**Statistical Reviewer Briefing Document for the Advisory Committee**

NDA20-998

**Name of Drug**: Celebrex (celebrex)

**Applicant**: G. D. Searle

**Indication**: Lower Upper Gastrointestinal Adverse Events Compared
with NSAID

**Documents Reviewed**: Statistical Section of NDA20998 Dated 06/14/00
by CDER

**Medical Reviewer**: Lawrance Goldkind, M.D., James Witter, MD

**Reviewer**: Hong Laura Lu, Ph.D.

**Date of Review**: 6/00-

## Background

This NDA is submitted to support the claim that celebrex causes lower
incidence of clinically significant upper gastrointestinal adverse
events (CSUGIE) compared to ibuprofen and diclofenac during chronic
administration (up to 12 months) in patients with osteoarthritis (OA)

or rheumatoid arthritis (RA). This review focuses on the two phase III
studies (Studies 035 and 102).

## Study Protocol (Study 035 and Study 102)

Study 035 was a randomized, double-blind, parallel group, multicenter
study designed to compare the incidence of CSUGIEs associated with
celebrex 400 mg BID to that associated with ibuprofen 800 mg TID in
patients with OA or RA. Study 102 was identically designed as Study 035
except that the active control group was diclofenac 75 mg BID.

The treatment period for both studies was defined as the 52-week
interval during which study medication was taken or until the trial was
officially concluded, whichever occurred first. Patients were evaluated
at Week 4, Week 13, Week 26, Week 39, Week 52 and the end of the
treatment.

The primary comparison was the incidence of CSUGIEs associated with
celebrex 400 mg BID to that associated with ibuprofen 800 mg TID and
diclofenac 75 mg BID. Time-to-event analysis was performed to assess the
difference between groups in the CSUGIE rate distribution across time.
CSUGIE occurring within 2 days after first dosing or beyond 2 days after
last dosing was censored and not included in these analyses. The
log-rank test was used to compare the survival curves of the two
treatment groups (celebrex vs. the NSAID groups) with respect to this
primary outcome variable. Patients who withdrew from the study because
of reasons other than incidence of CSUGIE were censored at the time of
withdrawal. Patients who complete the study without a CSUGIE were
censored at the final visit. Two primary treatment comparisons were
performed: celebrex vs. ibuprofen and celebrex vs. diclofenac. A
stepwise procedure was used to strongly control the type-I error. In
this procedure, the first step was to test the overall hypothesis
whether celebrex and the pooled NSAIDs were different. If the test is
not significant, the null hypothesis is retained and the procedure
stops. If the test is significant, the second step will be the pairwise
tests between celebrex and each of the two NSAIDs. Celebrex will be
claimed to be different from an NSAID if both overall and pairwise
comparisons of celebrex vs. that NSAID are significant. Each test was
performed at level α. No α adjustment was needed for each test. Two
primary endpoints were analyzed. One was based on the traditional
definition of CSUGIE and the other alternative one was proposed by FDA.
To control the type-I error rate, a pre-specified stepwise procedure was
used. The first step was to test treatment difference based on the
traditional definition of endpoint. If it is significant, then test on
the alternate endpoint. If both steps show significance, celebrex will
be claimed to be different from the NSAID(s) on both endpoints. If only
the first step shows significance, celebrex will be claimed to be
different from the NSAID(s) on the traditional endpoint.

Potential risk factors such as age and history of peptic ulcer, for the
development of a clinically significant UGI adverse event were
identified prior to analysis and the proportional hazard model was used
to assess the significance of these factors and their impact on the
effect of treatment on outcome. Mean values and their confidence
intervals for the Patient\'s Global Assessment of Arthritis, the
Patient\'s Assessment of Arthritis Pain, and Health Assessment
Questionnaire (HAQ) were tabulated. Information for Incidence of
withdrawal due to lack of arthritis efficacy

was provided.

All analyses were carried out on the intent-to-treat cohort, which
consisted of all randomized patients from both studies who received at
least one dose of study medication.

The sample size determination was based on the assumption that the
probability for experiencing a CSUGIE was 0.3% per year with celebrex
and 1.2% per year with NSAIDs as a group. To detect this difference with
at least 90% power at a 5% significance level (two-sided test) and
assuming a withdrawal rate of 35%, a sample size of 8,000 patients
(4,000 patients for the celebrex and 2000 for each NSAID group) was
sufficient to obtain approximately a total of 40 clinically significant
UGI adverse events.

## Study Report for Studies 035 and 102

### III.1 Patient Disposition

A total of 8059 patients were randomized: 4031 to the celebrex 400 mg
BID group, 2019 to the diclofenac 75 mg BID group, and 2009 to the
ibuprofen 800 mg TID group. Ninety-one (91) patients were determined
never to have taken any study medication. The majority of withdrawals in
all treatment groups were due to adverse events (22.7% in celebrex
group, 27.1% in diclofenac group and 23.2% in ibuprofen group),
treatment failure (17.3% in celebrex group, 15.5% in diclofenac group
and 23.0% in ibuprofen group), or protocol noncompliance (14.7% in
celebrex group, 9.9% in diclofenac group and 18.4% in ibuprofen group).
Detailed results for patient disposition are presented in Table 1 below.

#### Table 1. Patient Disposition

+----------------+-----------------+----------------+-----------------+
|                | ###### Celebrex | **Diclofenac** | **Ibuprofen**   |
+----------------+-----------------+----------------+-----------------+
| Overall        | 3987            | 1996           | 1985            |
+----------------+-----------------+----------------+-----------------+
| Completed      | 1779(44.6%)     | 939(47.0%)     | 691(34.8%)      |
| Study          |                 |                |                 |
+----------------+-----------------+----------------+-----------------+
| Complete With  | 401             | 257            | 187             |
| GI AE          |                 |                |                 |
+----------------+-----------------+----------------+-----------------+
| Withdrawn      | 2208(55.4%)     | 1057(53.0%)    | 1294(65.2%)     |
+----------------+-----------------+----------------+-----------------+
| Reason for     |                 |                |                 |
| Withdrawal:    |                 |                |                 |
+----------------+-----------------+----------------+-----------------+
| Lost to        | 0(0.0%)         | 0(0.0%)        | 0(0.0%)         |
| Follow-Up      |                 |                |                 |
+----------------+-----------------+----------------+-----------------+
| Pre-Existing   | 27(0.7%)        | 11(0.6%)       | 12(0.6%)        |
|                |                 |                |                 |
| Violation      |                 |                |                 |
+----------------+-----------------+----------------+-----------------+
| Protocol       | 585(14.7%)      | 197(9.9%)      | 365(18.4%)      |
|                |                 |                |                 |
| Noncompliance  |                 |                |                 |
+----------------+-----------------+----------------+-----------------+
| Treatment      | 691(17.3%)      | 309(15.5%)     | 456(23.0%)      |
| Failure        |                 |                |                 |
+----------------+-----------------+----------------+-----------------+
| Adverse Event  | 905(22.7%)      | 540(27.1%)     | 461(23.2%)      |
+----------------+-----------------+----------------+-----------------+

### III.2 Demographics

Baseline demographic characteristics, vital signs and GI risk factors
are generally balanced between treatment groups. Detailed demographic
information is summarized in Tables a1-a4 in Appendix A.

### III.3 Sponsor's Analysis and Results of UGI Safety Results (reviewer's comments and analyses are in Section IV)

### III.3.1 CSUGIE results for entire study period

A total of 44 events were found to represent CSUGIE throughout the
entire study. Twenty events (20) occurred on celebrex treatment, 11 on
diclofenac, and 13 on ibuprofen. Among these events, a total of 6 were
considered censored (3 in the celebrex group, 1 in the diclofenac group,
and 2 in the ibuprofen group) due to the timing of their occurrence
(occurred within 2 days after first dosing or beyond 2 days after last
dosing).

As shown in Figure 1, the uncensored events were shown to continue to
accrue in the celebrex group at a generally steady rate through the end
of the study. In contrast, only one uncensored event occurred in the
diclofenac group after 182 days, and none occurred in the ibuprofen
group. The curves for the two NSAIDs therefore become essentially flat
after this time, with the result that the end points of the three curves
were similar by the end of the study. None of the differences in time to
event among the treatment groups were statistically significant. Summary
results for CSUGIE were presented in Table 2.

![](media/image1.wmf)

# **Table 2.** Summary of CSUGIE Incidence

+-------------+---------+---------+---------+--------+--------+--------+
|             | **Cel   | **Diclo | **Ibup  | **Lo   |        |        |
|             | ebrex** | fenac** | rofen** | g-Rank |        |        |
|             |         |         |         | P      |        |        |
|             | **400   | **75 mg | **800   | Values |        |        |
|             | mg      | BID**   | mg      | for    |        |        |
|             | BID**   |         | TID**   | Ce     |        |        |
|             |         |         |         | lebrex |        |        |
|             |         |         |         | vs.    |        |        |
|             |         |         |         | Dicl   |        |        |
|             |         |         |         | ofenac |        |        |
|             |         |         |         | Ibu    |        |        |
|             |         |         |         | profen |        |        |
|             |         |         |         | Both** |        |        |
+-------------+---------+---------+---------+--------+--------+--------+
| No. of      | n=3987  | n=1996  | n=1985  |        |        |        |
| Patients    |         |         |         |        |        |        |
+-------------+---------+---------+---------+--------+--------+--------+
| No. of      | 17      | 10      | 11      |        |        |        |
| CSUGIE      |         |         |         |        |        |        |
|             | 3       | 1       | 2       |        |        |        |
| Uncensored  |         |         |         |        |        |        |
|             | 20      | 11      | 13      |        |        |        |
| C           |         |         |         |        |        |        |
| ensored^\*^ |         |         |         |        |        |        |
|             |         |         |         |        |        |        |
| Total       |         |         |         |        |        |        |
+-------------+---------+---------+---------+--------+--------+--------+
| Week 52     | 0.43%   | 0.50%   | 0.55%   | 0.640  | 0.414  | 0.450  |
| crude rate  |         |         |         |        |        |        |
+-------------+---------+---------+---------+--------+--------+--------+

\*Occurred before 48 hours after midnight of the first dose day or more
than 48 hours after midnight of the last dose day (unless

occurred within two weeks after last dose and was determined by GEC to
be treatment-related).

A total of 35 events were found to satisfy the alternate definition of
CSUGIE. No statistical analysis was performed since the lack of
statistical significance in the results of CSUGIE with traditional
definition. However, the event rates with alternate definition followed
the same trend as that with traditional definition. The results are
presented in Table 3 below.

Table 3. Summary of CSUGIE Incidence: Alternate Definitions

+----------------+-----------------+-----------------+-----------------+
|                | **Celebrex\     | **Diclofenac\   | **Ibuprofen\    |
|                | 400 mg BID**    | 75 mg BID**     | 800 mg TID**    |
|                |                 |                 |                 |
|                | **(n=3987)**    | **(n=1996)**    | **(n=1985)**    |
+================+=================+=================+=================+
| No. of CSUGIEs |                 |                 |                 |
+----------------+-----------------+-----------------+-----------------+
| Uncensored     | 17              | 5               | 9               |
+----------------+-----------------+-----------------+-----------------+
| Censored       | 2               | 1               | 1               |
+----------------+-----------------+-----------------+-----------------+
| Total          | 19              | 6               | 10              |
+----------------+-----------------+-----------------+-----------------+
| Week 52 crude  | 0.43%           | 0.25%           | 0.45%           |
| rate           |                 |                 |                 |
+----------------+-----------------+-----------------+-----------------+

### III.3.2 Post-Hoc Safety Analyses

### III.3.2.a Analysis for the first 6 months

The sponsor also conducted analysis for CSUGIE with only the first 6
months data based on the argument that the large dropout rate in the
later stage of the study depleted high-risk patients. The 6 months' data
showed that the CSUGIE rates of ibuprofen and diclofenac (0.55% and
0.45%, respectively) were numerically higher than that of celebrex
(0.28%), but the difference did not reach statistical significance
(p=0.092). The results are summarized in Table 5 below.

#### Table 5. Summary of CSUGIE Incidence - First Six Months

+--------------+---------+----------+---------+-------+-------+-------+
|              | **Cel   | **Dicl   | **Ibup  | **Log |       |       |
|              | ebrex** | ofenac** | rofen** | -Rank |       |       |
|              |         |          |         | P     |       |       |
|              | **400   | **75 mg  | **800   | V     |       |       |
|              | mg      | BID**    | mg      | alues |       |       |
|              | BID**   |          | TID**   | for   |       |       |
|              |         |          |         | Cel   |       |       |
|              |         |          |         | ebrex |       |       |
|              |         |          |         | vs.** |       |       |
|              |         |          |         |       |       |       |
|              |         |          |         | **    |       |       |
|              |         |          |         | Diclo |       |       |
|              |         |          |         | fenac |       |       |
|              |         |          |         | Ibup  |       |       |
|              |         |          |         | rofen |       |       |
|              |         |          |         | B     |       |       |
|              |         |          |         | oth** |       |       |
+--------------+---------+----------+---------+-------+-------+-------+
|              | n=3987  | n=1996   | n=1985  |       |       |       |
+--------------+---------+----------+---------+-------+-------+-------+
| No. of       | 11      | 9        | 11      |       |       |       |
| CSUGIEs      |         |          |         |       |       |       |
|              | 2       | 0        | 2       |       |       |       |
| Uncensored   |         |          |         |       |       |       |
|              | 13      | 9        | 13      |       |       |       |
| Censored\*   |         |          |         |       |       |       |
|              |         |          |         |       |       |       |
| Total        |         |          |         |       |       |       |
+--------------+---------+----------+---------+-------+-------+-------+
| Week 26      | 0.28%   | 0.45%    | 0.55%   | 0.264 | 0.073 | 0.092 |
| crude rate   |         |          |         |       |       |       |
+--------------+---------+----------+---------+-------+-------+-------+

\*Occurred before 48 hours after midnight of the first dose day or more
than 48 hours after midnight of the last dose day (unless

occurred within two weeks after last dose and was determined by GEC to
be treatment-related).

### III.3.2.b Subgroup analysis

Analysis for CSUGIE was also conducted for non-aspirin users with the
argument that aspirin was an independent cause for CSUGIEs. Among
non-aspirin users, celebrex did not show statistically significant
(p=0.185) reduction in CSUGIEs over the entire study period. However,
with only the first 6 months data, the CSUGIE rate of celebrex was
numerically lower than that of ibuprofen and diclofenac with a p-value
less than 0.05. The detailed results for the entire study period and the
first 6 months are presented in Table 6 below.

Table 6. CSUGIE Incidence in Patients not Taking Aspirin

+--------------+---------+----------+---------+-------+-------+-------+
|              | **Cel   | **Dicl   | **Ibup  | **Log |       |       |
|              | ebrex** | ofenac** | rofen** | -Rank |       |       |
|              |         |          |         | P     |       |       |
|              | **400   | **75 mg  | **800   | V     |       |       |
|              | mg      | BID**    | mg      | alues |       |       |
|              | BID**   |          | TID**   | for   |       |       |
|              |         |          |         | Cel   |       |       |
|              |         |          |         | ebrex |       |       |
|              |         |          |         | vs.** |       |       |
|              |         |          |         |       |       |       |
|              |         |          |         | **    |       |       |
|              |         |          |         | Diclo |       |       |
|              |         |          |         | fenac |       |       |
|              |         |          |         | Ibup  |       |       |
|              |         |          |         | rofen |       |       |
|              |         |          |         | B     |       |       |
|              |         |          |         | oth** |       |       |
+--------------+---------+----------+---------+-------+-------+-------+
| **Entire     |         |          |         |       |       |       |
| Study        |         |          |         |       |       |       |
| Period**     |         |          |         |       |       |       |
+--------------+---------+----------+---------+-------+-------+-------+
|              | n=3105  | n=1551   | n=1573  |       |       |       |
+--------------+---------+----------+---------+-------+-------+-------+
| No. of       | 8       | 4        | 10      |       |       |       |
| CSUGIEs      |         |          |         |       |       |       |
|              | 1       | 0        | 1       |       |       |       |
| Uncensored   |         |          |         |       |       |       |
|              | 9       | 4        | 11      |       |       |       |
| Censored\*   |         |          |         |       |       |       |
|              |         |          |         |       |       |       |
| Total        |         |          |         |       |       |       |
+--------------+---------+----------+---------+-------+-------+-------+
| Week 52      | 0.26%   | 0.26%    | 0.64%   | 0.972 | 0.037 | 0.185 |
| crude rate   |         |          |         |       |       |       |
+--------------+---------+----------+---------+-------+-------+-------+
| **First 6    |         |          |         |       |       |       |
| Months**     |         |          |         |       |       |       |
+--------------+---------+----------+---------+-------+-------+-------+
|              | n=3154  | n=1567   | n=1602  |       |       |       |
+--------------+---------+----------+---------+-------+-------+-------+
| No. of       | 5       | 4        | 10      |       |       |       |
| CSUGIEs      |         |          |         |       |       |       |
|              | 1       | 0        | 1       |       |       |       |
| Uncensored   |         |          |         |       |       |       |
|              | 6       | 4        | 11      |       |       |       |
| Censored\*   |         |          |         |       |       |       |
|              |         |          |         |       |       |       |
| Total        |         |          |         |       |       |       |
+--------------+---------+----------+---------+-------+-------+-------+
| Week 26      | 0.16%   | 0.26%    | 0.62%   | 0.476 | 0.005 | 0.037 |
| crude rate   |         |          |         |       |       |       |
+--------------+---------+----------+---------+-------+-------+-------+

\*Occurred before 48 hours after midnight of the first dose day or more
than 48 hours after midnight of the last dose day (unless

occurred within two weeks after last dose and was determined by GEC to
be treatment-related).

### 

### III.3.2.c Analysis for Combined CSUGIE/GDU Events

The sponsor also conducted analysis for combined CSUGIE/gastrodudenal
ulcer (GDU) events. A total of 111 CSUGIEs/GDUs occurred over the entire
study period: 46 in the celebrex group, 27 in the diclofenac group, and
38 in the ibuprofen group. The cumulative event rates were lower over
the entire study period for celebrex than for the NSAID comparators
pooled (p=0.040) and ibuprofen (p=0.017). When only patients not taking
aspirin were included in the analysis, the celebrex event rate over 52
weeks was lower than the rate for the NSAIDs pooled (p=0.020) and the
rate for ibuprofen (p\<0.001). The detailed results are included in
Table 7 below.

**Table 7. Summary of CSUGIE/GDU Incidence**

+--------------+---------+---------+---------+-------+-------+-------+
|              | **Cel   | **Diclo | **Ibup  | **Log |       |       |
|              | ebrex** | fenac** | rofen** | -Rank |       |       |
|              |         |         |         | P     |       |       |
|              | **400   | **75 mg | **800   | V     |       |       |
|              | mg      | BID**   | mg      | alues |       |       |
|              | BID**   |         | TID**   | for** |       |       |
|              |         |         |         |       |       |       |
|              |         |         |         | **Cel |       |       |
|              |         |         |         | ebrex |       |       |
|              |         |         |         | vs.** |       |       |
|              |         |         |         |       |       |       |
|              |         |         |         | **    |       |       |
|              |         |         |         | Diclo |       |       |
|              |         |         |         | fenac |       |       |
|              |         |         |         | Ibup  |       |       |
|              |         |         |         | rofen |       |       |
|              |         |         |         | B     |       |       |
|              |         |         |         | oth** |       |       |
+--------------+---------+---------+---------+-------+-------+-------+
| **All        |         |         |         |       |       |       |
| Patients**   |         |         |         |       |       |       |
+--------------+---------+---------+---------+-------+-------+-------+
|              | n=3987  | n=1996  | n=1985  |       |       |       |
+--------------+---------+---------+---------+-------+-------+-------+
| No. of       | 43      | 26      | 36      |       |       |       |
| CSUGIEs      |         |         |         |       |       |       |
|              | 3       | 1       | 2       |       |       |       |
| Uncensored   |         |         |         |       |       |       |
|              | 46      | 27      | 38      |       |       |       |
| Censored\*   |         |         |         |       |       |       |
|              |         |         |         |       |       |       |
| Total        |         |         |         |       |       |       |
+--------------+---------+---------+---------+-------+-------+-------+
| Week 52      | 1.05%   | 1.30%   | 1.76%   | 0.296 | 0.017 | 0.040 |
| crude rate   |         |         |         |       |       |       |
+--------------+---------+---------+---------+-------+-------+-------+
| **Patients   |         |         |         |       |       |       |
| not Taking   |         |         |         |       |       |       |
| Aspirin**    |         |         |         |       |       |       |
+--------------+---------+---------+---------+-------+-------+-------+
|              | n=3105  | n=1551  | n=1573  |       |       |       |
+--------------+---------+---------+---------+-------+-------+-------+
| No. of       | 21      | 10      | 28      |       |       |       |
| CSUGIEs      |         |         |         |       |       |       |
|              | 1       | 0       | 1       |       |       |       |
| Uncensored   |         |         |         |       |       |       |
|              | 22      | 10      | 29      |       |       |       |
| Censored\*   |         |         |         |       |       |       |
|              |         |         |         |       |       |       |
| Total        |         |         |         |       |       |       |
+--------------+---------+---------+---------+-------+-------+-------+
| Week 52      | 0.68%   | 0.64%   | 1.78%   | 0.992 | \<    | 0.020 |
| crude rate   |         |         |         |       | 0.001 |       |
+--------------+---------+---------+---------+-------+-------+-------+

\*Occurred before 48 hours after midnight of the first dose day or more
than 48 hours after midnight of the last dose day (unless

occurred within two weeks after last dose and was determined by GEC to
be treatment-related).

### III.3.2.d Data Imputation

The sponsor argued that since GI adverse events represent risk factors
for events, withdrawals due to GI adverse events represent loss of
patients at risk. Based on this argument, the sponsor calculated
incidences for patients who did/did not experience GI symptoms and who
continued in the study, and these incidences were then applied to
patients who discontinued with/without GI symptoms and the expected
numbers of CSUGIE in these two patient groups were estimated. Details
for imputation and calculation for CSUGIE incidence are in Appendix B.

Table 8 below shows the estimated CSUGIE numbers and rates after
imputation for the withdrawal group. The p-values in Table 8 were
generated by Fisher's exact test on the expected numbers of CSUGIE.

Table 8. Crude Incidence Rates of CSUGIEs with Imputation for
Withdrawals

+-------------+---------+---------+---------+-----------+-----------+
|             | **C     | **Dic   | **Ib    | *         | *         |
|             | elebrex | lofenac | uprofen | *Celebrex | *Celebrex |
|             | 400 mg  | 75 mg   | 800 mg  | vs.       | vs.       |
|             | BID**   | BID**   | TID**   | Dic       | Ib        |
|             |         |         |         | lofenac** | uprofen** |
|             | **(n=   | **(n=   | **(n=   |           |           |
|             | 3987)** | 1996)** | 1985)** |           |           |
+-------------+---------+---------+---------+-----------+-----------+
| First six   |         |         |         |           |           |
| months      |         |         |         |           |           |
+-------------+---------+---------+---------+-----------+-----------+
| CSUGIE      | 15      | 16      | 16      | p=0.036   | p=0.035   |
|             | (0.4%)  | (0.8%)  | (0.8%)  |           |           |
+-------------+---------+---------+---------+-----------+-----------+
| Entire      |         |         |         |           |           |
| study       |         |         |         |           |           |
+-------------+---------+---------+---------+-----------+-----------+
| CSUGIE      | 25      | 23      | 21      | p=0.044   | p=0.084   |
|             | (0.6%)  | (1.2%)  | (1.1%)  |           |           |
+-------------+---------+---------+---------+-----------+-----------+

**III.3.3 Efficacy Analyses**

Efficacy of the three treatment groups were assessed by patient's
global, patient's assessment of arthritis pain, time to withdrawal due
to lack of arthritis efficacy, and HAQ. The three treatment groups were
numerically comparable in efficacy results. The means and confidence
intervals are reported in Tables a5-a8 Appendix A.

## Reviewer's Comments

**IV.1** Imputation of CSUGIE Rates

The sponsor's rationales for imputation of CSUGIE were that 1) the
patients with GI adverse events would have higher probability to develop
a CSUGIE over the treatment duration (see Table 2 in Appendix B) and 2)
higher withdrawal incidence with earlier withdrawal time in the
diclofenac group were observed (see Table 1 in Appendix B), an
estimation for the entire study period without adjustment for these
informative censoring would not be appropriate for interpretation.

The above two reasons are not valid based on this reviewer's analysis.
Table 9 displays the time to GI AEs (mild-moderate-severe GI AE,
moderate-severe GI AE and severe GI AE) and time to CSUGIE for patients
who had both GI AE and CSUGIE. A phenomenon observed in this Table is
that, for most patients, the time to GI AEs and time to CSUGIE are
identical. For example, among the 8 patients who had both severe GI AE
and CSUGIE, 6 of them developed the GI AE and CSUGIE on the same day,
one of them developed CSUGIE in two days after GI AE, and the other one
had CSUGIE 20 days before GI AE. So instead of being a pre-event that
predicts CSUGIE, most GI AEs were actually the sentinel symptoms of
CSUGIE themselves, providing no predictive value at all (see Dr.
Goldkind's review for further comments). As suggested by the medical
reviewer, this reviewer recalculated the relative risk of the GI AE
group vs. non-GI AE group by defining predictive GI AEs as those
happened more then 48 hours before a CSUGIE, so that those GI AEs
happened within 48 hours of a CSUGIE are excluded from GI AE groups. The
results presented in Table 10 show that the GI AE groups
(mild-moderate-severe, moderate-severe and sever GI AE) actually have
lower risks than the non-GI AE group. So the sponsor's rationales for
imputation of the CSUGIEs is not supported by the data.

#### Table 9. Time to GI AEs and Time to CSUGIE in Patients with Both GI AE and CSUGIE

##### \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

#####  **Patient \# Treatment T_MD-MT-SV\* T_MT-SEV\*\* T_SEV\*\*\* T_CSUGIE\*\*\*\***

12391 celebrex 261 . . 261

10761 celebrex 307 307 307 307

20349 celebrex 199 . . 199

11159 celebrex 43 63 63 43

10012 celebrex 12 . . 276

11153 celebrex 67 67 67 67

11341 celebrex 10 150 150 150

12176 celebrex 139 139 . 139

20035 declofenac 6 6 . 6

10032 declofenac 66 66 . 66

10193 declofenac 8 8 8 8

10294 declofenac 7 7 7 9

20398 declofenac 41 41 . 49

11559 declofenac 261 261 . 253

12252 declofenac 11 11 11 11

12815 declofenac 7 7 7 7

10579 Ibuprofen 13 18 . 13

11377 Ibuprofen 4 4 . 4

11767 Ibuprofen 123 123 . 123

21191 Ibuprofen 13 13 . 17

12446 Ibuprofen 9 9 9 5

11011 Ibuprofen 112 . . 124

\* :Time to Mild-Moderate-Severe GI AE

\*\* :Time to Moderate-Severe GI AE

\*\*\* :Time to Severe GI AE

\*\*\*\*:Time to CSUGIE

#### Table 10. CSUGIE Incidence in GI AE Groups and Non-GI AE Groups

  ------------------ -------------- ---------------- ---------------- -------------
                     **Celebrex**   **Declofenac**   **Ibupfrofen**   **Overall**

  With MD-MT-SEV GI  2/1383 (0.14%) 1/857 (0.12%)    2/639 (0.31%)    5/2879
  AE                                                                  (0.17%)

  Without MD-MT-SEV  15/2604        9/1139 (0.79%)   9/1346 (0.67%)   33/5089
  GI AE              (0.58%)                                          (0.65%)

  Relative Risk      25.10%         14.77%           46.81%           26.78%

                                                                      

  With MT-SEV GI AE  0/694 (0.00%)  1/441 (0.23%)    1/332 (0.30%)    2/1467
                                                                      (0.14%)

  Without MT-SEV GI  17/3293        9/1555 (0.58%)   10/1653 (0.60%)  36/6501
  AE                 (0.52%)                                          (0.55%)

  Relative Risk      0.00%          39.18%           49.79%           24.62%

                                                                      

  With SEV GI AE     0/154 (0.00%)  0/125 (0.00%)    0/71 (0.00%)     0/350 (0.00%)

  Without SEV GI AE  17/3833        10/1871 (0.53%)  11/1914 (0.57%)  38/7618
                     (0.44%)                                          (0.50%)

  Relative Risk      0.00%          0.00%            0.00%            0.00%
  ------------------ -------------- ---------------- ---------------- -------------

### IV. 2 Analysis for the First 6 Months Data

The sponsor's rationale for analyzing the first 6 months data only is
that the large dropout rate in the later stage of the study depleted
high-risk patients\--patients who dropped out due to GI AEs. This
rationale is not valid due to the following reasons.

1)  Current statistical methods in survival analysis (K-M estimator,
    tests for time to events) can make valid statistical inference even
    with high proportion of censoring, unless the censoring is
    informative. Sponsor's argument for the existence of informative
    censoring was not supported by the data as discussed in Comment 1
    above. Therefore, this reviewer regards the analysis for data for
    the entire study period as specified in the protocol, which includes
    most information, the appropriate analysis.

2)  The 6 months analysis is not valid even with concern of informative
    censoring. As presented in Table 11, the drop-out rates due to GI AE
    were increased gradually without sudden increase at Month 6
    (Week 26) in any of the treatment groups. The numerical order of the
    drop-out rates stayed the same across the entire study period.
    Therefore, there is no reason to include information only in the
    first 6 months.

#### Table 11. Drop-out Rates (%) due to GI AE 

+----------------+-----------------+----------------+-----------------+
| **TimePoint**  | ##              | **Diclofenac** | **Ibuprofen**   |
|                | ###### Celebrex |                |                 |
|                |                 | **(n=1996)**   | **(n=1985)**    |
|                | **(n=3987)**    |                |                 |
+----------------+-----------------+----------------+-----------------+
| Week1          | 2.85            | 4.25           | 2.80            |
+----------------+-----------------+----------------+-----------------+
| Week4          | 5.08            | 7.46           | 5.09            |
+----------------+-----------------+----------------+-----------------+
| Week13         | 8.20            | 11.05          | 8.94            |
+----------------+-----------------+----------------+-----------------+
| Week26         | 9.90            | 13.66          | 10.54           |
+----------------+-----------------+----------------+-----------------+
| Week39         | 11.09           | 14.65          | 11.59           |
+----------------+-----------------+----------------+-----------------+
| Week52         | 11.41           | 14.95          | 11.71           |
+----------------+-----------------+----------------+-----------------+
| Week65         | 11.41           | 14.95          | 11.99           |
+----------------+-----------------+----------------+-----------------+

**IV.3 Subgroup Analysis for Non-Aspirin Users**

As presented in Table 6 and Table 7, the sponsor conducted analysis for
CSUGIE and combined CSUGIE/GDU event rates in non-aspirin users. The
sponsor's analyses showed that celebrex had a numerically lower
CSUGIE/GDU incidence (0.3%) than in ibuprofen group (0.6%) with a
p-value 0.185 and a numerically lower CSUGIE/GDU incidence (0.7%) than
in ibuprofen group (1.8%) with a p-value less than 0.05. These p-values
can not be interpreted by their face values since 1) the primary
endpoint did not show statistical significance, 2) numerous subgroup
analyses had been conducted (at least 34, see Tables a9-a11 in Appendix
A for the results of risk factor analyses) in exploratory faction with
no pre-specified plan of statistical inference, and 3) subgroup analyses
based on aspirin use was not even mentioned in the protocol. However, if
these subgroup analyses are clinically meaningful and the results are
supported by external information (see DR. Goldkind's review for further
comments), the conventional frequentist's approach of adjusting α may
not be appropriate. But a formal statistical inference is impossible
without a pre-specified analysis plan..

It is also worth noticing that the results of CSUGIE and combined
CSUGIE/GDU event rates in aspirin users were numerically inconsistent
with that in the non-user group---celebrex had higher incidences (1.0%
for CSUGIE and 2.5% for combined CSUGIE/GDU event) than ibuprofen group
(0.2% for CSUGIE and 1.9% for combined CSUGIE/GDU event) (see Tables a11
and a12 in Appendix A).

## Final Conclusion

Celebrex 400 mg BID did not show significant reduction in CSUGIE
incidence compared to two NSAIDs: ibuprofen 800 mg TID and diclofenac 75
mg BID in patients with OA or RA.

In a post hoc analysis of non-aspirin users, the incidence of combined
CSUGIE/GDU event in the celebrex group was lower than that in ibuprofen
group with p-values less than 0.05. However, this p-value can not be
easily interpreted statistically by its face value due to lack of
pre-specified analysis plan and the failure of showing statistical
significance in the primary endpoint.

Hong Laura Lu. Ph.D

Concur:

Stan Lin, Ph.D.

Team Leader

CC:

NDA 20998

HFD-550/MO/Goldkind/Witter/Bullj

HFD-550/PM/Kongy

HFD-550/Div. File

HFD-725/Lu/Lin ST./Huque

HFD-725/Div. File

**Appendix A**

Table a1. Baseline Demographics

![](media/image2.png){width="6.489583333333333in"
height="4.186805555555556in"}

Table a2. Additional Baseline Characters

![](media/image3.png){width="5.2in" height="2.397222222222222in"}

![](media/image4.png){width="6.488888888888889in"
height="4.504166666666666in"}Table a3. Vital Signs

Table a4. GI Risk Factors

![](media/image5.png){width="6.486111111111111in"
height="4.000694444444444in"}

![](media/image6.png){width="6.49375in"
height="3.292361111111111in"}Table a4. GI Risk Factors (continue)

![](media/image7.png){width="6.496527777777778in"
height="3.1909722222222223in"}

Table a5. Summary of Patient's Global Assessment Results

+-----------------------+-------------+---------------+--------------+
|                       | **Celebrex  | **Diclofenac  | **Ibuprofen  |
|                       | 400 mg BID  | 75 mg BID     | 800 mg TID   |
|                       | (n=3987)**  | (n=1996)**    | (n=1985)**   |
+-----------------------+-------------+---------------+--------------+
| Mean (95% CI)\*       | 2.96        | 2.95          | 2.96         |
|                       | (2.93-2.98) | (2.91-2.99)   | (2.92-3.00)  |
| Baseline              |             |               |              |
|                       | 2.68        | 2.71          | 2.73         |
| Week 26               | (2.65-2.71) | (2.67-2.76)   | (2.68-2.78)  |
|                       |             |               |              |
| Final                 | 2.71        | 2.72          | 2.76         |
|                       | (2.68-2.74) | (2.67-2.77)   | (2.71-2.81)  |
+-----------------------+-------------+---------------+--------------+
| Categorical analysis, | 38 (37-40)  | 40 (38-42)    | 32 (30-34)   |
| % (95% CI)            |             |               |              |
|                       | 46 (45-48)  | 43 (41-45)    | 48 (46-50)   |
| Week 26               |             |               |              |
|                       | 16 (15-17)  | 17 (15-18)    | 20 (18-21)   |
| Improved              |             |               |              |
|                       | 37 (35-38)  | 40 (38-43)    | 31 (29-33)   |
| No Change             |             |               |              |
|                       | 46 (44-47)  | 42 (40-44)    | 48 (46-50)   |
| Worsened              |             |               |              |
|                       | 18 (16-19)  | 18 (16-19)    | 21 (19-23)   |
| Final                 |             |               |              |
|                       |             |               |              |
| Improved              |             |               |              |
|                       |             |               |              |
| No Change             |             |               |              |
|                       |             |               |              |
| Worsened              |             |               |              |
+-----------------------+-------------+---------------+--------------+

Table a6. Summary of Patient's Assessment of Arthritis Pain (VAS)
Results

+------------+-----------------+------------------+------------------+
|            | **Celebrex 400  | **Diclofenac 75  | **Ibuprofen 800  |
|            | mg BID          | mg BID           | mg TID           |
|            | (n=3987)**      | (n=1996)**       | (n=1985)**       |
+------------+-----------------+------------------+------------------+
| Mean (95%  | 50.7            | 50.8 (49.6-52.1) | 50.6 (49.3-51.9) |
| CI)        | (49.9-51.6)     |                  |                  |
|            |                 | 43.4 (42.0-44.8) | 45.0 (43.6-46.4) |
| Baseline   | 42.9            |                  |                  |
|            | (42.0-43.7)     | 44.2 (42.7-45.6) | 45.9 (44.5-47.4) |
| Week 26    |                 |                  |                  |
|            | 44.0            |                  |                  |
| Final      | (43.1-44.9)     |                  |                  |
+------------+-----------------+------------------+------------------+

####### Table a7. Incidence of Withdrawal Due to Lack of Arthritis Efficacy

+---------------------+---------------+---------------+---------------+
|                     | **Celebrex    | **Diclofenac  | **Ibuprofen   |
|                     | 400 mg BID    | 75 mg BID     | 800 mg TID    |
|                     | (n=3987)**    | (n=1996)**    | (n=1985)**    |
+---------------------+---------------+---------------+---------------+
| Number (Percent)    | 691(17%)      | 309(15%)      | 456(23%)      |
|                     |               |               |               |
| (95% Confidence     | (16% - 19%)   | (14% - 17%)   | (21% - 25%)   |
| Interval)           |               |               |               |
+---------------------+---------------+---------------+---------------+

Table a8. Summary of Results in Selected SF-36 Health Survey Domains

+----------------+-------------------------+---------------------------+
| **SF-36 Health | **Celebrex 400 mg BID   | **Ibuprofen 800 mg TID    |
| Survey         | (n=1990)**              | (n=1985)**                |
| Domain**       |                         |                           |
+----------------+-------------------------+---------------------------+
| Bodily Pain    | 39.5 (38.6-40.4)        | 39.9 (39.0-40.8)          |
|                |                         |                           |
| Baseline       | 46.0 (45.1-46.9)        | 44.8 (43.9-45.8)          |
|                |                         |                           |
| Week 26        | 45.9 (45.0-46.9)        | 44.7 (43.8-45.7)          |
|                |                         |                           |
| Final          |                         |                           |
+----------------+-------------------------+---------------------------+
| Physical       | 48.3 (47.1-49.5)        | 48.6 (47.4-49.9)          |
| Function       |                         |                           |
|                | 51.4 (50.5-52.3)        | 50.4 (49.4-51.3)          |
| Baseline       |                         |                           |
|                | 50.8 (49.9-51.7)        | 50.1 (49.2-51.0)          |
| Week 26        |                         |                           |
|                |                         |                           |
| Final          |                         |                           |
+----------------+-------------------------+---------------------------+
| Vitality       | 45.4 (44.3-46.4)        | 46.1 (45.0-47.1)          |
|                |                         |                           |
| Baseline       | 47.6 (46.7-48.4)        | 46.9 (46.0-47.7)          |
|                |                         |                           |
| Week 26        | 47.0 (46.1-47.8)        | 46.3 (45.5-47.1)          |
|                |                         |                           |
| Final          |                         |                           |
+----------------+-------------------------+---------------------------+
| Role-Physical  | 37.9 (35.9-39.8)        | 38.4 (36.4-40.3)          |
|                |                         |                           |
| Baseline       | 42.6 (40.8-44.4)        | 41.0 (39.2-42.8)          |
|                |                         |                           |
| Week 26        | 42.1 (40.4-43.9)        | 41.0 (39.2-42.8)          |
|                |                         |                           |
| Final          |                         |                           |
+----------------+-------------------------+---------------------------+

Table a9. Risk Factor Analysis of Clinically Significant UGI Events
(Demographics)

![](media/image8.png){width="6.490277777777778in" height="3.3in"}

![](media/image9.png){width="6.498611111111111in" height="3.6in"}**Table
a10. Risk Factor Analysis of Clinically Significant UGI Events (GI
History)**

**Table a11. Risk Factor Analysis of Clinically Significant UGI Events**

**(Medication, Alcohol, and Tobacco Use)**

![](media/image10.png){width="6.48125in" height="3.089583333333333in"}

#### Table a12. Risk Factor Analysis of Clinically Significant UGI Events or GD Ulcer 

#### (Medication, Alcohol, and Tobacco Use) 

#### ![](media/image11.png){width="6.489583333333333in" height="3.3in"}  {#section-2 .unnumbered}

#### Appendix B

# **Discussions On Informative Censoring And Risk Factor-Related Withdrawal**

In design and analysis of failure data with censoring, an important
requirement is that dropouts are non-informative, that is, the failure
time is independent of the reason for the individual to drop out before
the event is possibly observed. However, this assumption cannot be met
if the failure time is censored through withdrawal as a result of a
deterioration of patient condition. This type of censoring is known as
informative censoring, a special type of non-ignorable missing data.
When present, informative censoring causes bias in standard analyses,
and interpretation of such analyses may be misleading. In this section,
we discuss the informative censoring in the present study caused by
withdrawal due to GI-related symptoms, and the statistical analysis and
simulation adjusted for the informative censoring. We also present the
withdrawal vs. GI risk factors over time and its impact on the analysis.

## Informative Censoring Caused by Withdrawal due to GI-Related Symptoms {#informative-censoring-caused-by-withdrawal-due-to-gi-related-symptoms .unnumbered}

In this study, informative censoring with respect to study end points,
namely clinically significant UGI events (CSUGIEs) and CSUGIEs combined
with gastroduodenal ulcers (CSUGIEs/GDUs), was observed in patients who
dropped out due to GI-related adverse events, including dyspepsia,
abdominal pain, nausea, diarrhea, and vomiting. First, a treatment
differentiation in time to and incidence of dropout due to GI adverse
events was detected. Second, the rates of CSUGIEs were different in
patients without GI adverse events than in patients with GI adverse
events. Patients who experienced GI adverse events had a higher
incidence of CSUGIEs than patients who did not report GI adverse events.
Clearly, a patient whose failure time is censored due to a GI adverse
event causing withdrawal represents a higher risk for an event than
those who have not had an adverse event up to that time.

**Table 1.** **Summary of Abdominal Pain, Dyspepsia, Nausea, Diarrhea
and Vomiting Incidence and Withdrawals (Moderate to Severe)**

**Celecoxib Diclofenac Ibuprofen**

**n (%) n (%) n (%)**

Treated 3987 1996 1985

Any GI AE 699 448 336

Withdrawal 298 (7.5) 191 (9.6) 149 (7.5)

Similar summaries including mild, moderate, and severe GI adverse events
and withdrawals are included in Appendix 2.4.17. Significantly higher
withdrawal incidence and earlier withdrawal time in the diclofenac group
were detected than in the other treatment groups (p\<0.01). To assess
whether the withdrawals due to GI-related adverse events affected the
estimation of clinically significant UGI event rates, we examined the
relative risks of CSUGIEs and CSUGIEs/GDUs in patients with and without
GI symptoms.

**Table 2.** **Summary of CSUGIE Rates and Relative Risks With and
Without Five GI Adverse Events (Moderate to Severe)**

**Celecoxib Diclofenac Ibuprofen**

**CSUGIEs**

With AE 5/699 8/448 5/336

Without AE 12/3288 2/1548 6/1649

Relative risk 1.96 13.82 4.09

**CSUGIEs / GDUs**

With AE 22/699 20/448 20/336

Without AE 21/3288 6/1548 16/1649

Relative risk 4.93 11.52 6.13

The table indicates that the patients with GI adverse events would have
higher probability to develop an event over the treatment duration. A
high and early withdrawal rate due to GI-related adverse events
diminished the real event rate of the patient population. A bias would
have been created in favor of treatments with high withdrawal rates due
to shorter exposure time to treatment, hence lower event rates.
Therefore, an estimation for the entire study period without adjustment
for informative dropouts would not be appropriate for interpretation.

## Statistical Adjustment for Informative Censoring

Informative censoring has been widely discussed in many statistical
journals over the past 20 years. There have been some proposals under
certain assumptions dealing with continuous data and some other specific
types of data when dropouts do not occur at random. For references,
reviewers should refer to D. Rubin (1976, Biometrika, vol. 63, pp.
581-592), P. Diggle and M. Kenward (1994, Appl. Statist., Vol. 43, pp.
49-93), and J. Little (1995, JASA, vol. 90, pp. 1112-1121).

In this study, informative censoring occurred, and our primary end point
is survival-type data. We will analyze the data by estimating the events
missed due to informative withdrawal-based dropout incidences and times.
A total probability will be calculated and simulation will be performed
for Kaplan-Meier curves adjusted for the withdrawal. Fisher's exact test
will be performed on the adjusted event rates.

As seen in prior discussions, treatment differentiation withdrawals due
to GI adverse events and higher relative risks in the patients with GI
adverse events were observed. Intuitively, early withdrawal of patients
due to GI adverse events would have introduced underestimates of overall
CSUGIE and ulcer rates because the probability for a patient to develop
a UGI event or ulcer is higher if the patient has a GI adverse event or
discontinues due to a GI adverse event. Therefore, the overall CSUGIE or
ulcer rate, or the total probability of developing a CSUGIE or ulcer for
the treated patient population, should be estimated by partitioning the
samples into three subsets.

Prob. (event occurred) = P (event \| no GI AE) \* P (no GI AE)

\+ P (event \| GI AE and continue) \* P (GI AE and continue)

\+ P (event \| GI AE and withdrawal) \* P (GI AE and withdrawal)

The first and second terms shall be estimated by the corresponding
sample means, respectively. The third term represents the missing event
rate due GI adverse event-related withdrawal. To estimate the number of
CSUGIEs we would have observed had the patients not dropped out due to
adverse events, we calculated the total exposure time after the GI
adverse events were reported for the patients with adverse events who
did not drop out as a result. The total number of the events occurring
in these continuing patients with adverse events divided by this
exposure would give us the estimated rate by patient exposure time after
the adverse event was reported. We assume the rate in the patients who
discontinued due to GI adverse events over the period between the
adverse event and the end of the treatment would have been at least as
high had the patients continued treatment as the rate in those who
continued. The exposure times for the patients who withdrew due to
adverse events were estimated by calculating the time between the
dropout date and the end of the study. For the entire study period, the
date of 1/10/2000 was used as the end of the study. This date is one
month after the official letter of closing the study was issued, and is
five days after the last withdrawal due to a GI adverse event. For the
analyses of the first six months, the dates of 7/10/2000 and 9/10/2000
were used for protocols 035 and 102, respectively, due to the lag in
enrollment time of 102 by approximately two months.

Table 3 summarizes the adjusted event rates and statistical tests
applied. Detailed data can be found in Appendices 2.4.17.9 -- 2.4.17.14.

**Table 3.** **CSUGIE and Ulcer Rates Adjusted for Discontinuation due
to**

**Moderate and Severe GI Adverse Events**

**[p-values \_\_\_\_]{.underline}**

**Celecoxib Diclofenac Ibuprofen C/N C/D C/I**

Patients 3984 1995 1983

**First 6 Month**

CSUGIE 15 16 16 .013 .036 .035

CSUGIE/GDU 44 34 44 .002 .069 .001

**Entire period**

POB 25 23 21 .022 .044 .084

PUB 76 58 73 \<.01 .016 \<.01

With the above rates, we simulated Kaplan-Meier curves for the three
treatment groups. In each run, the estimated events were randomly
assigned to the patients who discontinued due to GI adverse events. The
simulations were performed 100 times; the averaged curve is presented
below.