools: FDA Considerations and Experience

1. 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

2. Outline • Definitions • General considerations • Concerns with current isotretinoin RMP • Candidate tools to address concerns • Related programs • Advantages, disadvantages of tool options

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

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

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

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

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

8. Experience: Tool Categories • Reminder/prompting/limited supply • alosetron, isotretinoin, lindane • Limited distribution • bosentan*, clozapine*, dofetilide*, mifepristone, thalidomide*, xyrem * lab testing required

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

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

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

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

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)

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

15. Contraception Tool Options • Improved education and outreach to patients to increase knowledge • Need for 2 methods • Effective methods • Ineffective methods

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

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

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

19. Medically Unsupervised UseTool 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

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%)

21. Clozapine 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. 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

23. Thalidomide 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. Thalidomide • 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. Comparison of Programs: Isotretinoin, Thalidomide, Clozapine • Warnings in labeling: All • Patient education materials: I, T • Medication guide: I, T • Patient informed consent: I, T

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

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

28. Comparison of Programs: Isotretinoin, Thalidomide, Clozapine • Pharmacist Registration • Required to dispense product: T, C • None: I

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

30. 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 Increasing Education and Outreach Tools Advantages/Disadvantages

31. 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 Increasing Reminder/Prompting Systems Advantages/Disadvantages

32. 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 Limited Distribution Advantages/Disadvantages

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