Food and Drug Administration

Center for Drug Evaluation and Research

Summary Minutes of the
Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee
of the Advisory Committee for Pharmaceutical Science

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

Members Present

M. Michael Wolfe, M.D., Chair Joel Richter, M.D.

David Colin Metz, M.D. Byron Cryer, M.D.

Robert Alan Levine, M.D. John Thomas LaMont, M.D.

Jurgen Venitz, M.D. Gloria Anderson, Ph.D., Consumer Rep.

Consultants

Peter Gross, M.D. Brian Leslie Strom, M.D., M.P.H.

Ruth S. Day, Ph.D. Jacqueline Gardner, Ph.D., M.P.H.

Eric S. Holmboe, M.D. William H. Campbell, Ph.D.

Stephanie Y. Crawford, Ph.D. Michael R. Cohen, R.Ph., M.S., D.Sc.

Thomas Fleming, Ph.D. Arthur Levin, M.P.H.

Guests

Alex Krist, M.D. Carlar Blackman, Patient Rep.

Guest Industry Representatives

George S. Goldstein, M.D. John T. Sullivan, M.D.

FDA Participants

Florence Houn, M.D., M.P.H. Victor Raczkowski, M.D.

Paul Seligman, M.D., M.P.H. Julie Beitz, M.D.

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.

Introduction James B.D. Palmer, M.D.

Burden of Illness & Efficacy of Alosetron Peter Traber, M.D.
Safety Assessment & Benefit Risk Overview Eric Carter, M.D., Ph.D.
Proposed Risk David Wheadon, M.D.
Management Plan Clinicianís Perspective Robert Sandler, M.D.

Summary and Conclusions James B.D. Palmer, M.D.

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

Introduction Victor Raczkowski, M.D.

Lotronex: Clinical Trial Experience Thomas Permutt, Ph.D.

Post-Marketing Experience with Lotronex Ann Corken Mackey, R.Ph., M.P.H.

Lotronex Risk-Management Program Toni Piazza-Hepp, Pharm.D.

Risk-Benefit Issues, Summary & Conclusions Victor Raczkowski, M.D.

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

Sidney M. Wolfe, M.D. Public Citizen's Health Research Group

Nancy Norton International Foundation for Functional GI Disorders

Jeffrey D. Roberts Irritable Bowel Syndrome Self Help Group

Corey Miller Lotronex Action Group

Gary C. Stein, Ph.D. American Society of Health-System Pharmacists

William Brown, Esq.

Lisa Kenney

Maria Zargo

Julia R. Alberino

Terry Olifiers

Diana Hoyt

Kathleen Kelly Ghawi

Mike Schmidt

Brenda and Franklin Compton

Dennis K. Larry, Esq.

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.

 

Questions for the Committee

  1. Can a patient population with diarrhea-predominant irritable bowel syndrome (IBS) be described for which the benefits of LotronexTM 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.
  2. 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.

     

  3. 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.
  4. 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.

  5. 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.
  6. 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.

     

  7. 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 patientís 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?
  2. The panel generally felt that this proposal was not adequate.

    Vote: Inadequate 16 Abstain 2

  3. 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.
  4. 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.

  5. GSK proposes a pharmacy-based study using the Slone Epidemiology Unit and Eckerd Corporation to audit patientsí 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 GSKís or another knowledge audit.
  6. The panel generally felt that this proposal was not adequate.

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

Vote: Favor Registration 13 Not in Favor 3 Abstain 2

The panel generally felt that registration should be a part of the risk management plan, and that consideration could be given to having registration as a condition of receiving drug to gather the needed information.

 

  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 patientís medical record. Is the sponsorís 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?

Generally the panel favored having a registry for certified physicians over the sticker concept. The complete details of the committee member responses are recorded on the meeting transcripts to which those interested are referred.

6. Regarding pharmacists:

GSK proposes that pharmacists accept only written prescriptions with an attached sticker. The goal is to verify in real-time that patients being dispensed Lotronex are under the care of enrolled physicians. Also, pharmacists will provide Medication Guides to patients whenever Lotronex prescriptions are filled or refilled. The goal is to provide patients with written information about the safe and effective use of Lotronex.

    1. Are the sponsorís 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?

The panel generally felt that this proposal was not adequate. While a means of permitting pharmacists to be assured that the prescribers are certified is needed, several members voiced objections about problems and concerns they have about the inadequacy of the sticker concept as a means of communication.

7. Regarding safety outcomes:

    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.

The complete details of the committee member responses are recorded on the meeting transcripts to which those interested are referred. The Committee referred to earlier discussion that addressed this question.

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

Studies are needed to identify the subgroup of patients likely to benefit from the drug, so that use of the drug can be restricted to those individuals, rather than the much larger number of patients who is much less likely to benefit and in whom the risk/benefit balance is not likely to be positive.

Dr. Fleming stated that further information gathering is needed in the way of studies to determine risk. He suggested a 2 arm randomized trial to assess what sub cohort of patients that would benefit from drug treatment followed by a larger cohort study to identify an optimal drug dosing schedule. Many other study ideas emerged earlier in the day.