Holiday Inn
8120 Wisconsin Ave., Bethesda, MD.
April 23, 2002

These summary minutes for the April 23, 2002 meeting of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee of the Advisory Committee for Pharmaceutical Science were approved on May 8, 2002.

I certify that I attended the April 23, 2002 meeting of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee of the Advisory Committee for Pharmaceutical Science, and that these minutes accurately reflect what transpired.

________/S/______________________ ____________/S/__________________

Thomas H. Perez, M.P.H., R.Ph. M. Michael Wolfe, M.D
Executive Secretary Chair

The Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee of the Advisory Committee for Pharmaceutical Science, of the Food and Drug Administration, Center for Drug Evaluation and Research met April 23, 2002 at the Holiday Inn, 8120 Wisconsin Ave., Bethesda, MD.

The Committee discussed risk management for (NDA) 21-107, Lotronex™ (alosetron), GlaxoSmithKline.

The Committee had received a briefing document from the FDA, a background package from GlaxoSmithKline, and a package containing correspondence received from members of the public.

There were approximately 300 persons in the audience. The meeting was called to order at 8:00am by the Chair, M. Michael Wolfe, M.D. The Committee members and discussants introduced themselves. Thomas H. Perez, Executive Secretary of the Gastrointestinal Drugs Advisory Committee read the Meeting Statement. A welcome and opening comments were provided by Florence Houn, M.D., M.P.H., Director, Office of Drug Evaluation III, and Paul Seligman, M.D., M.P.H., Office of Pharmacoepidemiology and Statistical Science.

GlaxoSmithKline representatives began their presentations at 8:25 a.m. and proceeded as follows.

FDA representatives began their presentations at 10:05 a.m. and proceeded as follows.

The Open Public Hearing included 16 participants, and began at approximately 11:30 a.m.

The meeting was reconvened after lunch at 1:50 p.m. with clarifying questions to the FDA and GlaxoSmithKline presentations. This was followed by an introduction to the Questions for the Committee and the Charge to the Committee given by Victor F.C. Raczkowski, M.D., Deputy Director, Office of Drug Evaluation III.

A thorough discussion of the questions followed, and the meeting was adjourned at 5:20 p.m.

The Committee discussed the following questions. The discussion will be made available through the meeting transcripts to be placed on the web when they become available.

1. Can a patient population with diarrhea-predominant irritable bowel syndrome (IBS) be described for which the benefits of Lotronex^TM outweigh the risks? If not, why not? If so, describe the population in terms of the following characteristics: severity of symptoms, degree of disability, chronicity of IBS, failure of conventional IBS therapies, and any other important characteristics.

Vote: Yes 14 No 4

The panel generally felt that there is a need to define what are severe symptoms, what is the criteria, and what screenings are necessary to determine IBS. That patients selected for treatment be those who suffer from long term illness and exhibit a high severity and frequency of symptoms. Those most disabled appear to benefit the most. More work is needed to define, in addition to that, the subgroup of patients likely to respond substantially.

 

2. At this time, should Lotronex be a) available to patients with diarrhea-predominant IBS without marketing restrictions, b) available to IBS patients with appropriate marketing restrictions (to be defined), or c) withheld from the market? Explain.

Vote: a = 0 b = 16 c = 2

The complete details of the committee member responses are recorded on the meeting transcripts to which those interested are referred.

3. If Lotronex is marketed, should the ability to prescribe Lotronex be limited to certain types of physicians? If so, describe the physicians in terms of the following qualifications: knowledge, experience, specialty, and any other important characteristics.

Yes, there should be limits. As to the specific limits, the Committee provided a variety of responses. Some of the responses most frequently expressed include the following listed in order of most frequent first.

Consultation between Internist and Gastroenterologist (Book knowledge & Experience with a diagnostic algorithm type check list and possible audit of its use)

Physician with certification from some well developed and accessible credentialing program to document expertise.

Board certified Gastroenterologist with some type of CME

Restrict to Gastroenterologist for one year, appraise adverse events and relax requirement to physician plus CME approach.

 

4. Regarding patients:

1. GlaxoSmithKline (GSK) proposes to restrict use of Lotronex to patients who sign a Patient-Physician Agreement. This agreement is then filed in the patient’s medical record. Is this adequate to ensure that only patients with the most favorable benefit-risk balance receive Lotronex? Is auditing of this agreement needed?

The panel generally felt that this proposal was not adequate.

Vote: Inadequate 16 Abstain 2

2. GSK proposes a utilization study of the UnitedHealthcare Research Database (UHC) as a mechanism to audit whether appropriate patients are being prescribed Lotronex. Is this auditing mechanism adequate to achieve the goal? If not, describe an adequate auditing mechanism.

The panel generally felt that this proposal may be useful but was not adequate. A mandatory program that is interactive (other than written) for both patients and physicians requiring correct responses seemed to be preferred.

3. GSK proposes a pharmacy-based study using the Slone Epidemiology Unit and Eckerd Corporation to audit patients’ knowledge and awareness of the risks and benefits of Lotronex. Is this auditing mechanism adequate to achieve the goal? If not, describe an adequate auditing mechanism. Define adequate performance on either GSK’s or another knowledge audit.

The panel generally felt that this proposal was not adequate.

4. Should patient enrollment (e.g., registration) be part of the risk-management plan?

1. Regarding physicians:

1. GSK proposes a plan in which physicians call a 1-800 number to receive a self-attestation kit, including stickers. The physicians self attest to their qualifications by signing the "Section for the Physician" on the Patient-Physician Agreement. This agreement is then filed in the patient’s medical record. Is the sponsor’s proposal adequate to allow for evaluation of physician adherence to the program (e.g., the extent of Lotronex prescribing outside of the program)? If not, describe an adequate auditing mechanism.
2. Define an adequate level of adherence to the program by physicians.
3. Should physician enrollment (e.g., registration) be part of the risk-management plan?

1. Are the sponsor’s proposals to meet each of these goals adequate? If not, describe adequate mechanisms.
2. Should pharmacist adherence to the program be audited? If so, how?

1. Should clinical outcomes (e.g., ischemic colitis, severe constipation, and death) be used to assess the success of the risk-management program? For example, should the rates and/or degree of severity of ischemic colitis and constipation be monitored with the specific goal of evaluating the effectiveness of the program?
2. If so, specify the adverse events that should be assessed and when the assessment(s) should be made. Describe acceptable rates for these adverse events and/or acceptable degrees of severity.

8. Please provide any additional comments that you may have about a Lotronex risk-management program (e.g., suggestions for additional studies).