**Food and Drug Administration**

Center for Drug Evaluation and Research

Advisory Committee Conference Room, Rm. 1066, 5630 Fishers Lane,
Rockville, MD.

# Summary Minutes of the July 14, 2004 meeting of the

# Gastrointestinal Drugs Advisory Committee

# *New drug application 21-200/S-005, Zelnorm*^®^ *(tegaserod maleate) Tablets, Novartis Pharmaceuticals Corp.*

*"for the proposed indication of the treatment of patients with chronic
constipation and relief of associated symptoms of straining, hard or
lumpy stools and infrequent defecation.."*

## **Members Present**

Ronald P. Fogel, M.D., Acting Chair David Colin Metz, M.D. David Sachar,
M.D.

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

Alan Buchman, M.D.

###### **Consultants**

Allen Mangel, M.D. Brian L. Strom, M.D. Curt Furberg, M.D.

Ralph D'Agostino, Ph.D. Arthur A. Levin, M.P.H.

**Federal Employee**

Maria H. Sjogren, M.D.

**Industry Representative**

Jose Vega, M.D.

######## FDA Participants

> Julie Beitz, M.D., M.P.H. Robert Justice, M.D.
>
> Robert Prizont, M.D. Garry Della'Zanna, D.O., M.Sc.

These summary minutes for the July 14, 2004 meeting of the
Gastrointestinal Drugs Advisory Committee were approved on July 23,
2004.

I certify that I attended the July 14, 2004 meeting of the
Gastrointestinal Drugs Advisory, and that these minutes accurately
reflect what transpired.

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Thomas H. Perez, M.P.H., R.Ph. Ronald P. Fogel, M.D.

**Executive Secretary Acting Chair**

The Gastrointestinal Drugs Advisory Committee of the Food and Drug
Administration, Center for Drug Evaluation and Research met July 14,
2004 at the Advisory Committee Conference Room, Rm. 1066, 5630 Fishers
Lane, Rockville, MD. Conference room D in the Parklawn building was used
to accommodate the overflow of attendees to this meeting.

# 

# The Committee discussed new drug application (NDA) 21-200/S-005, Zelnorm^®^ (tegaserod maleate) Tablets, Novartis Pharmaceuticals Corp., for the proposed indication of the treatment of patients with chronic constipation and relief of associated symptoms of straining, hard or lumpy stools and infrequent defecation.

The Committee had received a briefing document from the FDA, and a
background package from Novartis Pharmaceutical Corp., in preparation
for this meeting.

There were approximately 100 members of the public present in the
meeting. Additionally Novartis brought 59 attendees to the meeting. The
meeting was called to order at 8:35 a.m. by the Acting Chair, Ronald P.
Fogel, M.D. The Committee members and discussants introduced themselves.
Thomas H. Perez, Executive Secretary of the Gastrointestinal Drugs
Advisory Committee read the Meeting Statement. Welcome and opening
comments were provided by Robert Justice, M.D., Director, Division of
Gastrointestinal and Coagulation Drug Products

Novartis Pharmaceutical Corp., representatives began their presentations
at 8:45 a.m. The presentations proceeded as follows.

Introduction John R. Cutt, Ph.D., Novartis Executive Director

> Global Head GI, Drug Regulatory Affairs

Chronic Constipation: An Unresolved Charlene M. Prather, M.D.

Problem for Many Patients St. Louis University School of Medicine

Zelnorm^®^: Efficacy and Safety Eslie Dennis, M.D., Novartis Senior
Medical Director,

in Chronic Constipation GI Clinical Development and Medical Affairs

Zelnorm: Safety Overview Bo Joelsson, M.D., Novartis Head
Gastroenterology

> Clinical Research and Development

Benefit/Risk Philip Schoenfeld, M.D.

> University of Michigan School of Medicine

The presentations were followed by a question and answer period. After a
15 minute break the Committee reconvened at 11:45 with the following two
presentations from the FDA.

FDA Efficacy Presentation Robert Prizont, M.D., Medical Officer

> Division of Gastrointestinal and Coagulation Drug Products

FDA Safety Presentation Gary Della\'Zanna, D.O., M.Sc., Medical Officer

> Division of Gastrointestinal and Coagulation Drug Products

Each of the FDA presentations was followed by a question and answer
period, and the Committee recessed for lunch at 1:15 p.m.

The meeting reconvened at 2:15 p.m., with the Open Public Hearing. There
were three participants, Mr. Jeffrey Roberts, President of the IBS
Association / IBS Self Help and Support Group, Ms. Constance Hill and
Ms. Lynda K. Roepke.

At 2:40 **t**he Committee continued with additional clarifying questions
to the FDA and Sponsor on their presentations prior to a discussion of
the meeting questions. The meeting was adjourned at 4:35 p.m.

The meeting transcript will be made available on the web in
approximately three weeks. Transcripts may be accessed at the following
web address
[www.fda.gov/ohrms/dockets/ac/acmenu.htm](http://www.fda.gov/ohrms/dockets/ac/acmenu.htm).

The Committee discussed the following questions.

Gastrointestinal Drugs Advisory Committee

Questions for NDA 21-200/S-005, Zelnorm^®^ (tegaserod maleate) Tablets

1.  Efficacy

    a.  Discuss the appropriateness of a primary efficacy endpoint of an
        increase of ≥1 complete spontaneous bowel movement per week vs.
        a total of ≥3 complete spontaneous bowel movements per week.

> ***The Committee felt that there is some improvement of constipation
> quantitatively in some subpopulation, but individuals remain
> constipated. Although [\>]{.underline} 1 CSBM is a suitable endpoint
> it is not significant. Several committee members stated that there is
> a need for a global assessment metric. One suggestion was that in
> future studies, improvement be measured on such a global assessment
> that includes a quality of life assessment and considered this to be a
> better end point.***

b.  Is the population studied representative of patients with chronic
    constipation? If not, how do the populations differ?

> ***Yes [6]{.underline} No [5]{.underline} Abstain [2]{.underline}***
>
> ***Some of the comments offered by members included the following.***
>
> ***The population is not representative on age, gender, and ethnic or
> racial minorities.***
>
> ***IBS was not excluded from the population.***

c.  Only 9 to 16% of subjects were ≥65 years of age and the treatment
    effect was significantly smaller in older patients. Are these data
    adequate for an indication that is common in the elderly?

> ***Yes [0]{.underline} No [13]{.underline}***

d.  Only 9 to 14% of the subjects were male and the treatment effect was
    smaller in males than females. Are these data adequate to support
    approval of Zelnorm^®^ for use in the treatment of chronic
    constipation in males?

> ***Yes [5]{.underline} No [8]{.underline}***

e.  Are the clinical trial data adequate with respect to the population
    of non-IBS patients with chronic constipation that is likely to be
    treated with Zelnorm^®^?

> ***Yes [9]{.underline} No [3]{.underline} Abstain [1]{.underline}***
>
> ***The yes votes included a number of caveats including:***
>
> ***Concern about patients being treated with other disease states. The
> use of direct to consumer advertising. Also concern that 50% of the
> patients did not have constipation, the small number of patients
> considered elderly, and the chronic use, \> 12 weeks of therapy.***

f.  Is Zelnorm^®^ effective for the treatment of chronic constipation
    and associated symptoms?

> ***Yes [8]{.underline} No [4]{.underline} Abstain [1]{.underline}***

2.  Safety

    a.  Post-marketing cases of ischemic colitis and serious
        complications of diarrhea were not limited to patients with
        irritable bowel syndrome. What are the implications of these
        adverse events for patients with chronic constipation?

> ***The committee provided the following comments:***
>
> ***Concern that there will be an overuse and off-label use of the
> drug, and of potential serious complications. There may be a need for
> limited access to the drug and the use of proactive postmarketing
> surveillance efforts. Concern that there may be an increase in
> ischemic colitis in constipated patients. Concern that safety is not
> adequately established in patients that are at highest risk, such as
> patients over 65.***

b.  The incidence of diarrhea and discontinuations due to diarrhea was
    higher in patients ≥65 years of age. Is there sufficient information
    that Zelnorm^®^ is safe for use in this age group?

> ***Yes [0]{.underline} No [13]{.underline}***

c.  Do the adverse event data from the clinical trials and
    post-marketing surveillance provide adequate evidence of safety of
    Zelnorm^®^ for the treatment of chronic constipation?

> ***Yes [9]{.underline} No [3]{.underline} Abstain [1]{.underline}***

d.  Should the information on the post-marketing cases of ischemic
    colitis and intestinal ischemia be moved from the PRECAUTIONS
    section to the WARNINGS section of the package insert?

> *The labeling regulations state that the PRECAUTIONS section of the
> labeling "shall contain information regarding any special care to be
> exercised by the practitioner for safe and effective use of the
> drug..." The WARNINGS section "shall describe serious adverse
> reactions and potential safety hazards, limitations in use imposed by
> them, and steps that should be taken if they occur. The labeling shall
> be revised to include a warning as soon as there is reasonable
> evidence of an association of a serious hazard with a drug; a causal
> relationship need not have been proved." In addition, the WARNINGS
> section should include any potentially fatal adverse reaction.*
>
> ***Yes [7]{.underline} No [6]{.underline}***

3.  Should Zelnorm^®^ be approved for the proposed indication of *the
    treatment of patients with chronic constipation and relief of the
    associated symptoms of straining, hard or lumpy stools, and
    infrequent defecation*?

> ***As Stated above Yes [0]{.underline} No [13]{.underline}***
>
> ***The following proposals to the indication were provided by the
> panel members and each was subjected to a vote and tallied: (except
> for "No under any circumstances" exclusions are not mutually
> exclusive)***
>
> ***Exclude 65 or older - 10***
>
> ***Exclude males - - - 8***
>
> ***Limited to 12 weeks therapy - - - - - 6***
>
> ***Require a risk management plan***
>
> ***And/or medication guide - - - - 2***
>
> ***Only for functional or idiopathic constipation - - 1***
>
> ***No approval under any circumstances - - 3***