Food and Drug
Administration
Center for Drug Evaluation and Research
Advisory
Committee Conference Room, Rm. 1066,
“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..”
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.
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
I
certify that I attended the
_________//S//______________________ ___________//S//____________________
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
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
Novartis Pharmaceutical Corp., representatives began their
presentations at
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
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
The presentations were
followed by a question and answer period.
After a 15 minute break the Committee reconvened at
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
The meeting reconvened at
At
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.
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 > 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 No 5 Abstain
2
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 No 13
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 No 8
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 No 3 Abstain 1
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 No 4 Abstain 1
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 No 13
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 No 3 Abstain 1
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 No 6
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 No 13
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