1. 1 Goals of a Lotronex ® Risk Management Program Toni Piazza-Hepp, Pharm.D. Deputy Director Division of Surveillance, Research and Communication Support Office of Drug Safety

2. 2 From: Managing the risks from medical product use; creating a risk management framework, Report to the Commissioner from the FDA Task Force on Risk Management, May 1999

3. 3 Options for Drug Access No Patient Access –Drug not approved or marketing suspended Investigational New Drug (IND) Access –Availability only under study protocol Marketing Under Restricted Distribution –Topic of this presentation Normal Marketing Conditions –No special restrictions to drug access

4. 4 Components of Current Risk Management Programs Education –Patients, prescribers, pharmacists Registration –Patients, prescribers, pharmacists Prescribing and dispensing restrictions Patient monitoring Assessment of: –Compliance with program elements –Ability of program to manage drug risks

5. 5 Education: Patients, Prescribers, Pharmacists Purpose –Provides description of the program –Communicates risks and benefits of treatment –Can be used to: Encourage participation in plan assessment activities such as surveys Encourage reporting of adverse events Considerations –Burdensome, expensive, time-consuming

6. 6 Registration: Patients, Prescribers, and/or Pharmacists Purpose –Creates a target population for education, monitoring, and follow-up surveys –Provides mechanisms to measure plan success Patient denominator, mandatory surveys associated with registrations, etc. Considerations –Burdensome, expensive, time-consuming –Patient privacy concerns

7. 7 Prescibing and Dispensing Restrictions Purpose –Limits drug access to targeted patients –Allows pharmacist to verify that prescriptions are written by authorized prescribers –No Refills ensures patients return for follow-up –Drug distribution in special packaging can: limit drug supply, include MedGuide, have reinforcing messages on packaging, etc. Considerations –Burdensome, expensive, time-consuming –Patient access issues: needy or remotely located –May encourage alternate sourcing

8. 8 Patient Monitoring at Regular Intervals Purpose –Assures patient follow-up Benefit and Safety –Opportunity for reinforcing safety messages –Opportunity for obtaining and evaluating adverse event information Considerations –Burdensome, expensive, time-consuming –Additional office visits may be necessary

9. 9 Assessment of Compliance with Program Elements Purpose –Surveys of patients, prescribers, and/or pharmacists to measure plan compliance, adverse events, etc. Considerations –Burdensome, expensive, time-consuming –Voluntary surveys: level of participation may be inadequate Question whether respondents are representative of all patients receiving drug

10. 10 Current Risk Management Programs Some (not all) programs are approved under the Subpart H regulation –Provides requirement for postmarketing restrictions

11. 11 21CFR 314 Subpart H: Accelerated approval for serious or life-threatening illnesses 314.520 FDA will require postmarketing restrictions if it concludes that a drug product can be safely used only if distribution or use is restricted –e.g. restrictions to certain facilities, physicians with special training or experience, the performance of specified medical procedures

12. 12 21CFR 314 Subpart H: Accelerated approval for serious or life-threatening illnesses 314.530 FDA may withdraw approval, following a hearing, if demonstrated that postmarketing restrictions are: –inadequate to assure safe use or –if the applicant fails to adhere to the agreed upon postmarketing restrictions under Subpart H 314.550 Promotional materials must be preapproved

13. 13 Advantages of Subpart H vs. Voluntary Restriction Program Regulatory control by FDA –Rapid withdrawal possible if restrictions not met or plan fails to accomplish safe use Auditing needed to assess this Review of promotional material (advertising) mandatory

14. 14 Drugs with Restricted Distribution Approved under Subpart H Thalidomide (Thalomid): for erythema nodosum leprosum –Teratogenicity Fentanyl (Actiq): for breakthrough cancer pain –Child Safety / Abuse and Diversion Bosentan (Tracleer): for pulmonary hypertension –hepatotoxicity and teratogencity Mifepristone (Mifeprex): for pregnancy termination –appropriate pt management, drug security

15. 15 Potential Options for the Design of a Lotronex Risk Management Plan

16. 16 GlaxoSmithKline Proposal: Reintroduce Lotronex to the Market and Restrict Access Under the Provisions of Subpart H

17. 17 GSK Proposed Plan: Strengths Educational Component Enhanced Labeling Medication Guide Special Packaging –Provides for limited supply –MedGuide included Dose titration phase –1mg per day for first 4 weeks

18. 18 GSK Proposed Plan: Strengths Expedited reporting of targeted adverse events Pre-approval of promotional materials Program evaluation component –Patient survey (Slone Epidemiology Unit) –Prescribing practices (UnitedHealthcare) Continued study (no refills)

19. 19 GSK Proposed Plan: Weaknesses Patient selection: –failed conventional therapy not adequate to describe severe or debilitating disease Qualified prescribers: attestation of qualifications only is proposed –In current plan, prescribers do not receive education, certification, or registration with GSK prior to receiving kit with stickers –Program does not limit prescribing to gastroenterologists or similarly trained MDs Monitoring of patients by prescribers on a regular basis: not in current plan –Patient burden to identify problems and contact MD

20. 20 GSK Proposed Plan: Weaknesses Program submitted did not include no sticker-no drug concept –sticker only on initial prescription; refills allowed without new prescription –GSK planning to add this concept to plan Utility of stickers as an authorized prescriber check is an untested method Program assessment not designed to measure compliance with use of stickers

21. 21 GSK Proposed Plan: Weaknesses Program assessment includes voluntary survey using Eckerd Pharmacy patients –No assurance that survey will be representative of all Lotronex patients –Program does not include other means to more widely distribute survey (via prescriber or special packaging) or mandatory survey (via registration of all patients)

22. 22 Considerations in Developing Goals for a Lotronex Risk Management Plan: Goals stated in Letter Regarding Lotronex from CDER to IBS patients December 18, 2000 –Safer use of Lotronex in appropriately informed patients –Continued access to Lotronex by severely affected IBS patients under closely monitored conditions –Continued clinical studies of the benefits and risks, and safe use of Lotronex

23. 23 Additional Considerations in Developing Goals for a Lotronex Risk Management Plan: Risk factors for ischemic colitis not known –continued IC events must be expected Complications of constipation may be prevented by recognizing constipation –but some patients did not report constipation before complications occurred Subpart H considerations –serious/life-threatening disease –ability to determine success of plan

24. 24 Proposed FDA Goals for a Lotronex Risk Management Plan 1) Provide access to severely affected IBS patients 2) Limit prescribers to qualified physicians 3) Identify IC and SCC symptoms early through close medical monitoring (regular follow-up) 4) Measure success of plan (auditing)

25. 25

26. 26 Plan Design Considerations GSK plan does not appear to meet FDA goals Alternate plan designs should be considered in order to better meet FDA goals Consider incorporation of additional components from other risk management programs Seek advice from the Advisory Committee

27. 27

28. 28 Conclusion The full range of drug access options needs to be considered If approach is to market under Subpart H, begin with a more restrictive plan than that proposed by GSK in order to meet the proposed FDA goals Re-evaluate the program at a specified time (e.g., at one year post-implementation) for: –Compliance with program elements –Ability of program to manage risks Modify program at that time if appropriate