**DIVISION OF GASTROINTESTINAL AND COAGULATION DRUG PRODUCTS**

**GASTROINTESTINAL ADVISORY COMMITTEE MEETING, JUNE 26, 2000**

**PRELIMINARY MEDICAL/STATISTICAL REVIEW**

This document addresses the clinical and statistical issues for the
application for Zelmac (tegaserod tablets), NDA 21-200. The document
does not present the reviewers' final recommendations and should not be
viewed as the final review. The document is divided into four sections:
background information, comments on study design and analyses, safety,
and conclusions.

**1.0 BACKGROUND**

**1.1 Study Description and Sponsor Efficacy Results**

This application for Zelmac (tegaserod) was submitted for the indication
of the treatment of irritable bowel syndrome in patients who identify
abdominal pain/discomfort and constipation as their predominant symptoms
(C-IBS).

Three Phase 3 studies were submitted in the application: B301, B307, and
B351. The designs and patient populations in the three studies were
similar. Each study was a 16-week (a 4-week baseline period and a
12-week treatment period), double-blind, placebo-controlled, parallel
group, double-dummy, multicenter, and multinational study in male and
female outpatients aged 18 years or older with constipation-predominant
irritable bowel syndrome (C-IBS). Each study consisted of a 4-week
baseline period (with no placebo) and a 12-week double-blind treatment
period. Patients took their treatment tablets in a double-dummy fashion,
with water, within 30 minutes prior to meals in the morning and evening.
Patient clinical visits were monthly. The target enrollment for entry
into the randomized double-blind phase of each study was 693 intent to
treat patients in approximately 50 centers.

Studies B351 and B301 had identical study designs: following a 4 week
baseline period, eligible patients were randomized, in equal allocation
(231 patients per treatment group), to receive either placebo, 4 mg/d or
12 mg/d of tegaserod. In Study B307, following a 4 week baseline period,
eligible patients were randomized, in equal allocation (231 patients per
treatment group), to receive either a fixed dose of 4 mg of tegaserod, a
dose-titration regimen or placebo. The patients randomized to
dose-titration received 4 mg of tegaserod and underwent dose titration
at week 4 to 12 mg if the response on the SGA of relief was complete or
considerable relief \<50% of the time. Patients in the 4 mg and placebo
groups underwent a mock dose titration at week 4.

Each study's objective was to determine the efficacy of two dose levels
of tegaserod by comparison to placebo. Efficacy was defined as the
relief of constipation, pain, and discomfort. Efficacy was assessed
based on the following two primary efficacy measures that were evaluated
by the patient on a weekly basis:

-   Subject Global Assessment of Relief - Patients responded to the
    following question:

    *\"Please consider how you felt this past week in regard to your
    IBS, in particular your overall well-being, and symptoms of
    abdominal discomfort, pain and altered bowel habit. Compared to the
    way you usually felt before entering the study, how would you rate
    your relief of symptoms during the past week?\"*

    The choices were: completely relieved, considerably relieved,
    somewhat relieved, unchanged, or worse. The definition of responder
    at endpoint for this variable was defined as follows:

-   At least 50% of the SGAs at endpoint with complete or considerable
    relief

-   Number of days with laxative\* use during treatment period ≤5 and no
    laxative\* use during the last 28 days of treatment (\* with the
    exception of bulk-forming laxatives)

-   Duration of exposure to study medication ≥28 days

-   At least one post-baseline SGA of relief

-   Subject Global Assessment of abdominal discomfort/pain (a 100 mm VAS
    with verbal descriptors for abdominal discomfort/pain) - Patients
    placed a vertical mark on the line in response to the following
    question:

    *\"How much of a problem was your abdominal discomfort/pain over the
    last week?\"*

+-----+------+--------+-------+--------------+-----------+-----+---+
|     |      |        |       |              |           |     |   |
+-----+------+--------+-------+--------------+-----------+-----+---+
| Abs |      |        | Very  | Mild         | Moderate  | Sev | V |
| ent |      |        |       |              |           | ere | e |
|     |      |        | Mild  |              |           |     | r |
|     |      |        |       |              |           |     | y |
|     |      |        |       |              |           |     |   |
|     |      |        |       |              |           |     | s |
|     |      |        |       |              |           |     | e |
|     |      |        |       |              |           |     | v |
|     |      |        |       |              |           |     | e |
|     |      |        |       |              |           |     | r |
|     |      |        |       |              |           |     | e |
+-----+------+--------+-------+--------------+-----------+-----+---+

The definition of responder at endpoint for this variable was defined as
follows:

-   a ≥ 20 mm and ≥ 40% reduction in mean VAS at endpoint compared to
    the baseline

-   Number of days with laxative\* use during treatment period ≤5 and no
    laxative\* use during the last 28 days of treatment (\* with the
    exception of bulk-forming laxatives)

-   Duration of exposure to study medication ≥28 days

-   At least one post-baseline SGA of relief

    All three studies began at about the same time but study B351 was
    completed before the other two. Study B351 was unblinded and the
    data were analyzed according to protocol. The results for the two
    primary efficacy variables of SGA of relief and SGA of abdominal
    pain/discomfort were not statistically significant. This prompted
    the sponsor to redefine the responders for the SGA of relief
    variable and drop the co-primary variable of SGA of abdominal
    discomfort/pain to a secondary variable after post-hoc analyses of
    the data for study B351. These changes were submitted as protocol
    amendments to be applied to the remaining two studies, B301 and
    B307, which were still ongoing. The new definition of a responder
    for SGA of relief is as follows:

-   At least 50% of the SGAs at endpoint with complete or considerable
    relief **OR**

    All of the SGAs at endpoint with at least somewhat relief (i.e.
    complete, considerable or somewhat)

-   Number of days with laxative\* use during treatment period ≤5 and no
    laxative\* use during the last 28 days of treatment (\* with the
    exception of bulk-forming laxatives)

-   Duration of exposure to study medication ≥28 days

-   At least one post-baseline SGA of relief

    A detailed description of these amendments and the sponsor's
    rationale for the changes are presented in section 1.2. Because of
    the hypothesis generating nature of the post-hoc data analysis of
    study B351, the Division deemed that study B351 was no longer
    pivotal.

    *Patient Demographics*

    Table 1.1 presents a summary of the patient demographics for the ITT
    population. The number of patients randomized to studies B301, B307,
    and B351 are 881, 841, and 799, respectively. In all three studies
    there were more females (83% to 87%) than males (13% to 17%), the
    majority of patients were Caucasian (88% to 98%), the majority of
    the patients were less than 65 years old (89% to 93%), and the mean
    duration of C-IBS symptoms was 13.2 to 14.6 years.

    **Table 1.1**

    **Demographics and Baseline Characteristics for ITT Population by
    Study**

+-----------------------------+-----------+-------------+-------------+
|                             | B301      | B307        | B351        |
|                             |           |             |             |
|                             | (N=881)   | (N=841)     | (N=799)     |
+-----------------------------+-----------+-------------+-------------+
| Gender -- N (%)             | 150       | 138 (16.4)  | 102 (12.8)  |
|                             | (17.0)    |             |             |
| Male                        |           | 703 (83.6)  | 697 (87.2)  |
|                             | 731       |             |             |
| Female                      | (83.0)    |             |             |
+-----------------------------+-----------+-------------+-------------+
| Race -- N (%)               | 863       | 760 (90.4)  | 702 (87.9)  |
|                             | (98.0)    |             |             |
| Caucasian                   |           | 46 (5.5)    | 68 (8.5)    |
|                             | 7 (0.8)   |             |             |
| Black                       |           | 35 (4.2)    | 29 (3.7)    |
|                             | 11 (1.3)  |             |             |
| Other                       |           |             |             |
+-----------------------------+-----------+-------------+-------------+
| Age (years) -- N (%)        | 787       | 750 (89.2)  | 744 (93.1)  |
|                             | (89.3)    |             |             |
| \< 65                       |           | 91 (10.8)   | 55 (6.9)    |
|                             | 94 (10.7) |             |             |
| ≥ 65                        |           |             |             |
+-----------------------------+-----------+-------------+-------------+
| Duration of C-IBS symptoms  | 158.1     | 166.4       | 174.6       |
| (months)                    | (147.6)   | (120.0)     | (120.0)     |
|                             |           |             |             |
| Months: Mean (SD)           | 13.2      | 13.9 (10.0) | 14.6 (10.0) |
|                             | (12.3)    |             |             |
| Years: Mean (SD)            |           |             |             |
+-----------------------------+-----------+-------------+-------------+

*Primary Efficacy: Subject Global Assessment of Relief*

The following remarks pertain to the new definition of SGA of relief.
The results for the original definition of SGA of relief are presented
for completeness to compare the effect of changing the definition of
responder. The results for all studies are presented in Table 1.2 and
are as follow:

-   In study B301, both treatment groups had higher response rates
    compared with the placebo group. The therapeutic gain was 9% in the
    4 mg group and 8% in the 12 mg group, both were statistically
    significant.

-   In study B307, the 4 mg group had a similar response to the placebo
    group and the 4-12 titration group had a higher response rate
    compared to the placebo group. The therapeutic gain was 0.8% in the
    4 mg group and 6% in the 4-12 mg titration group, neither of which
    was statistically significant.

-   In study B351, both treatment groups had higher response rates
    compared with the placebo group. The therapeutic gain was 6% in the
    4 mg group and 12% in the12 mg group, of which only the 12 mg group
    was statistically significant.

    **Table 1.2**

    **Subject Global Assessment of Relief by Study**

+-------------+---+-------+--------+------+---+--------+--------+--------+
|             |   | **Ori |        |      |   | **New  |        |        |
|             |   | ginal |        |      |   | Defi   |        |        |
|             |   | Defin |        |      |   | nition |        |        |
|             |   | ition |        |      |   | of SGA |        |        |
|             |   | of    |        |      |   | of     |        |        |
|             |   | SGA   |        |      |   | Re     |        |        |
|             |   | of    |        |      |   | lief** |        |        |
|             |   | Rel   |        |      |   |        |        |        |
|             |   | ief** |        |      |   |        |        |        |
+-------------+---+-------+--------+------+---+--------+--------+--------+
|             |   |       |        |      |   |        |        |        |
+-------------+---+-------+--------+------+---+--------+--------+--------+
| **Study     | * | **4   | **12   | *    |   | **4    | **12   | **Pla  |
| B301**      | * | mg    | mg     | *Pla |   | mg**   | mg**   | cebo** |
|             | N | (n)** | (n)**  | cebo |   |        |        |        |
|             | * |       |        | (    |   |        |        |        |
|             | * |       |        | n)** |   |        |        |        |
+-------------+---+-------+--------+------+---+--------+--------+--------+
| Response    | 8 | 27.8  | 26.2   | 20.5 |   | 38.8   | 38.4   | 30.2   |
| Rate        | 8 | (299) | (294)  | (    |   |        |        |        |
|             | 1 |       |        | 288) |   | 9.1    | 8.3    |        |
| Therapeutic |   | 7.6   | 5.5    |      |   |        |        |        |
| Gain^1^     |   |       |        |      |   | 0.018  | 0.033  |        |
|             |   | 0.028 | 0.116  |      |   |        |        |        |
| p-value^2^  |   |       |        |      |   | 0      | 0      |        |
|             |   | 0.056 | 0.116  |      |   | .033\* | .033\* |        |
| Adjusted    |   |       |        |      |   |        |        |        |
| p-value^3^  |   |       |        |      |   |        |        |        |
+-------------+---+-------+--------+------+---+--------+--------+--------+
|             |   |       |        |      |   |        |        |        |
+-------------+---+-------+--------+------+---+--------+--------+--------+
| **Study     | * | **4   | **4-12 | *    |   | **4    | **4-12 | **Pla  |
| B307**      | * | mg    | mg     | *Pla |   | mg**   | mg**   | cebo** |
|             | N | (n)** | (n)**  | cebo |   |        |        |        |
|             | * |       |        | (    |   |        |        |        |
|             | * |       |        | n)** |   |        |        |        |
+-------------+---+-------+--------+------+---+--------+--------+--------+
| Response    | 8 | 25.5  | 26.5   | 28.2 |   | 38.3   | 42.2   | 37.0   |
| Rate        | 4 | (282) | (275)  | (    |   |        |        |        |
|             | 1 |       |        | 284) |   | 0.8    | 6.0    |        |
| Therapeutic |   | -3.0  | -1.4   |      |   |        |        |        |
| Gain^1^     |   |       |        |      |   | 0.837  | 0.142  |        |
|             |   | 0.422 | 0.703  |      |   |        |        |        |
| p-value^2^  |   |       |        |      |   | 0.837  | 0.284  |        |
|             |   | 0.703 | 0.703  |      |   |        |        |        |
| Adjusted    |   |       |        |      |   |        |        |        |
| p-value^3^  |   |       |        |      |   |        |        |        |
+-------------+---+-------+--------+------+---+--------+--------+--------+
|             |   |       |        |      |   |        |        |        |
+-------------+---+-------+--------+------+---+--------+--------+--------+
| **Study     | * | **4   | **12   | *    |   | **4    | **12   | **Pla  |
| B351**      | * | mg    | mg     | *Pla |   | mg**   | mg**   | cebo** |
|             | N | (n)** | (n)**  | cebo |   |        |        |        |
|             | * |       |        | (    |   |        |        |        |
|             | * |       |        | n)** |   |        |        |        |
+-------------+---+-------+--------+------+---+--------+--------+--------+
| Response    | 7 | 29.4  | 26.2   | 22.1 |   | 38.9   | 45.7   | 33.3   |
| Rate        | 9 | (265) | (267)  | (    |   |        |        |        |
|             | 9 |       |        | 267) |   | 6.0    | 12.4   |        |
| Therapeutic |   | 7.5   | 4.1    |      |   |        |        |        |
| Gain^1^     |   |       |        |      |   | 0.157  | 0.004  |        |
|             |   | 0.050 | 0.266  |      |   |        |        |        |
| p-value^2^  |   |       |        |      |   | 0.314  | 0      |        |
|             |   | 0.200 | 0.370  |      |   |        | .016\* |        |
| Adjusted    |   |       |        |      |   |        |        |        |
| p-value^3^  |   |       |        |      |   |        |        |        |
+-------------+---+-------+--------+------+---+--------+--------+--------+

^1^ Therapeutic gain is the weighted difference of response rates
between the drug group and placebo group, taking into account center
effect.

^2^ Nominal p-value based on the Mantel-Haenszel test stratified by
center.

^3^ p-value adjusted using Hochberg\'s multiple comparison procedure
adjusting for two doses in studies B301 and B307, or using Holm\'s
multiple comparison procedure adjusting for two doses and co-primary
efficacy variable of SGA of abdominal discomfort/pain in study B351.

\* Statistically significant at the 0.05 significance level, using
Hochberg\'s (B301 and B307) or Holm's (B351) multiple comparison
procedure.

*Secondary Efficacy: Subject Global Assessment of Abdominal
Discomfort/Pain*

The results for all studies are presented in Table 1.3 and are as
follow:

-   In study B301, both treatment groups had higher response rates
    compared with the placebo group. The therapeutic gain was 7% in both
    the 4 mg group and the 12 mg group.

-   In study B307, both treatment groups did not have higher response
    rates compared to the placebo group. The therapeutic gain was -6% in
    the 4 mg group and -3% in the 4-12 mg titration group.

-   In study B351, both treatment groups had higher response rates
    compared with the placebo group. The therapeutic gain was 5% in the
    4 mg group and 6% in the12 mg group.

    **Table 1.3**

    **Subject Global Assessment of Abdominal Discomfort/Pain by Study**

+-----------------------+----+-------------+-------------+-------------+
|                       |    |             |             |             |
+-----------------------+----+-------------+-------------+-------------+
| **Study B301**        | *  | **4 mg      | **12 mg     | **Placebo   |
|                       | *N | (n)**       | (n)**       | (n)**       |
|                       | ** |             |             |             |
+-----------------------+----+-------------+-------------+-------------+
| Response Rate         | 8  | 29.8 (299)  | 29.9 (294)  | 22.6 (287)  |
|                       | 80 |             |             |             |
| Therapeutic Gain^1^   |    | 7.0         | 7.3         |             |
|                       |    |             |             |             |
| p-value^2^            |    | 0.055       | 0.044       |             |
+-----------------------+----+-------------+-------------+-------------+
|                       |    |             |             |             |
+-----------------------+----+-------------+-------------+-------------+
| **Study B307**        | *  | **4 mg      | **4-12 mg   | **Placebo   |
|                       | *N | (n)**       | (n)**       | (n)**       |
|                       | ** |             |             |             |
+-----------------------+----+-------------+-------------+-------------+
| Response Rate         | 8  | 25.5 (282)  | 27.6 (275)  | 30.6 (284)  |
|                       | 41 |             |             |             |
| Therapeutic Gain^1^   |    | -5.5        | -3.1        |             |
|                       |    |             |             |             |
| p-value^2^            |    | 0.141       | 0.411       |             |
+-----------------------+----+-------------+-------------+-------------+
|                       |    |             |             |             |
+-----------------------+----+-------------+-------------+-------------+
| **Study B351**        | *  | **4 mg      | **12 mg     | **Placebo   |
|                       | *N | (n)**       | (n)**       | (n)**       |
|                       | ** |             |             |             |
+-----------------------+----+-------------+-------------+-------------+
| Response Rate         | 7  | 23.4 (265)  | 25.1 (267)  | 18.7 (267)  |
|                       | 99 |             |             |             |
| Therapeutic Gain^1^   |    | 4.8         | 6.4         |             |
|                       |    |             |             |             |
| p-value^2^            |    | 0.185       | 0.075       |             |
+-----------------------+----+-------------+-------------+-------------+

^1^ Therapeutic gain is the weighted difference of response rates
between the drug group and placebo group, taking into account center
effect.

^2^ Nominal p-value based on the Mantel-Haenszel test stratified by
country.

**1.2 Protocol Amendments**

In the original protocol, there was one primary efficacy variable, the
Subject Global Assessment (SGA) of abdominal discomfort/pain. Three
protocol amendments were subsequently submitted. Discussed below are the
2 protocol amendments that pertain to changes in the statistical design.

The first amendment was written prior to the start of all three studies.
Its aim was to:

-   introduce a second primary efficacy variable, the SGA of relief, and
    to adjust for the sample size accordingly (Holm's procedure was
    introduced, leading to an increase in sample size)

-   introduced Holm's procedure to adjust for multiplicity

-   The target enrollment for entry into the randomized double-blind
    phase of the study was increased from 591 ITT patients (in
    approximately 45 centers) to 693 ITT patients (in approximately 50
    centers).

    The sponsor's rationale for a second primary efficacy variable was
    based on the idea that both the SGA of relief and the SGA of
    abdominal discomfort/pain were considered clinically relevant
    variables in irritable bowel syndrome. That is, the sponsor was not
    clear which of the two variables was more meaningful in evaluating
    C-IBS, so either variable was considered important.

    The other amendment was written prior to breaking the double-blind
    treatment code in studies B301 and B307. Its aim was to:

-   modify the responder for the SGA of relief original definition of a
    single criterion of "considerable or complete relief at least 50% of
    the time during the last 4 weeks on treatment" to also include the
    criterion "OR somewhat, considerable, or complete relief for all of
    the last 4 weeks on treatment"

-   introduce a modified primary efficacy analysis where SGA of relief
    became the only primary outcome measure

-   eliminate SGA of abdominal discomfort/pain as a primary efficacy
    variable and keep it as a secondary variable

-   introduce additional secondary efficacy variables

-   apply Hochberg's procedure for the multiple comparisons of the two
    tegaserod treatment groups versus placebo in the primary analysis

The sponsor's rationale for modifying the primary outcome measure was
based on the low responder rates in both the tegaserod groups and the
placebo group in study B351, which indicated that the definition of
response for both the SGA of relief and the SGA of abdominal
discomfort/pain was too stringent and therefore the response definition
appeared to lack the sensitivity to detect a significant treatment
effect. The Division considered the change in definition of responder
acceptable and requested that the study results be presented using both
the original SGA of relief and the new SGA of relief. The reason for
presenting both results is to see how the redefinition affected the
original study results.

The sponsor's rationale for eliminating the SGA of abdominal
discomfort/pain as a primary efficacy variable and retaining it as a
secondary efficacy variable is that there are inherent problems with the
use of the VAS, including the patient's potential difficulties in
translating her/his experiences to the scale and the difficulty in
defining a responder on the VAS.

**1.3 Post-Hoc Analyses**

The sponsor has presented post-hoc analyses for the primary efficacy
variables pooled across all three studies, across studies B301 and B351,
and across studies B301 and B307. The sponsor also presented post-hoc
analyses using the number of months (0, 1, 2, or 3 months) that a
patient was a responder. In this analysis, only the SGA of relief
outcome was used without accounting for laxative use. Comments to these
analyses are provided in the following section.

**2.0 COMMENTS ON STUDY DESIGN AND ANALYSES**

The comments pertaining to the study design and efficacy analyses are
primarily statistical. The following issues will be discussed in
detail: 1) Efficacy analysis by gender, 2) Change of the primary
efficacy variables, 3) Pooling of study centers, 4) Pooling of study
results, 5) Laxative use, 6) Expansion of study population, 7) Patient
enrollment by centers, 8) Investigator participation in multiple
studies, 9) Additional issues.

**2.1 Efficacy Analyses by Gender**

This section presents the reviewer's analyses of the primary efficacy
variable of SGA of relief and secondary efficacy variable of SGA of
abdominal discomfort/pain by gender. The sponsor did not present these
analyses by study.

*Patient Demographics and Baseline Characteristics by Gender*

Table 2.1 presents a summary of patient demographics and baseline
characteristics for the ITT population by gender. Several differences in
demographics and baseline variables were noted between males and
females. Study B301 had more Caucasians for both males and females than
the other two studies. Males weighed more than females in all studies.
The duration of C-IBS among males was longer in study B307 than the
other 2 studies, and in females was longer in study B351 than in the
other two studies. Males had less number of days without bowel movements
and less percent of days with hard/very hard stools than females in all
studies. Male had more bowel movements than females in all studies.

**Table 2.1**

Studies B301, B307, and B351: Demographics and Baseline Characteristics
in the ITT Population by Gender

+--------------------------+------+------+------+------+------+------+
|                          | **B3 |      | **B3 |      | **B3 |      |
|                          | 01** |      | 07** |      | 51** |      |
+--------------------------+------+------+------+------+------+------+
| **Demographic/Baseline   | **F  | *    | **F  | *    | **F  | *    |
| variable**               | emal | *Mal | emal | *Mal | emal | *Mal |
|                          | es** | es** | es** | es** | es** | es** |
|                          |      |      |      |      |      |      |
|                          | **   | **(  | **(  | **(  | **(  | **(  |
|                          | (n=7 | n=15 | n=70 | n=13 | n=67 | n=10 |
|                          | 31** | 0)** | 0)** | 5)** | 5)** | 0)** |
+--------------------------+------+------+------+------+------+------+
| Age (yrs)                | 45 ± | 49 ± | 44 ± | 49 ± | 42 ± | 48 ± |
|                          | 14   | 14   | 13   | 14   | 12   | 13   |
+--------------------------+------+------+------+------+------+------+
| Age [\>]{.underline} 65  | 10%  | 16%  | 10%  | 16%  | 6%   | 14%  |
| years                    |      |      |      |      |      |      |
+--------------------------+------+------+------+------+------+------+
| Race: Caucasian          | 98%  | 97%  | 90%  | 91%  | 87%  | 91%  |
+--------------------------+------+------+------+------+------+------+
| Race: Black              | 1%   | 0%   | 6%   | 4%   | 9%   | 5%   |
+--------------------------+------+------+------+------+------+------+
| Race: Other              | 1%   | 3%   | 4%   | 4%   | 4%   | 4%   |
+--------------------------+------+------+------+------+------+------+
| Weight (kg)              | 65 ± | 79 ± | 68 ± | 83 ± | 69 ± | 86 ± |
|                          | 13   | 12   | 15   | 15   | 15   | 17   |
+--------------------------+------+------+------+------+------+------+
| Duration of C-IBS        | 165  | 127  | 169  | 151  | 181  | 135  |
| (months)                 | ±    | ±    | ±    | ±    | ±    | ±    |
|                          | 150  | 130  | 150  | 168  | 161  | 144  |
+--------------------------+------+------+------+------+------+------+
| Abdominal                | 61 ± | 57   | 62 ± | 58 ± | 64 ± | 61 ± |
| discomfort/pain VAS      | 13   | ±12  | 13   | 12   | 13   | 10   |
| score (mm)               |      |      |      |      |      |      |
+--------------------------+------+------+------+------+------+------+
| Bowel habit VAS score    | 61 ± | 56 ± | 62 ± | 58 ± | 65 ± | 62 ± |
| (mm)                     | 14   | 12   | 14   | 14   | 14   | 13   |
+--------------------------+------+------+------+------+------+------+
| No. of days/28 days with | 23   | 24   | 24 ± | 25 ± | 24 ± | 25 ± |
| significant^1^           | ±6   | ±6   | 6    | 6    | 5    | 6    |
| discomfort/pain          |      |      |      |      |      |      |
+--------------------------+------+------+------+------+------+------+
| No. of days/28 days with | 23 ± | 23 ± | 24 ± | 23 ± | 25 ± | 23 ± |
| significant^1^ bloating  | 7    | 7    | 6    | 8    | 5    | 8    |
+--------------------------+------+------+------+------+------+------+
| No. of days/28 days      | 13   | 9 ±8 | 12 ± | 9 ±  | 14 ± | 9 ±  |
| without bowel movements  | ±7   |      | 7    | 7    | 7    | 8    |
+--------------------------+------+------+------+------+------+------+
| No. of bowel             | 20   | 28 ± | 24 ± | 30 ± | 21 ± | 32 ± |
| movements/28 days        | ±14  | 22   | 19   | 24   | 16   | 25   |
+--------------------------+------+------+------+------+------+------+
| \% of days^2^ with       | 29 ± | 22 ± | 30 ± | 24 ± | 32 ± | 28 ± |
| hard/very hard stools    | 29   | 27   | 28   | 25   | 29   | 26   |
+--------------------------+------+------+------+------+------+------+

Note: results are expressed as mean ± SD.

^1^ Defined as at least mild (daily score ≥ 2 on a 6-point scale). ^2^
Denominator is days with bowel movements.

*Primary Efficacy: Subject Global Assessment of Relief*

Given that a large number of centers did not recruit the minimum of 15
ITT patient per center (see Table 2.4) and that the randomization list
was generated by country, centers were pooled across country and country
was used as a stratification variable in the primary and secondary
efficacy analyses. Also, the therapeutic gain is based on the weighted
average of the responder rate. The weight for country k is proportional
to N{k1}\*N{k2}/(N{k1}+N{k2}), where N{ki} is the number of patients in
the i-th treatment group in country k.

Also, the ITT populations for studies B307 and B351 differ from the
sponsor's ITT populations. In study B307, the reviewer's ITT population
was of size 835 instead of size 841 because one Canadian center with 6
randomized patients was removed from the ITT population. The center was
removed because the sponsor suspended the investigator due to audit
findings demonstrating significant departures from GCP (good clinical
practice). In study B351, the reviewer's ITT population was of size 775
instead of size 799 because two Canadian centers with 18 and 6
randomized patients were removed from the ITT population. Both Canadian
centers in the ITT population were removed from the ITT population
because:

-   The sponsor suspended one center's investigator because audit
    findings demonstrated significant departures from GCP.

-   The other center had 6 randomized patients, which are not enough to
    include in the analysis as the contribution from Canada.

    The results for study B301 are presented in Table 2.2 and are as
    follow:

-   Female patients in both treatment groups had higher response rates
    compared with the placebo group. The therapeutic gain was 10% in the
    4 mg group and 11% in the 12 mg group.

-   Male patients in both treatment groups did not have higher response
    rates compared with the placebo group. The therapeutic gain was 0.5%
    in the 4 mg group and -8% in the12 mg group.

    **Table 2.2**

    **Study B301: Subject Global Assessment of Relief by Gender**

+--------------+---+-------+-------+-------+---+-------+-------+-------+
|              |   | **Ori |       |       |   | **New |       |       |
|              |   | ginal |       |       |   | Defin |       |       |
|              |   | Defin |       |       |   | ition |       |       |
|              |   | ition |       |       |   | of    |       |       |
|              |   | of    |       |       |   | SGA   |       |       |
|              |   | SGA   |       |       |   | of    |       |       |
|              |   | of    |       |       |   | Rel   |       |       |
|              |   | Rel   |       |       |   | ief** |       |       |
|              |   | ief** |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+
|              | * | **4   | **12  | **Pl  |   | **4   | **12  | *     |
|              | * | mg    | mg    | acebo |   | mg**  | mg**  | *Plac |
|              | N | (n)** | (n)** | (n)** |   |       |       | ebo** |
|              | * |       |       |       |   |       |       |       |
|              | * |       |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+
| **Male**     | 1 | 34.62 | 24.00 | 29.17 |   | 44.23 | 36.00 | 43.75 |
|              | 5 | (52)  | (50)  | (48)  |   |       |       |       |
| Response     | 0 |       |       |       |   | 0.48  | -7.75 |       |
| Rate         |   | 5.45  | -5.17 |       |   |       |       |       |
|              |   |       |       |       |   | 0.433 | 0.555 |       |
| Therapeutic  |   | 0.269 | 0.749 |       |   |       |       |       |
| Gain^1^      |   |       |       |       |   | 0.555 | 0.555 |       |
|              |   | 0.538 | 0.749 |       |   |       |       |       |
| p-value^2^   |   |       |       |       |   |       |       |       |
|              |   |       |       |       |   |       |       |       |
| Adjusted     |   |       |       |       |   |       |       |       |
| p-value^3^   |   |       |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+
|              |   |       |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+
| **Female**   | 7 | 26.32 | 26.64 | 18.75 |   | 37.65 | 38.93 | 27.50 |
|              | 3 | (247) | (244) | (240) |   |       |       |       |
| Response     | 1 |       |       |       |   | 10.15 | 11.43 |       |
| Rate         |   | 7.57  | 7.89  |       |   |       |       |       |
|              |   |       |       |       |   | 0.013 | 0.006 |       |
| Therapeutic  |   | 0.039 | 0.036 |       |   |       |       |       |
| Gain^1^      |   |       |       |       |   | 0.    | 0.    |       |
|              |   | 0.    | 0.    |       |   | 013\* | 012\* |       |
| p-value^2^   |   | 039\* | 039\* |       |   |       |       |       |
|              |   |       |       |       |   |       |       |       |
| Adjusted     |   |       |       |       |   |       |       |       |
| p-value^3^   |   |       |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+

^1^ Therapeutic gain is the raw difference of response rates between the
drug group and the placebo group.

^2^ Nominal p-value based on the Mantel-Haenszel test stratified by
country.

^3^ p-value adjusted using Hochberg\'s multiple comparison procedure.

\* Statistically significant at the 0.05 significance level, using
Hochberg\'s multiple comparison procedure.

The results for study B307 are presented in Table 2.3 and are as follow:

-   Female patients in both treatment groups had higher response rates
    compared with the placebo group. The therapeutic gain was 5% in both
    the 4 mg group and 4-12 mg titration group.

-   Male patients in both treatment groups had slightly higher response
    rates compared with the placebo group. The therapeutic gain was
    0.09% in the 4 mg group and 2% in the 4-12 mg titration group.

    **Table 2.3**

    **Study B307: Subject Global Assessment of Relief by Gender**

+--------------+---+-------+-------+-------+---+-------+-------+-------+
|              |   | **Ori |       |       |   | **New |       |       |
|              |   | ginal |       |       |   | Defin |       |       |
|              |   | Defin |       |       |   | ition |       |       |
|              |   | ition |       |       |   | of    |       |       |
|              |   | of    |       |       |   | SGA   |       |       |
|              |   | SGA   |       |       |   | of    |       |       |
|              |   | of    |       |       |   | Rel   |       |       |
|              |   | Rel   |       |       |   | ief** |       |       |
|              |   | ief** |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+
|              | * | **4   | *     | **Pl  |   | **4   | *     | *     |
|              | * | mg    | *4-12 | acebo |   | mg**  | *4-12 | *Plac |
|              | N | (n)** | mg    | (n)** |   |       | mg**  | ebo** |
|              | * |       | (n)** |       |   |       |       |       |
|              | * |       |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+
| **Male**     | 1 | 15.91 | 21.95 | 32.00 |   | 34.09 | 39.02 | 34.00 |
|              | 3 | (44)  | (41)  | (50)  |   |       |       |       |
| Response     | 5 |       |       |       |   | 0.09  | 5.02  |       |
| Rate         |   | -     | -     |       |   |       |       |       |
|              |   | 16.09 | 10.05 |       |   | 0.859 | 0.455 |       |
| Therapeutic  |   |       |       |       |   |       |       |       |
| Gain^1^      |   | 0.143 | 0.355 |       |   | 0.859 | 0.859 |       |
|              |   |       |       |       |   |       |       |       |
| p-value^2^   |   | 0.286 | 0.355 |       |   |       |       |       |
|              |   |       |       |       |   |       |       |       |
| Adjusted     |   |       |       |       |   |       |       |       |
| p-value^3^   |   |       |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+
|              |   |       |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+
| **Female**   | 7 | 27.54 | 27.59 | 27.16 |   | 38.98 | 42.67 | 37.50 |
|              | 0 | (236) | (232) | (232) |   |       |       |       |
| Response     | 0 |       |       |       |   | 1.48  | 5.17  |       |
| Rate         |   | 0.38  | 0.43  |       |   |       |       |       |
|              |   |       |       |       |   | 0.928 | 0.285 |       |
| Therapeutic  |   | 0.914 | 0.983 |       |   |       |       |       |
| Gain^1^      |   |       |       |       |   | 0.928 | 0.570 |       |
|              |   | 0.983 | 0.983 |       |   |       |       |       |
| p-value^2^   |   |       |       |       |   |       |       |       |
|              |   |       |       |       |   |       |       |       |
| Adjusted     |   |       |       |       |   |       |       |       |
| p-value^3^   |   |       |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+

^1^ Therapeutic gain is the raw difference of response rates between the
drug group and the placebo group.

^2^ Nominal p-value based on the Mantel-Haenszel test stratified by
country.

^3^ p-value adjusted using Hochberg\'s multiple comparison procedure.

\* Statistically significant at the 0.05 significance level, using
Hochberg\'s multiple comparison procedure.

The results for study B351 are presented in Table 2.4 and are as follow:

-   Female patients in both treatment groups had higher response rates
    compared with the placebo group. The therapeutic gain was 9% in the
    4 mg group and 15% in the 12 mg group.

-   Male patients in both treatment groups did not have higher response
    rates compared with the placebo group. The therapeutic gain was -2%
    in both the 4 mg group and 12 mg group.

    **Table 2.4**

    **Study B351: Subject Global Assessment of Relief by Gender**

+--------------+---+-------+-------+-------+---+-------+-------+-------+
|              |   | **Ori |       |       |   | **New |       |       |
|              |   | ginal |       |       |   | Defin |       |       |
|              |   | Defin |       |       |   | ition |       |       |
|              |   | ition |       |       |   | of    |       |       |
|              |   | of    |       |       |   | SGA   |       |       |
|              |   | SGA   |       |       |   | of    |       |       |
|              |   | of    |       |       |   | Rel   |       |       |
|              |   | Rel   |       |       |   | ief** |       |       |
|              |   | ief** |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+
|              | * | **4   | **12  | **Pl  |   | **4   | **12  | *     |
|              | * | mg    | mg    | acebo |   | mg**  | mg**  | *Plac |
|              | N | (n)** | (n)** | (n)** |   |       |       | ebo** |
|              | * |       |       |       |   |       |       |       |
|              | * |       |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+
| **Male**     | 1 | 24.32 | 19.35 | 18.75 |   | 32.43 | 32.26 | 34.38 |
|              | 0 | (37)  | (31)  | (32)  |   |       |       |       |
| Response     | 0 |       |       |       |   | -1.95 | -2.12 |       |
| Rate         |   | 5.57  | 0.60  |       |   |       |       |       |
|              |   |       |       |       |   | 1.00  | 1.00  |       |
| Therapeutic  |   | 0.771 | 1.00  |       |   |       |       |       |
| Gain^1^      |   |       |       |       |   | 1.00  | 1.00  |       |
|              |   | 1.00  | 1.00  |       |   |       |       |       |
| p-value^2^   |   |       |       |       |   |       |       |       |
|              |   |       |       |       |   |       |       |       |
| Adjusted     |   |       |       |       |   |       |       |       |
| p-value^3^   |   |       |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+
|              |   |       |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+
| **Female**   | 6 | 30.91 | 27.19 | 22.03 |   | 40.91 | 46.93 | 32.16 |
|              | 7 | (220) | (228) | (227) |   |       |       |       |
| Response     | 5 |       |       |       |   | 8.75  | 14.77 |       |
| Rate         |   | 8.88  | 5.16  |       |   |       |       |       |
|              |   |       |       |       |   | 0.062 | 0.002 |       |
| Therapeutic  |   | 0.041 | 0.231 |       |   |       |       |       |
| Gain^1^      |   |       |       |       |   | 0.062 | 0.    |       |
|              |   | 0.082 | 0.231 |       |   |       | 004\* |       |
| p-value^2^   |   |       |       |       |   |       |       |       |
|              |   |       |       |       |   |       |       |       |
| Adjusted     |   |       |       |       |   |       |       |       |
| p-value^3^   |   |       |       |       |   |       |       |       |
+--------------+---+-------+-------+-------+---+-------+-------+-------+

Note: Only United States centers were in the ITT population.

^1^ Therapeutic gain is the raw difference of response rates between the
drug group and the placebo group.

^2^ Nominal p-value based on Fisher's Exact test.

^3^ p-value adjusted using Hochberg\'s multiple comparison procedure.

\* Statistically significant at the 0.05 significance level, using
Hochberg\'s multiple comparison procedure.

Tegaserod is effective in female patient but no evidence of efficacy is
demonstrated for males in these studies. The results for male and female
patients may indicate a difference in the patho-physiology of C-IBS
between genders. Another explanation for the lack of evidence for
efficacy is that there is not sufficient number of male patients in
these studies. The overall positive treatment effect seen in the
analyses for all patients was driven primarily by the efficacy in female
patients.

*Secondary Efficacy: Subject Global Assessment of abdominal
discomfort/pain*

The results for study B301 are presented in Table 2.5 and are as follow:

-   Female patients in both treatment groups had higher response rates
    compared with the placebo group. The therapeutic gain was 9% in the
    4 mg group and 10% in the 12 mg group.

-   Male patients in both treatment groups did not have higher response
    rates compared with the placebo group. The therapeutic gain was -2%
    in the 4 mg group and -5% in the12 mg group.

    **Table 2.5**

    Study B301: Subject Global Assessment of Abdominal Discomfort/Pain

+------------------------+----+------------+------------+------------+
|                        | *  | **4 mg     | **12 mg    | **Placebo  |
|                        | *N | (n)**      | (n)**      | (n)**      |
|                        | ** |            |            |            |
+------------------------+----+------------+------------+------------+
| **Male**               | 1  | 26.92 (52) | 24.00 (50) | 29.17 (48) |
|                        | 50 |            |            |            |
| Response Rate          |    | -2.25      | -5.17      |            |
|                        |    |            |            |            |
| Therapeutic Gain^1^    |    | 0.864      | 0.985      |            |
|                        |    |            |            |            |
| p-value^2^             |    |            |            |            |
+------------------------+----+------------+------------+------------+
|                        |    |            |            |            |
+------------------------+----+------------+------------+------------+
| **Female**             | 7  | 30.36      | 31.15      | 21.34      |
|                        | 30 | (247)      | (244)      | (239)      |
| Response Rate          |    |            |            |            |
|                        |    | 9.02       | 9.81       |            |
| Therapeutic Gain^1^    |    |            |            |            |
|                        |    | 0.020      | 0.014      |            |
| p-value^2^             |    |            |            |            |
+------------------------+----+------------+------------+------------+

^1^ Therapeutic gain is the raw difference of response rates between the
drug group and the placebo group.

^2^ Nominal p-value based on the Mantel-Haenszel test stratified by
country.

The results for study B307 are presented in Table 2.6 and are as follow:

-   Female patients in both treatment groups did not have higher
    response rates compared with the placebo group. The therapeutic gain
    was -4% in the 4 mg group and --0.9% in the 4-12 mg titration group.

-   Male patients in both treatment groups did not have higher response
    rates compared with the placebo group. The therapeutic gain was -11%
    in the 4 mg group and -12% in the 4-12 mg titration group.

    **Table 2.6**

    Study B307: Subject Global Assessment of Abdominal Discomfort/Pain

+------------------------+----+------------+------------+------------+
|                        | *  | **4 mg     | **4-12 mg  | **Placebo  |
|                        | *N | (n)**      | (n)**      | (n)**      |
|                        | ** |            |            |            |
+------------------------+----+------------+------------+------------+
| **Male**               | 1  | 25.00 (44) | 21.95 (41) | 34.00 (50) |
|                        | 35 |            |            |            |
| Response Rate          |    | -11.00     | -12.05     |            |
|                        |    |            |            |            |
| Therapeutic Gain^1^    |    | 0.606      | 0.451      |            |
|                        |    |            |            |            |
| p-value^2^             |    |            |            |            |
+------------------------+----+------------+------------+------------+
|                        |    |            |            |            |
+------------------------+----+------------+------------+------------+
| **Female**             | 7  | 25.85      | 28.88      | 29.74      |
|                        | 00 | (236)      | (232)      | (232)      |
| Response Rate          |    |            |            |            |
|                        |    | -3.89      | -0.86      |            |
| Therapeutic Gain^1^    |    |            |            |            |
|                        |    | 0.273      | 0.808      |            |
| p-value^2^             |    |            |            |            |
+------------------------+----+------------+------------+------------+

^1^ Therapeutic gain is the raw difference of response rates between the
drug group and the placebo group.

^2^ Nominal p-value based on the Mantel-Haenszel test stratified by
country.

The results for study B351 are presented in Table 2.7 and are as follow:

-   Female patients in both treatment groups had higher response rates
    compared with the placebo group. The therapeutic gain was 5% in the
    4 mg group and 7% in the 12 mg group.

-   Male patients in the 4 mg group had a higher response rate compared
    with the placebo group and those in the 12 mg group had a lower
    response rate compared with the placebo group. The therapeutic gain
    was 8% in the 4 mg group and --6% in the 12 mg group.

**Table 2.7**

Study B351: Subject Global Assessment of Abdominal Discomfort/Pain

+------------------------+----+------------+------------+------------+
|                        | *  | **4 mg     | **12 mg    | **Placebo  |
|                        | *N | (n)**      | (n)**      | (n)**      |
|                        | ** |            |            |            |
+------------------------+----+------------+------------+------------+
| **Male**               | 1  | 29.73 (37) | 16.13 (31) | 21.88 (32) |
|                        | 00 |            |            |            |
| Response Rate          |    | 7.85       | -5.75      |            |
|                        |    |            |            |            |
| Therapeutic Gain^1^    |    | 0.585      | 0.750      |            |
|                        |    |            |            |            |
| p-value\*              |    |            |            |            |
+------------------------+----+------------+------------+------------+
|                        |    |            |            |            |
+------------------------+----+------------+------------+------------+
| **Female**             | 6  | 23.18      | 25.44      | 18.50      |
|                        | 75 | (220)      | (228)      | (227)      |
| Response Rate          |    |            |            |            |
|                        |    | 4.68       | 6.94       |            |
| Therapeutic Gain^1^    |    |            |            |            |
|                        |    | 0.245      | 0.089      |            |
| p-value^2^             |    |            |            |            |
+------------------------+----+------------+------------+------------+

> Note: Only United States centers were in the ITT population.
>
> ^1^ Therapeutic gain is the raw difference of response rates between
> the drug group and the placebo group.
>
> ^2^ Nominal p-value based on Fisher's Exact test.

**2.2 Change of the Primary Efficacy Variables**

The sponsor's scientific rationale for changing the co-primary efficacy
variable of SGA of abdominal discomfort/pain to a secondary efficacy
variable in protocol amendments for studies B301 and B307 is not clear
since abdominal discomfort/pain is an important component of C-IBS. The
following are three reasons found by the reviewer for the change:

1.  The sponsor stated that given both the patient's potential
    difficulties in translating her/his experiences to the visual analog
    scale (VAS) and the difficulty in defining a responder, the SGA of
    abdominal discomfort/pain will be eliminated as a primary efficacy
    variable and instead be retained as a secondary efficacy variable.
    Also, in study B351, the two primary efficacy variables (SGA of
    relief and SGA of abdominal discomfort/pain) had been highly
    correlated.

2.  The sponsor stated that the rationale for reclassifying the
    co-primary efficacy variable of SGA of abdominal discomfort/pain to
    a secondary efficacy variable was based on the fact that the VAS
    measurement was no longer the norm in assessing pain or other
    outcomes.

3.  The sponsor stated that in study B351 the results for SGA of
    abdominal discomfort/pain were not statistically significant.

**2.3 Pooling of Centers**

The sponsor developed an algorithm for pooling centers. In this
algorithm, centers within a country were pooled to ensure that the
pooling criteria (treatment row totals ≥2 and response column totals ≥1)
were fulfilled for both primary variables in all three of the following
data sets: ITT population at endpoint, Per Protocol population at
endpoint, and ITT population who completed the study. Specifically:

-   3\*2 tables were created for each center, with the three treatment
    groups as row headers and the response status for SGA of relief at
    endpoint (yes/no) as column headers.

-   Centers were sorted by country, center size, and center number in
    ascending order. Centers with a treatment row total \<2 or a
    response column total \<1 were placed, by center size and center
    number, at the top of the respective country category.

-   Centers were pooled sequentially by the sorting order in the same
    country category until fulfilling the pooling criteria.

-   The response column criterion had to be fulfilled for each of the
    two pairwise treatment comparisons, i.e. for the tegaserod 4 mg and
    placebo, and for the tegaserod 12 mg and placebo comparisons.

The sets of centers after pooling were used as strata in the
Mantel-Haenszel analysis of the primary efficacy variable.

This algorithm for pooling centers is not appropriate because it was
based on the number of responders and non-responders for each primary
efficacy variable after the blind was broken. Using the response column
totals as a criterion for pooling after the blind is broken could
potentially bias the results of the analyses. A preferable algorithm is
one that pools centers within a country based on the total number of
patients in the ITT population at that center until a minimum number of
patients is achieved.

Given that a large number of centers did not recruit the minimum of 15
ITT patient per center (see item 6. below) and that the randomization
list was generated by country, a better algorithm is to pool all centers
within a country. The analyses would then be stratified by country.

**2.4 Pooling of Study Results**

The sponsor has presented the results pooled across studies B301, B307,
and B351 are not appropriate. The following three pooled populations
were analyzed at endpoint and at month 1:

B351/B301, B351/B301/B307, and B301/B307. Pooling these studies is not
appropriate because of the following reasons:

a.  The pooled analyses were not pre-specified in the protocol. The
    pooled analyses are post-hoc and subject to bias and
    non-interpretability of any p-values because the decision to pool
    was data driven.

b.  Assuming pooled analysis was acceptable, this would constitute a
    single trial necessitating a second trial to provide replication of
    the pooled study results.

c.  The statistical significance of post-hoc, pooled results is
    problematic. The p-value from such an analysis is not interpretable
    because the analysis is data driven and potentially biased. A
    smaller p-value would be achieved because of the larger sample size
    (an issue of power).

d.  The sponsor's decision to pool was based on the non-significant
    results of study B307. Pooling was used to resolve the lack of
    statistical significance in study B307. Consequently, with pooling,
    study B307 appears acceptable in the light of a positive overview.

e.  The results of study B351 led the sponsor to change the
    protocol-specified definition of responder and to make one of the
    protocol-specified co-primary efficacy variables a secondary
    efficacy variable for the remaining two pivotal studies. The change
    was made because the results were not statistically significant in
    study B351. These changes were then applied to study B351 and gave
    post-hoc statistically significant results for the 12 mg group. The
    division deemed that study B351 is not pivotal. Thus, pooling study
    B351 with the other two pivotal studies is not appropriate since the
    post-hoc results bias the pooled results in favor of the active
    treatment.

f.  The three studies are not homogeneous with respect to the following
    demographic and study characteristics: 1) ethnic composition; 2) the
    percentage of primary, secondary, and tertiary participating
    centers; and 3) the baseline use of laxative.

> 1\) The following ethnic composition is found in the three studies:
> study B301 included European, U.S., South African, Turkish patients;
> study B307 had European patient only; and study B351 had U.S. and
> Canadian patients.
>
> 2\) The percentage of primary, secondary, and tertiary care centers
> for the three studies are presented in Table 2.8. There was a higher
> percentage of participating secondary centers in study B301, whereas
> studies B307 and B351 had a higher percentage of primary care centers.

**Table 2.8**

Number of Patients at Primary, Secondary, and Tertiary Care Centers

+--------------+-----------------+-----------------+-----------------+
| **Study**    | **Primary       | **Secondary     | **Tertiary      |
|              | Care**          | Care**          | Care**          |
|              |                 |                 |                 |
|              | **n (%)**       | **n (%)**       | **n (%)**       |
+--------------+-----------------+-----------------+-----------------+
| B301 (N=881) | 505 (57.3)      | 309 (35.1)      | 67 (7.6)        |
+--------------+-----------------+-----------------+-----------------+
| B307 (N=835) | 621 (74.4)      | 174 (20.8)      | 40 (4.8)        |
+--------------+-----------------+-----------------+-----------------+
| B351 (N=775) | 602 (77.7)      | 111 (14.3)      | 62 (8.0)        |
+--------------+-----------------+-----------------+-----------------+

> 3\) The baseline use of laxative is different across studies for each
> treatment group. Table 2.9 presents the number of patients who took
> laxatives and/or cathartics during the baseline period of the study.
> Within the 4 mg group, the percentage of patients (20.2%) in study
> B307 who took laxatives and/or cathartics was less than in studies
> B301 and B351 (30.4% and 27.9%). Within the 12 mg group, the
> percentage of patients (26.2%) in study B351 who took laxatives and/or
> cathartics was less than in study B301 (30.3%). Within the placebo
> group, the percentage of patients (24.3%) in study B307 who took
> laxatives and/or cathartics was less than in studies B301 and B351
> (28.8% and 29.2%).

**Table 2.9**

Number of Patients who Took Laxatives and/or Cathartics during the
Baseline Study Period

+---------------------------------------+------------------------------+
|                                       | **n (%)**                    |
+---------------------------------------+------------------------------+
| **B301** 4 mg (N=299)                 | 91 (30.4)                    |
|                                       |                              |
| 12 mg (N=294)                         | 89 (30.3)                    |
|                                       |                              |
| Placebo (N=288)                       | 83 (28.8)                    |
+---------------------------------------+------------------------------+
|                                       |                              |
+---------------------------------------+------------------------------+
| **B307** 4 mg (N=282)                 | 57 (20.2)                    |
|                                       |                              |
| 4-12 mg (N=275)                       | 72 (26.2)                    |
|                                       |                              |
| Placebo (N=284)                       | 69 (24.3)                    |
+---------------------------------------+------------------------------+
|                                       |                              |
+---------------------------------------+------------------------------+
| **B351** 4 mg (N=265)                 | 74 (27.9)                    |
|                                       |                              |
| 12 mg (N=267)                         | 70 (26.2)                    |
|                                       |                              |
| Placebo (N=267)                       | 78 (29.2)                    |
+---------------------------------------+------------------------------+

g.  The primary endpoints for all three studies are not the same. Study
    B351 had two primary efficacy variables, SGA of relief and SGA for
    discomfort/pain and studies B301 and B307 had one primary efficacy
    variable, SGA of relief. The pain endpoint was dropped to a
    secondary endpoint in studies B301 and B307 through a protocol
    amendment after the sponsor reviewed the results of study B351
    (see 2. above).

h.  The study design of study B307 is different from the other two
    studies. In studies B301 and B351, patients were randomized into one
    of the following three fixed dose groups: 4 mg, 12 mg, and placebo.
    In study B307, patients were randomized into one of the following
    three dose regimen groups: 4 mg fixed dose, 4 to 12 mg titration
    dose, placebo. The fixed 12 mg group and the 4 to 12 mg titration
    group cannot be pooled into one group since not all patients in the
    4 to 12 mg titration group were at a constant dose.

i.  Study B307 tests a fixed doe regimen and a dose-titrating regimen
    while studies B301 and B307 test two fixed doses.

j.  Study B307 needs to be analyzed using the original definition of SGA
    of relief responder because the original definition was used to
    determine if the patient was to be up titrated after 4 weeks of
    treatment. In study B307, patients randomized to dose-titration
    received tegaserod 4 mg and underwent dose titration at week 4 to 12
    mg if their response on the SGA of relief was complete or
    considerable relief less than 50% of the time during the 4 week
    period, that is, a non-responder. Thus, this study can only be
    analyzed with the original definition of responder since the
    category "at least somewhat relief for all 4 weeks," as used in the
    new definition of responder, was not incorporated in the rule for
    (dose-titration) defining a non-responder for assignment to up
    titration from 4 mg to 12 mg after 4 weeks of treatment.

k.  The 4-12 mg dose titration group in Study B307 cannot be combined
    with the 4 mg group for the month 1 pooled analyses and then with
    the 12 mg group for the at endpoint pooled analyses. The sponsor
    stated that at endpoint, the titration group in study B307 was
    pooled together with 12 mg fixed dose since 65% of the patients in
    the titration group were titrated to 12 mg, and most of titrated
    patients were treated with 12 mg for 2 months. At Month 1, the
    titration group (4-12 mg) in study B307 was pooled together with 4
    mg fixed dose since all patients in the titration group were treated
    with 4 mg in the first month of the treatment.

l.  The sample size for each of the three studies is not small (see
    item 5. below), like what can be seen with a rare disease, so
    pooling is not necessary. There is sufficient sample size in each
    study to give an adequate evaluation of the treatment effect on a
    per study basis.

m.  The studies are not independent because the same U.S. principal
    investigators participated in two of the three studies (see item 7.
    below).

n.  Pooling these three studies, which have varying results, leads to an
    overall result that does not provide a useful guide to physicians.

**2.5 Laxative Use**

All per protocol and post-hoc analyses need to take into account
laxative use. Laxative use is a confounding variable in the response of
a patient to the efficacy variable of SGA of relief and any other
efficacy variable. It is difficult to totally ignore the effects of
laxative use in any study that evaluates patients with constipation. Per
protocol, laxative use was permitted for purposes of rescue therapy. A
patient could use laxative up to 4 times in the first two months of
treatment and still be considered a responder. Also, not adjusting for
laxative use inflates the responder rates in all treatment groups.

Additionally, information about the use of bulking agents was not
adequately collected. Per protocol, patients taking chronic stable doses
of bulking agent could continue to do so but there was no data collected
about the amount of bulking agent used or the frequency of use by the
patient while on treatment. This unquantified use of bulking agents
throughout the studies may add an unknown confounding variable.

**2.6 Expansion of Study Population**

Studies B301 and B307 recruited more patients to the ITT population than
was planned for in the protocol. Table 2.10 presents an overview of the
sample size for studies B301 and B307. The original protocol, with one
primary efficacy variable tested at two dose groups compared to placebo
called for a total of 531 patients in the ITT population. An amendment
to the protocol, which increased the number of primary efficacy
variables to two tested at two dose groups compared to placebo, called
for a total of 693 patients in the ITT population. Another protocol
amendment, which changed the number of primary efficacy variables to one
tested at two dose groups, made no adjustment to the sample size. The
final number of patients in the ITT population for studies B301 and B307
were 881 and 835, respectively.

**Table 2.10**

**Sample Size\* Overview for Studies B301 and B307**

+----------------------------------------+--------------+--------------+
|                                        | **Study      | **Study      |
|                                        | B301**       | B307**       |
|                                        |              |              |
|                                        | N (n per     | N (n per     |
|                                        | group)       | group)       |
+----------------------------------------+--------------+--------------+
| Original Protocol ITT Population       | 531 (197)    | 531 (197)    |
| Sample Size                            |              |              |
|                                        | 1            | 1            |
| Number of Primary Variables            |              |              |
+----------------------------------------+--------------+--------------+
| First Protocol Amendment ITT           | 693 (231)    | 693 (231)    |
| Population Sample Size                 |              |              |
|                                        | 2            | 2            |
| Number of Primary Variables            |              |              |
+----------------------------------------+--------------+--------------+
| Second Protocol Amendment ITT          | 693          | 693          |
| Population Sample Size                 |              |              |
|                                        | 1            | 1            |
| Number of Primary Variables            |              |              |
+----------------------------------------+--------------+--------------+
| ITT Population Sample Size at End of   | 881          | 835          |
| Study                                  |              |              |
+----------------------------------------+--------------+--------------+
| Sample Size at Study End Increase from | 350          | 304          |
| Original Protocol                      |              |              |
|                                        | 69.5%        | 57.2%        |
| \% Increase from Original Protocol     |              |              |
+----------------------------------------+--------------+--------------+
| Sample Size at Study End Increase from | 188          | 142          |
| First Amendment                        |              |              |
|                                        | 27.1%        | 20.5%        |
| \% Increase from First Amendment       |              |              |
+----------------------------------------+--------------+--------------+

> \* Sample size calculations assumed a placebo responder rate of 0.30,
> an active treatment effect of 0.45 for both doses (resulting in a 0.15
> difference in response rates), 80% power, 0.05 significance level, and
> adjustment for multiple comparisons (two doses) using either Holm's or
> Hochberg's procedure for multiple comparisons.
>
> Source: Statistical Reviewer's listing.

The final sample size was over 55% larger than what was planned for in
the original protocol, which also had one primary efficacy variable
tested at two dose groups compared to placebo. In addition,

the final sample size was over 20% larger than what was planned for in
the first amendment, whose protocol had two primary efficacy variables
tested at two dose groups compared to placebo. In response to a question
from the reviewer about the over recruitment of patients, the sponsor
responded that there was no prospective decision to recruit and
randomize more than 231 patients per study arm in each of these studies
\[B301 and B307\]. At the end of the enrollment phase in each of these
studies, the sponsor allowed patients who had entered the baseline phase
of the study \[who signed informed consent\] to continue on through
randomization and complete the study because those patients had
undergone diagnostic procedures, including endoscopy. The sponsor felt
that patients completing the baseline should be allowed to complete the
study. This resulted in an over-enrollment for each study.

The reviewer is not clear why the sponsor did not end enrollment once
the target ITT population size for the second protocol amendment was
reached. These larger sample sizes result in an increase in the power of
the statistical tests for the primary efficacy outcomes.

**2.7 Patient Enrollment by Centers**

Recruitment of the per protocol minimum number of patients at each study
center for the ITT population in studies B301, B307, and B351 was not
achieved at all centers. Per protocol, each study center was to recruit
a minimum of 15 ITT patients up to a maximum of about 30 ITT patients.
Table 2.11 presents a listing of the number of centers that recruited
the minimum of 15 ITT patients. The proportion of centers that had at
least 15 patients was 22%, 39%, and 51% for studies B301, B307, and
B351, respectively. This lack of recruitment of at least 15 ITT patients
per center may have resulted from adding more centers to each study. The
protocol specified that each study would have approximately 50 centers.
Instead, study B301 had 95 centers and study B307 had 66 centers in the
ITT population.

**Table 2.11**

Number of Centers that Recruited a Minimum of 15 ITT Patients, by
Country

+----------+------+----------+---+------+----------+---+------+----------+
|          | **S  |          |   | **S  |          |   | **S  |          |
|          | tudy |          |   | tudy |          |   | tudy |          |
|          | B3   |          |   | B3   |          |   | B3   |          |
|          | 01** |          |   | 07** |          |   | 51** |          |
+----------+------+----------+---+------+----------+---+------+----------+
| **C      | **Nu | **Number |   | **Nu | **Number |   | **Nu | **Number |
| ountry** | mber | of       |   | mber | of       |   | mber | of       |
|          | of   | Centers  |   | of   | Centers  |   | of   | Centers  |
|          | C    | that had |   | C    | that had |   | C    | that had |
|          | ente | at least |   | ente | at least |   | ente | at least |
|          | rs** | 15       |   | rs** | 15       |   | rs** | 15       |
|          |      | pa       |   |      | pa       |   |      | pa       |
|          |      | tients** |   |      | tients** |   |      | tients** |
+----------+------+----------+---+------+----------+---+------+----------+
| Austria  | 3    | 3        |   | \-   | \-       |   | \-   | \-       |
|          |      |          |   |      |          |   |      |          |
| Belgium  | \-   | \-       |   | 3    | 0        |   | \-   | \-       |
|          |      |          |   |      |          |   |      |          |
| Canada   | \-   | \-       |   | 3    | 0        |   | 2    | 1        |
|          |      |          |   |      |          |   |      |          |
| Finland  | 4    | 1        |   | \-   | \-       |   | \-   | \-       |
|          |      |          |   |      |          |   |      |          |
| France   | \-   | \-       |   | 8    | 3        |   | \-   | \-       |
|          |      |          |   |      |          |   |      |          |
| Germany  | 16   | 7        |   | 5    | 1        |   | \-   | \-       |
|          |      |          |   |      |          |   |      |          |
| Italy    | 7    | 2        |   | \-   | \-       |   | \-   | \-       |
|          |      |          |   |      |          |   |      |          |
| Net      | 12   | 1        |   | \-   | \-       |   | \-   | \-       |
| herlands |      |          |   |      |          |   |      |          |
|          | 2    | 0        |   | \-   | \-       |   | \-   | \-       |
| Portugal |      |          |   |      |          |   |      |          |
|          | 6    | 0        |   | \-   | \-       |   | \-   | \-       |
| South    |      |          |   |      |          |   |      |          |
| Africa   | 1    | 0        |   | 1    | 1        |   | \-   | \-       |
|          |      |          |   |      |          |   |      |          |
| Spain    | 9    | 2        |   | \-   | \-       |   | \-   | \-       |
|          |      |          |   |      |          |   |      |          |
| Swi      | 6    | 1        |   | \-   | \-       |   | \-   | \-       |
| tzerland |      |          |   |      |          |   |      |          |
|          | 18   | 4        |   | 10   | 2        |   | \-   | \-       |
| Turkey   |      |          |   |      |          |   |      |          |
|          | 11   | 0        |   | 37   | 19       |   | 47   | 24       |
| United   |      |          |   |      |          |   |      |          |
| Kingdom  | **   | **21     |   | **   | **26     |   | **   | **25     |
|          | 95** | (        |   | 67** | (        |   | 49** | (        |
| United   |      | 22.1%)** |   |      | 38.8%)** |   |      | 51.0%)** |
| States   |      |          |   |      |          |   |      |          |
|          |      |          |   |      |          |   |      |          |
| *        |      |          |   |      |          |   |      |          |
| *Total** |      |          |   |      |          |   |      |          |
+----------+------+----------+---+------+----------+---+------+----------+

> Source: Statistical Reviewer's listing.

**2.8 Investigators Participation in Multiple Studies**

Participation in more than one Phase 3 study by the same principal
investigator does not meet the assumption of independent studies. Of the
11 U.S. centers in study B301, 8 came from the U.S. centers in study
B351 and three from the U.S. centers in study B307. Of the 41 U.S.
centers in study B307, 9 came from the U.S. centers in study B351. Study
B351 was completed before both studies B301 and B307 were completed. It
was after study B351 was completed that the principal investigators
participated in the other studies. The same is true for those principal
investigators in study B307 who participated in study B301.

**2.9 Additional Issues**

Responding to a question from the reviewer about when the randomization
lists were generated, the sponsor stated that they were generated on
June 24, 1997. An inconsistency arises in the randomization lists for
study B301 that show the following date information:

-   The randomization lists for the Netherlands, the United States, and
    South Africa come from files dated in 1998.

-   A second randomization list for the United Kingdom and for Germany
    come from files dated in 1998.

-   All other randomization lists are from files dated in 1997.

    This reviewer is not clear why the dates differ. The reviewer has no
    comment on the other two studies because the randomization lists
    were not included in the submission.

    The sponsor acknowledged in a correspondence that protocol
    amendments were not prepared for the following items:

-   Per protocol, study B301 was a European study. The study report in
    the application includes the United States and South Africa as
    additional countries.

-   Per protocol, studies B301 and B307 were each to have approximately
    50 centers total in the ITT population. The study reports in the
    application show that study B301 had 95 centers and study B307 had
    66 centers in the ITT population.

Ethnic differences may have to be considered in view of the difference
in symptoms and natural history of C-IBS among ethnic groups. The
following ethnic composition is found in the three studies: study B301
included European, U.S., South African, Turkish patients; study B307 had
European patient only; and study B351 had U.S. and Canadian patients.
Also, the percentage of blacks in studies B301, B307, and B351was 1%,
6%, and 9%, respectively. The applicability of the results to the U.S.
population will have to take into consideration the fact that the
representation of the black population in the U.S. was not adequate.

The percentage of males in each study ranged from 13% to 17%. This small
number of male patients may not be adequate to evaluate efficacy in this
population. Also, by gender analyses suggest that males may respond
differently to treatment.

**3.0 SAFETY**

**3.1 Clinical Safety Issues**

A total of 1679 patients received Tegaserod at the dose ranging from 4
mg/d to 12 mg/d in Phase 3 studies of 12-week duration. Approximately
70% of patients received treatment for 85 days or longer.

Adverse events (AEs) were reported in 6.8% of patients receiving
Tegaserod compared to 5.1% of patients receiving placebo. The most
frequent AE was headache, which occurred in about 20% of patients in all
treatment groups, including placebo. Other AEs included GI events,
backpain, influenza-like symptoms, UTI, dizziness. Except for diarrhea,
there was no difference in the incidence of AEs between the treated and
placebo groups or relationship to Tegaserod dose. Diarrhea was reported
by 11.7% and 5.4% of Tegaserod-treated and placebo patients
respectively. Diarrhea occurred during the first week of therapy, and in
about half of cases during the first day of therapy. Overall, 2.1% of
patients discontinued treatment because of diarrhea.

A total of 8.4% of Tegaserod-treated patients discontinued treatment
primarily because of GI adverse events compared to 6.3 patients in the
placebo group.

A total of 1.9% of patients experienced serious adverse events (SAEs) in
Phase 2 and 3 clinical trials, the incidence of SAEs increased to 4.1%
in the long-term study. Four SAEs were reported by the sponsor as
possibly or probably related to study drug: abdominal pain (2),
gastritis (1), supraventricular tachycardia (1), hypoglycemia (1).

Dizziness occurred in 5-6% of patients with equal frequency between
treated and placebo patients. The incidence of postural hypotension was
also similar, but syncope occurred more frequently in patients treated
with Tegaserod (0.5%) than on the placebo group (0.1%).

A total of 567 patients (\>90% Caucasian females) have been evaluated in
a long-term safety study, of these patients, more than 150 have received
Tegaserod for 365 days and more than 290 have received Tegaserod for
more than 290 days. Discontinuation has occurred in 12% of patients due
to lack of efficacy and in 11% of patients because of GI adverse events,
mainly diarrhea, or headache.

The effects of Tegaserod and of its main metabolite on cardiac
repolarization were assessed in three in vitro studies and in one in
vivo study of ECG parameters in dogs. No effect on QT prolongation was
observed at therapeutic plasma concentrations. No effects of Tegaserod
were observed in the Phase 3 and in the long-term clinical trials on
ECG. Thus far, there appears to be no difference in ECG parameters
between Tegaserod-treated and placebo patients.

Nine cases of ovarian cyst (8 Tegaserod, one placebo patient) were
reported in the Integrated Summary of Safety (ISS). Five cases occurring
in Tegaserod-treated patients required surgery. Case Report Forms are
available for the 5 patients undergoing surgery (Appendix 1). Only
limited information is available on the 3 patients who did not undergo
surgery. Two patients, one in the Tegaserod and 1 in the placebo group
were diagnosed as having Polycystic Ovarian Syndrome not requiring
surgery. No additional information is available on these patients.

The estimated frequency of ovarian cysts in tegaserod users is 0.3% per
100.000 women-years (95% CI= 0; 4057) and 0.1% of placebo users per
100.000 women-years (95% CI=0; 4057). Although the incidence of ovarian
cysts does not seem to be different from that in the general population,
the cases reported for the Tegaserod patients resulted in
hospitalization and surgical intervention.

Further evaluation of the relevance of these findings is required.

**3.2 Preclinical Safety Issues**

In a two-year oral (dietary) carcinogenicity study in mice, (CD-1),
treatment with SDZ HTF 919 at 600 mg/kg/day produced mucosal hyperplasia
(in 13.3% males and 11.7% females) and adenocarcinoma (in 10% males and
3.3% females) of small intestines. Treatment with lower doses of 200 and
60 mg/kg/day did not produce such effects. Adenocarcinoma of small
intestine is a rare tumor for mice and as well as humans. The
implications of the findings in the context of human safety.are unclear
at present.

Treatment of female rats (HanIbm Wistar) with SDZ HTF 919 at 20, 80 and
180 mg/kg/day (in diet) for 110 weeks produced dose-related increase in
the incidence of \"Ovarian\" cysts (12, 14 and 20%, respectively) when
compared to incidence in controls (0 to 4%). In rats, ovarian follicular
cysts can be produced by exposure to constant light, or androgens during
neonatal period, or by induced hypothyroidism. The sponsor has conducted
histopathology reevaluation of the ovarian material from the rat
studies. The relevance of the findings in rats and the implications in
the context of the incidences of ovarian cysts noted in women treated
with Tegaserod are unclear.

**4.0 CONCLUSIONS**

Three clinical studies were submitted to the application for Tegaserod,
which is indicated for the treatment of patients with constipation
predominate irritable bowel syndrome. Two of the three studies were
pivotal and one was supportive. Efficacy was demonstrated for only one
of the two pivotal studies for both the 4 mg and 12 mg doses. The
supportive study demonstrated efficacy for the 12 mg dose only.

Given that all three clinical studies included 15% males on average, a
by gender analysis demonstrated efficacy only in female patients.
Analyses of the efficacy results for the male population as a separate
group failed to show statistical significance. Additional studies with
larger male population are required to determine whether the compound is
also efficacious in males.

In addition to gender differences, ethnic and racial patient
representation need further assessment. The Phase 3 clinical trials
included patients from countries such as Turkey and South Africa where
the symptoms and natural history of IBS are not well standardized. The
percentage of blacks in the clinical trials ranged from 1% to 9%, not
representative of the percentage of blacks in the U.S.

The potential confounding effect of laxative use remains to be
determined given the fact that the studies evaluated the effectiveness
of Tegaserod in constipation predominant IBS.

Tegaserod exhibited a favorable safety profile with no evidence of
systemic effects other than gastrointestinal. Diarrhea appeared to be
self-limited and required discontinuation in 2.1% of patients. The
significance of the occurrence of ovarian cysts in 8 patients treated
with Tegaserod is unclear at present.