UPDATE ON THE TNF- BLOCKING AGENTS

# INTRODUCTION

The intent of this document is to summarize the efficacy data that
resulted in the licensure of the three tumor necrosis factor (TNF)
blocking agents and to provide a more comprehensive update on their
safety. The three products, Etanercept (Enbrel), Infliximab (Remicade)
and Adalimumab (Humira) are indicated for treatment of patients with RA.
Clinical studies have shown the products to improve signs and symptoms,
inhibit the progression of structural damage, and impact functional
outcomes in patients with RA. The efficacy section will begin with a
summary of Adalimumab, the newest of the TNF blocking therapies.

While all these agents have demonstrated efficacy in patients with
active RA despite treatment with other DMARDs (disease modifying
anti-rheumatic drugs), they have also been associated with certain
uncommon but serious adverse events. Most of these events have come to
light through the post-marketing passive surveillance program. At the
time of approval of the first two TNF blocking agents, the total numbers
of patients treated and extent of exposure from controlled clinical
trials and the open label extension studies were relatively limited. As
will be summarized in the safety section of this document, the post
market safety updates and data from controlled clinical trials in other
settings have triggered several different FDA actions, including updates
to the prescribing information in the package inserts, communications to
health care providers (Dear Health Care Provider Letters) a safety
update on August 17, 2001 to the AAC, as well as presentations at ACR
and other national and international meetings and publications in
journals. This safety update will summarize safety data from the
randomized controlled trials contained in the Biologics License
Application (BLA) of Adalimumab for RA, and provide an update on safety
information for Remicade and Enbrel. One major focus of this safety
update will be a more in-depth review of the cases of lymphomas that
have developed in patients treated with TNF blocking therapy. We
specifically seek the committee's advice on issues regarding the
association between these products and lymphoma and input regarding how
to best transmit this information in prescribing information.

# EFFICACY OF TNF BLOCKING AGENTS

## Humira 

Humira is a human-derived recombinant IgG1 monoclonal antibody
engineered by gene technology. Humira binds to TNF-α but not TNF-β and
has a half-life of approximately 2 weeks. It was approved for use in
patients with RA December 31, 2002. The paragraphs below summarize the
major efficacy findings; the Humira safety summary is presented in
Section III. Appendix A provides the full medical review of the BLA.

The sponsor conducted four randomized, double-blind efficacy studies in
patients ≥ age 18 with active rheumatoid arthritis diagnosed according
to American College of

Rheumatology (ACR) criteria. Patients had at least 6 swollen and 9
tender joints. Adalimumab was administered subcutaneously in combination
with MTX (12.5 to 25 mg, Studies I and III) or as monotherapy (Study II)
or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study
IV).

Study I (DE009) evaluated 271 patients who had failed therapy with at
least one but no more than four DMARDs and had inadequate response to
MTX. Doses of 20, 40 or 80 mg of HUMIRA or placebo were given every
other week for 24 weeks.

Study II (DE011) evaluated 544 patients who had failed therapy with at
least one DMARD. Doses of placebo, 20 or 40 mg of HUMIRA were given as
monotherapy every other week or weekly for 26 weeks.

Study III (DE 019) evaluated 619 patients who had an inadequate response
to MTX. Patients received placebo, 40 mg of HUMIRA every other week with
placebo injections on alternate weeks, or 20 mg of HUMIRA weekly for up
to 52 weeks. Study III had an additional primary endpoint at 52 weeks of
inhibition of disease progression (as detected by X-ray results).

Study IV (DE031) assessed safety in 636 patients who were either
DMARD-naive or were permitted to remain on their pre-existing
rheumatologic therapy provided that therapy was stable for a minimum of
28 days. Patients were randomized to 40 mg of HUMIRA or placebo every
other week for 24 weeks.

Table 1 summarizes the ACR 20, 50, and 70 findings.

Table 1 : Summary of Percentage of ACR20, ACR50, and ACR70 Responses for
All Adalimumab Studies At 6 and 12 Months at the recommended dose

+-----------------+------------------+----------------+----------------+
| ####            | **Adalimumab**   |                | **Placebo/**   |
| # *Study* {#stu |                  |                |                |
| dy .unnumbered} | **40 mg Q2w**    |                | **Comparator** |
+-----------------+------------------+----------------+----------------+
|                 | **24 or 26       |                |                |
|                 | Weeks**          |                |                |
+-----------------+------------------+----------------+----------------+
| I Dose ranging  | **ACR20**        | **67**         | **13**         |
|                 |                  |                |                |
| \+ MTX          |                  |                |                |
+-----------------+------------------+----------------+----------------+
|                 | **ACR50**        | **54**         | **7**          |
+-----------------+------------------+----------------+----------------+
|                 | **ACR70**        | **24**         | **3**          |
+-----------------+------------------+----------------+----------------+
| II Monotherapy  | **ACR20**        | **46**         | **20**         |
+-----------------+------------------+----------------+----------------+
|                 | **ACR50**        | **22**         | **8**          |
+-----------------+------------------+----------------+----------------+
|                 | **ACR70**        | **12**         | **2**          |
+-----------------+------------------+----------------+----------------+
| III (+ MTX)     | **ACR20**        | **63**         | **30**         |
+-----------------+------------------+----------------+----------------+
|                 | **ACR50**        | **39**         | **10**         |
+-----------------+------------------+----------------+----------------+
|                 | **ACR70**        | **21**         | **3**          |
+-----------------+------------------+----------------+----------------+
| IV (Added to    | **ACR20**        | **53**         | **35**         |
| Usual           |                  |                |                |
|                 |                  |                |                |
| Clinical        |                  |                |                |
| Practice)       |                  |                |                |
+-----------------+------------------+----------------+----------------+
|                 | **ACR50**        | **29**         | **11**         |
+-----------------+------------------+----------------+----------------+
|                 | **ACR70**        | **15**         | **3**          |
+-----------------+------------------+----------------+----------------+
| III (+ MTX)     | **52 Weeks**     |                |                |
+-----------------+------------------+----------------+----------------+
|                 | **ACR20**        | **55**         | **25**         |
+-----------------+------------------+----------------+----------------+
|                 | **ACR50**        | **42**         | **10**         |
+-----------------+------------------+----------------+----------------+
|                 | **ACR70**        | **23**         | **5**          |
+-----------------+------------------+----------------+----------------+

**ACR Responses in Placebo-Controlled Trials (Percent of Patients)**

The results of the components of the ACR response criteria for Studies
II and III are shown in the table below. Improvement was seen in all
components and was maintained to week 52.

The time course of ACR 20 response for Study III is shown in figure 1.

In Study III, 85% of patients with ACR 20 responses at week 24
maintained the response at 52 weeks. The time course of ACR 20 response
for Study I and Study II were similar.

![](media/image1.wmf)

In Study III, structural joint damage was assessed radiographically and
expressed as change in Total Sharp Score (TSS) and its components, the
erosion score and Joint Space Narrowing (JSN) score, at month 12
compared to baseline. At baseline, the median TSS was approximately 55
in the placebo and 40 mg every other week groups. The results are shown
in Table 3. HUMIRA/MTX treated patients demonstrated less radiographic
progression than patients receiving MTX alone.

+---------------+-----------+-------------+---------------+-----------+
| Table 3       |           |             |               |           |
| Radiographic  |           |             |               |           |
| data - change |           |             |               |           |
| in score      |           |             |               |           |
| compared to   |           |             |               |           |
| baseline      |           |             |               |           |
+---------------+-----------+-------------+---------------+-----------+
| []{.mark}     | Pl        | HUMIRA/MTX  | Placebo/M     | P-        |
|               | acebo/MTX |             | TX-HUMIRA/MTX | value\*\* |
|               |           | 40 mg every | (95%          |           |
|               |           | other week  | Confidence    |           |
|               |           |             | Interval\*)   |           |
+---------------+-----------+-------------+---------------+-----------+
| Total Sharp   | 2.7       | 0.1         | 2.6 (1.4,     | \<0.001   |
| score         |           |             | 3.8)          |           |
+---------------+-----------+-------------+---------------+-----------+
| Erosion score | 1.6       | 0.0         | 1.6 (0.9,     | \<0.001   |
|               |           |             | 2.2)          |           |
+---------------+-----------+-------------+---------------+-----------+
| JSN score     | 1.0       | 0.1         | 0.9 (0.3,     | 0.002     |
|               |           |             | 1.4)          |           |
+---------------+-----------+-------------+---------------+-----------+

\*95% confidence intervals for the differences in change scores between
MTX and HUMIRA.

\*\*Based on rank analysis

The optimal dose of adalimumab is 40 mg sc every other week when given
in combination with MTX. Higher doses were not more effective. In study
II, which did not include MTX, although adalimumab 40 mg every other
week was effective (46% ACR20 responses at 6 months), 40 mg weekly was
associated with higher response rates (53% ACR20 responses at 6 months).
Comparisons across trials must be carried out with caution; however, the
higher point estimates of the response rates in 6-month trials of
adalimumab 40 mg every other week with MTX suggest that the addition of
MTX to adalimumab is more effective.

In all four studies, Humira showed significantly greater improvement
than placebo in the disability index of Health Assessment Questionnaire
(HAQ) from baseline to the end of study, and significantly greater
improvement than placebo in the health-outcomes as assessed by The Short
Form Health Survey (SF 36). Improvement was seen in both the Physical
Component Summary (PCS) and the Mental Component Summary (MCS). However,
the duration of the longest study (12 months) was not sufficient to
permit a claim of Improvement in Physical Function as delineated in the
RA Guidance.

Most patients enrolled in the controlled trials of adalimumab were
offered the opportunity to roll over into a long-term open-label
extension study. To assess tolerability of adalimumab treatment over
time, the data from clinical trials were analyzed to determine what
fractions of patients who were allowed to continue treatment for 1, 2, 3
or 4 years chose to do so. As shown in Table 4, 70% of patients who
began treatment with adalimumab chose to continue for 2 years and
approximately 60% chose to continue for 3 years.

Table 4: Percent of Adalimumab-Treated Subjects Choosing to Remain on
Treatment

  ---------------- ---------- ------------- ------------------------------
  Years of         \# exposed Total         **% choosing to remain on
  exposure                    possible      treatment**

  \<1 yr           2468       2468          100%

  ≥ 1 yr           1990       2444          81%

  ≥ 2 yrs          1258       1795          70%

  ≥ 3 yrs          331        534           62%

  ≥ 4 yrs          142        254           56%

  ≥ 5 yrs          41         89            46%
  ---------------- ---------- ------------- ------------------------------

## Enbrel efficacy summary 

The efficacy of Enbrel for improvement in signs and symptoms of
rheumatoid arthritis was established in 3 randomized controlled trials.
One efficacy trial was a study of Enbrel or placebo added onto
background therapy in patients who had failed one or more DMARDs (study
I, Table 5). Approximately 60% of patients had an ACR20 response at 6
months compared to approximately 10% of add-on placebo-treated patients.
Similar results were seen in a randomized controlled trial of Enbrel
added to background methotrexate in patients with active disease despite
methotrexate (study II). A median improvement of approximately 50-60%
was seen in each of the components of the ACR20. Continued durable
responses have been seen for up to 36 months in open-label extension
treatment trials when patients received Enbrel without interruption. The
third randomized trial was an active controlled trial that compared a
rapid dose escalation of methotrexate to Enbrel in patients with early
RA (see section VI for more details)

Most patients enrolled in the controlled trials of etanercept were
offered the opportunity to roll over into a long-term open-label
extension study. To assess tolerability of etanercept treatment over
time, the data from clinical trials were analyzed to determine what
fractions of patients who were allowed to continue treatment for 1, 2, 3
or 4 years chose to do so. As shown in Table 6, 73% of patients who
began treatment with etanercept chose to continue for 2 years and
approximately 50% chose to continue on study receiving etanercept for 3
years. It should be noted that these figures provide a conservative
estimate of the proportion of patients who elected to continue
etanercept as some patients dropped out of the study and received
etanercept by prescription once it once approved.

Radiographic findings at 1 and 2 year time-points are shown in Table 7.
Effects were seen on erosion and the joint space narrowing components of
the Sharp score. Etanercept is also approved for treatment of
polyarticular-course juvenile rheumatoid arthritis and for patients with
psoriatic arthritis.

Table 5: **ACR Responses in Placebo- and Active-Controlled Trials**

(Percent of Patients)

<table style="width:100%;">
<colgroup>
<col style="width: 15%" />
<col style="width: 9%" />
<col style="width: 12%" />
<col style="width: 1%" />
<col style="width: 1%" />
<col style="width: 14%" />
<col style="width: 17%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 13%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="6"><strong>Placebo Controlled</strong></td>
<td></td>
<td></td>
<td colspan="2"><strong>Active Controlled</strong></td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"><strong>Study I</strong></td>
<td></td>
<td></td>
<td colspan="2"><strong>Study II</strong></td>
<td></td>
<td></td>
<td colspan="2"><strong>Study III</strong></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td></td>
<td>Placebo</td>
<td>ENBREL<sup>a</sup></td>
<td></td>
<td></td>
<td>MTX/Placebo</td>
<td>MTX/ENBREL<sup>a</sup></td>
<td></td>
<td></td>
<td>MTX</td>
<td>ENBREL<sup>a</sup></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Response</td>
<td>N = 80</td>
<td>N = 78</td>
<td></td>
<td></td>
<td>N = 30</td>
<td>N = 59</td>
<td></td>
<td></td>
<td>N = 217</td>
<td>N = 207</td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong><u>ACR 20</u></strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Month 3</td>
<td>23%</td>
<td>62%<sup>b</sup></td>
<td></td>
<td></td>
<td>33%</td>
<td>66%<sup>b</sup></td>
<td></td>
<td></td>
<td>56%</td>
<td>62%</td>
</tr>
<tr class="odd">
<td>Month 6</td>
<td>11%</td>
<td>59%<sup>b</sup></td>
<td></td>
<td></td>
<td>27%</td>
<td>71%<sup>b</sup></td>
<td></td>
<td></td>
<td>58%</td>
<td>65%</td>
</tr>
<tr class="even">
<td>Month 12</td>
<td>NA</td>
<td>NA</td>
<td></td>
<td></td>
<td>NA</td>
<td>NA</td>
<td></td>
<td></td>
<td>65%</td>
<td>72%</td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong><u>ACR 50</u></strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Month 3</td>
<td>8%</td>
<td>41%<sup>b</sup></td>
<td></td>
<td></td>
<td>0%</td>
<td>42%<sup>b</sup></td>
<td></td>
<td></td>
<td>24%</td>
<td>29%</td>
</tr>
<tr class="odd">
<td>Month 6</td>
<td>5%</td>
<td>40%<sup>b</sup></td>
<td></td>
<td></td>
<td>3%</td>
<td>39%<sup>b</sup></td>
<td></td>
<td></td>
<td>32%</td>
<td>40%</td>
</tr>
<tr class="even">
<td>Month 12</td>
<td>NA</td>
<td>NA</td>
<td></td>
<td></td>
<td>NA</td>
<td>NA</td>
<td></td>
<td></td>
<td>43%</td>
<td>49%</td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong><u>ACR 70</u></strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Month 3</td>
<td>4%</td>
<td>15%<sup>b</sup></td>
<td></td>
<td></td>
<td>0</td>
<td>15%<sup>b</sup></td>
<td></td>
<td></td>
<td>7%</td>
<td>13%<sup>c</sup></td>
</tr>
<tr class="odd">
<td>Month 6</td>
<td>1%</td>
<td>15%<sup>b</sup></td>
<td></td>
<td></td>
<td>0</td>
<td>15%<sup>b</sup></td>
<td></td>
<td></td>
<td>14%</td>
<td>21%<sup>c</sup></td>
</tr>
<tr class="even">
<td>Month 12</td>
<td>NA</td>
<td>NA</td>
<td></td>
<td></td>
<td>NA</td>
<td>NA</td>
<td></td>
<td></td>
<td>22%</td>
<td>25%</td>
</tr>
<tr class="odd">
<td colspan="11"><p>a. 25 mg ENBREL SC twice weekly.</p>
<ol start="2" type="a">
<li><p>p &lt; 0.01, ENBREL vs. placebo.</p></li>
<li><p>p &lt; 0.05, ENBREL vs. MTX.</p></li>
</ol></td>
</tr>
</tbody>
</table>

Table 6: Percent of Etanercept-Treated Subjects Choosing to Remain on
Treatment

+---------------+---------+------------+--------------+--------------+
| Years of      | Early   | Later RA   | Total        | **Percent**  |
| exposure      | RA      |            |              |              |
|               |         | \(N\)      | \(N\)        | **(%)**      |
|               | \(N\)   |            |              |              |
+---------------+---------+------------+--------------+--------------+
| ≥ 1 yr        | 482     | 606        | 1088         | 81%          |
+---------------+---------+------------+--------------+--------------+
| ≥ 2 yrs       | 433     | 547        | 980          | 73%          |
+---------------+---------+------------+--------------+--------------+
| ≥ 3 yrs       | 295     | 501        | 796          | 52%          |
+---------------+---------+------------+--------------+--------------+
| ≥ 4 yrs       | 245     | 450        | 695          | 52%          |
+---------------+---------+------------+--------------+--------------+

Table 7: Mean Radiographic Change Over 6 and 12 Months in Study III

+-------+------------+-------+--------+---+------------------+----------+
|       |            | MTX   | 25 mg  |   | MTX-ENBREL       | P-value  |
|       |            |       | ENBREL |   |                  |          |
|       |            |       |        |   | (95% Confidence  |          |
|       |            |       |        |   | Interval\*)      |          |
+-------+------------+-------+--------+---+------------------+----------+
| 12    | Total      | 1.59  | 1.00   |   | > 0.59 (-0.12,   | 0.110    |
| M     | Sharp      |       |        |   | > 1.30)          |          |
| onths | score      |       |        |   |                  |          |
+-------+------------+-------+--------+---+------------------+----------+
|       | Erosion    | 1.03  | 0.47   |   | > 0.56 (0.11,    | 0.002    |
|       | score      |       |        |   | > 1.00)          |          |
+-------+------------+-------+--------+---+------------------+----------+
|       | JSN score  | 0.56  | 0.52   |   | > 0.04 (-0.39,   | 0.529    |
|       |            |       |        |   | > 0.46)          |          |
+-------+------------+-------+--------+---+------------------+----------+
|       |            |       |        |   |                  |          |
+-------+------------+-------+--------+---+------------------+----------+
| 6     | Total      | 1.06  | 0.57   |   | > 0.49 (0.06,    | 0.001    |
| M     | Sharp      |       |        |   | > 0.91)          |          |
| onths | score      |       |        |   |                  |          |
+-------+------------+-------+--------+---+------------------+----------+
|       | Erosion    | 0.68  | 0.30   |   | > 0.38 (0.09,    | 0.001    |
|       | score      |       |        |   | > 0.66)          |          |
+-------+------------+-------+--------+---+------------------+----------+
|       | JSN score  | 0.38  | 0.27   |   | > 0.11 (-0.14,   | 0.585    |
|       |            |       |        |   | > 0.35)          |          |
+-------+------------+-------+--------+---+------------------+----------+
|       |            |       |        |   |                  |          |
+-------+------------+-------+--------+---+------------------+----------+
| \*    |            |       |        |   |                  |          |
| 95%   |            |       |        |   |                  |          |
| confi |            |       |        |   |                  |          |
| dence |            |       |        |   |                  |          |
| inte  |            |       |        |   |                  |          |
| rvals |            |       |        |   |                  |          |
| for   |            |       |        |   |                  |          |
| the   |            |       |        |   |                  |          |
| d     |            |       |        |   |                  |          |
| iffer |            |       |        |   |                  |          |
| ences |            |       |        |   |                  |          |
| in    |            |       |        |   |                  |          |
| c     |            |       |        |   |                  |          |
| hange |            |       |        |   |                  |          |
| s     |            |       |        |   |                  |          |
| cores |            |       |        |   |                  |          |
| be    |            |       |        |   |                  |          |
| tween |            |       |        |   |                  |          |
| MTX   |            |       |        |   |                  |          |
| and   |            |       |        |   |                  |          |
| E     |            |       |        |   |                  |          |
| NBREL |            |       |        |   |                  |          |
+-------+------------+-------+--------+---+------------------+----------+

## Remicade Efficacy Summary

The efficacy of Remicade in combination with MTX, for improving the
signs and symptoms of rheumatoid arthritis and for inhibition of
progression of structural damage, was established in the ATTRACT trial
of patients with active rheumatoid arthritis despite treatment with
methotrexate. As shown in Table 8, treatment with Remicade increased the
proportion of patients with ACR20 at 6 and 12 months. Efficacy was seen
with each of the 4 dosing regimens, ranging from 3 mg IV q8w to 10 mg IV
q4w. Similar response rates were seen at 6 months with each of the dose
regimens. However, for patients in the lowest dose group, there was a
trend towards decreasing rates of ACR20 response between 6 months and 1
year. Higher rates of ACR 50 and 70 responses were also seen with
Remicade.

Remicade has also demonstrated efficacy for improvement in physical
function in RA, based on 2-year data from the ATTRACT trial. The
sponsor's primary analysis was the 2-year weighted mean change in HAQ
(Table 9). The means for the weighted mean change in HAQ increased from
0.3 u for patients receiving placebo to 0.4-0.5 for infliximab-treated
patients. The median values for the weighted mean change in HAQ was 0.1
u in the placebo arm and 0.3-0.4 for the 4 infliximab-treated arms. Both
the global differences between treatment arms and each of the pairwise
comparisons between infliximab and placebo were highly statistically
significant. Multiple other analyses of HAQ showed robust and consistent
effects \-- including a sustained improvement in HAQ of ≥0.3 u, a
benefit that exceeds the level of 0.22 u that has been demonstrated to
be clinically meaningful. (see Appendix B, Tables 26-28)

**Table 8: PERCENTAGE OF PATIENTS WHO ACHIEVED AN ACR RESPONSE AT WEEKS
30 AND 54**

+--------------+---+----------+---+----------+---------+---+--------+----------+
|              |   |          |   | **RE     |         |   |        |          |
|              |   |          |   | MICADE + |         |   |        |          |
|              |   |          |   | MTX**    |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+
|              |   |          | 3 |          |         |   | 10     |          |
|              |   |          |   |          |         |   |  mg/kg |          |
|              |   |          | m |          |         |   | ^a^    |          |
|              |   |          | g |          |         |   |        |          |
|              |   |          | / |          |         |   |        |          |
|              |   |          | k |          |         |   |        |          |
|              |   |          | g |          |         |   |        |          |
|              |   |          | ^ |          |         |   |        |          |
|              |   |          | a |          |         |   |        |          |
|              |   |          | ^ |          |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+
| [Response]   | P |          | [ |          | [q 4    |   | [q 8   | [q 4     |
| {.underline} | l |          | q |          | wk      |   | wks]   | wks]{.un |
|              | a |          | 8 |          | s]{.und |   | {.unde | derline} |
|              | c |          | w |          | erline} |   | rline} |          |
|              | e |          | k |          |         |   |        |          |
|              | b |          | s |          |         |   |        |          |
|              | o |          | ] |          |         |   |        |          |
|              |   |          | { |          |         |   |        |          |
|              | [ |          | . |          |         |   |        |          |
|              | + |          | u |          |         |   |        |          |
|              | M |          | n |          |         |   |        |          |
|              | T |          | d |          |         |   |        |          |
|              | X |          | e |          |         |   |        |          |
|              | ] |          | r |          |         |   |        |          |
|              | { |          | l |          |         |   |        |          |
|              | . |          | i |          |         |   |        |          |
|              | u |          | n |          |         |   |        |          |
|              | n |          | e |          |         |   |        |          |
|              | d |          | } |          |         |   |        |          |
|              | e |          |   |          |         |   |        |          |
|              | r |          |   |          |         |   |        |          |
|              | l |          |   |          |         |   |        |          |
|              | i |          |   |          |         |   |        |          |
|              | n |          |   |          |         |   |        |          |
|              | e |          |   |          |         |   |        |          |
|              | } |          |   |          |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+
|              | ( |          | ( |          | (n=86)  |   | (n=87) | (n=81)   |
|              | n |          | n |          |         |   |        |          |
|              | = |          | = |          |         |   |        |          |
|              | 8 |          | 8 |          |         |   |        |          |
|              | 8 |          | 6 |          |         |   |        |          |
|              | ) |          | ) |          |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+
| ACR 20       |   |          |   |          |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+
| Week 30      | 2 |          | 5 |          | 50%     |   | 52%    | 58%      |
|              | 0 |          | 0 |          |         |   |        |          |
|              | % |          | % |          |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+
| Week 54      | 1 |          | 4 |          | 48%     |   | 59%    | 59%      |
|              | 7 |          | 2 |          |         |   |        |          |
|              | % |          | % |          |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+
| ACR 50       |   |          |   |          |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+
| > Week 30    | 5 |          | 2 |          | 29%     |   | 31%    | 26%      |
|              | % |          | 7 |          |         |   |        |          |
|              |   |          | % |          |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+
| > Week 54    | 9 |          | 2 |          | 34%     |   | 40%    | 38%      |
|              | % |          | 1 |          |         |   |        |          |
|              |   |          | % |          |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+
| ACR 70       |   |          |   |          |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+
| > Week 30    | 0 |          | 8 |          | 11%     |   | 18%    | 11%      |
|              | % |          | % |          |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+
| > Week 54    | 2 |          | 1 |          | 18%     |   | 26%    | 19%      |
|              | % |          | 1 |          |         |   |        |          |
|              |   |          | % |          |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+
|              |   |          |   |          |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+
| ^a^ p \<     |   |          |   |          |         |   |        |          |
| 0.05 for     |   |          |   |          |         |   |        |          |
| each outcome |   |          |   |          |         |   |        |          |
| compared to  |   |          |   |          |         |   |        |          |
| placebo      |   |          |   |          |         |   |        |          |
+--------------+---+----------+---+----------+---------+---+--------+----------+

Table 9: Weighted Mean Change from Baseline in HAQ

  --------------------- --------- ------------ --------- ---------- ---------
                                  Infliximab                        

                                  3 mg/kg      3 mg/kg   10 mg/kg   10 mg/kg

                        Placebo   q 8 Wks      q 4 Wks   q 8 Wks    q 4 Wks

                                                                    

  Pts randomized        88        86           86        87         81

                                                                    

  Change from baseline                                              

  through week 102                                                  

  Pts evaluated         88        86           85        87         81

  Mean ± SD             0.3 ± 0.4 0.4 ± 0.3    0.5 ± 0.5 0.5 ± 0.5  0.4 ± 0.4

  Median                0.1       0.4          0.4       0.4        0.3

  IQ range              (0.0,     (0.1, 0.6)   (0.1,     (0.2, 0.9) (0.1,
                        0.4)                   0.7)                 0.5)

  Range                 (0.0,     (0.0, 1.5)   (0.0,     (0.0, 1.7) (0.0,
                        1.6)                   1.7)                 2.2)

  p-value vs placebo              0.006        \< 0.001  \< 0.001   0.002
  --------------------- --------- ------------ --------- ---------- ---------

In the ATTRACT trial, all patients were initially offered one year of
treatment. Of the subjects randomized to receive infliximab, 79% (268 of
340) remained on treatment for the full year. Subjects who completed one
year of treatment were then offered a second year of therapy. Of the 268
who completed the first year, 76% (203 patients) remained on therapy
through the end of the second year. Thus of the 340 patients initially
begun on infliximab, 60% remained on therapy for the full two years.

The ATTRACT trial also assessed inhibition of progression of structural
damage based on the 12-month change in the total Sharp score. As shown
in Table 10, patients in the placebo arm (i.e. receiving background MTX)
experienced a rate of progression of 4 u/yr, while patients in the 4
infliximab arms (receiving MTX plus infliximab) had rates of progression
of between --0.5 and 0.5. The differences between infliximab and placebo
were highly statistically significant. The rates of progression of both
erosion scores and joint space narrowing scores (JSN) were also reduced
in the infliximab arms.

Table 10: **RADIOGRAPHIC CHANGE FROM BASELINE TO WEEK 54**

+-----------+----------+--------+--------+---+--------+---------+------+
| Median    | Placebo  | REMI   |        |   |        |         |      |
|           |          | CADE + |        |   |        |         |      |
| (10, 90   | [+       | MTX    |        |   |        |         |      |
|           | MTX]{.un |        |        |   |        |         |      |
| [percent  | derline} |        |        |   |        |         |      |
| iles)]{.u |          |        |        |   |        |         |      |
| nderline} |          |        |        |   |        |         |      |
+-----------+----------+--------+--------+---+--------+---------+------+
|           |          | 3      |        |   | 10     |         |      |
|           |          |  mg/kg |        |   |  mg/kg |         |      |
+-----------+----------+--------+--------+---+--------+---------+------+
|           |          | [q     | [q 4   |   | [q 8   | [q 4    | [p‑v |
|           |          | 8wks]  | wks]   |   | wks]   | wk      | alue |
|           |          | {.unde | {.unde |   | {.unde | s]{.und | ^a^] |
|           |          | rline} | rline} |   | rline} | erline} | {.un |
|           |          |        |        |   |        |         | derl |
|           |          |        |        |   |        |         | ine} |
+-----------+----------+--------+--------+---+--------+---------+------+
|           | (n=64)   | (n=71) | (n=71) |   | (n=77) | (n=66)  |      |
+-----------+----------+--------+--------+---+--------+---------+------+
| *Total    |          |        |        |   |        |         |      |
| Score*    |          |        |        |   |        |         |      |
+-----------+----------+--------+--------+---+--------+---------+------+
| Baseline  | 55       | 57     | 45     |   | 56     | 43      |      |
|           |          |        |        |   |        |         |      |
|           | (14,     | (15,   | (8,    |   | (6,    | (7,     |      |
|           | 188)     | 187)   | 162)   |   | 143)   | 178)    |      |
+-----------+----------+--------+--------+---+--------+---------+------+
| Change    | 4.0      | 0.5    | 0.1    |   | 0.5    | -0.5    | p\<0 |
| from      |          |        |        |   |        |         | .001 |
| baseline  | (-1.0,   | (-3.0, | (-5.2, |   | (-4.8, | (-5.7,  |      |
|           | 19.0)    | 5.5)   | 9.0)   |   | 5.0)   | 4.0)    |      |
+-----------+----------+--------+--------+---+--------+---------+------+
| *Erosion  |          |        |        |   |        |         |      |
| Score*    |          |        |        |   |        |         |      |
+-----------+----------+--------+--------+---+--------+---------+------+
| Baseline  | 25       | 29     | 22     |   | 22     | 26      |      |
|           |          |        |        |   |        |         |      |
|           | (8, 110) | (9,    | (3,    |   | (3,    | (4,     |      |
|           |          | 100)   | 91)    |   | 80)    | 104)    |      |
+-----------+----------+--------+--------+---+--------+---------+------+
| Change    | 2.0      | 0.0    | -0.3   |   | 0.5    | -0.5    | p\<0 |
| from      |          |        |        |   |        |         | .001 |
| baseline  | (-1.0,   | (-3.0, | (-3.1, |   | (-3.0, | (-2.7,  |      |
|           | 9.7)     | 4.3)   | 2.5)   |   | 2.5)   | 2.5)    |      |
+-----------+----------+--------+--------+---+--------+---------+------+
| *JSN      |          |        |        |   |        |         |      |
| Score*    |          |        |        |   |        |         |      |
+-----------+----------+--------+--------+---+--------+---------+------+
| Baseline  | 26 (3,   | 29 (4, | 20 (3, |   | 24 (1, | 25 (3,  |      |
|           | 88)      | 80)    | 83)    |   | 79)    | 77)     |      |
+-----------+----------+--------+--------+---+--------+---------+------+
| Change    | 1.5      | 0.0    | 0.0    |   | 0.0    | 0.0     | p\<0 |
| from      |          |        |        |   |        |         | .001 |
| baseline  | (-0.8,   | (-2.5, | (-3.4, |   | (-3.0, | (-3.0,  |      |
|           | 8.0)     | 4.5)   | 5.0)   |   | 2.5)   | 3.5)    |      |
+-----------+----------+--------+--------+---+--------+---------+------+
|           |          |        |        |   |        |         |      |
+-----------+----------+--------+--------+---+--------+---------+------+
| ^a^ For   |          |        |        |   |        |         |      |
| co        |          |        |        |   |        |         |      |
| mparisons |          |        |        |   |        |         |      |
| of each   |          |        |        |   |        |         |      |
| dose      |          |        |        |   |        |         |      |
| against   |          |        |        |   |        |         |      |
| placebo   |          |        |        |   |        |         |      |
+-----------+----------+--------+--------+---+--------+---------+------+

Infliximab is also approved for the treatment of Crohn's Disease.

#  {#section .unnumbered}

# SAFETY REVIEW OF TNF BLOCKING AGENTS

## General 

An extensive update of the safety experience with Enbrel and Remicade
was provided to the AAC at the August 17, 2001 meeting. The update
focused on the following serious events that were observed during
postmarketing experience with either or both products: demyelinating
disease, seizures, aplastic anemia, intestinal perforation, cutaneous
lupus rash, tuberculosis and other opportunistic infections, and
lymphomas. The August 2001 briefing document is provided in appendix C.
The more recent post-marketing experience with Remicade and Enbrel in
the RA population has not resulted in new types of adverse events, and
controlled clinical trial experience for new indications (e.g.,
psoriatic arthritis) in general have not resulted in new findings,
though two exceptions deserve more discussion: safety findings in
patients with congestive heart failure (CHF) and cases of hepatic
toxicity in patients with Crohn's disease receiving Remicade for long
term maintenance. A more comprehensive review of all cases of lymphomas
associated with the TNF blocking therapies will be presented in section
V, following the safety review of Humira.

## CHF 

Promising data from animal models of CHF and elevated levels of TNF-α
observed in patients with CHF led to the conduct of clinical trials of
TNF-blockers in CHF. Two large pivotal trials of etanercept, termed
RECOVER and RENAISSANCE, were begun but were halted early because of
lack of improvement with treatment (see appendix D for full study
report).

Subsequently, the FDA reviewed the AERS database for post-marketing
reports of CHF with etanercept and infliximab. The search revealed 51
reports of CHF among patients receiving TNF blockers, of whom 30 were
receiving etanercept and 21 were receiving infliximab. Half the cases
had a documented history of risk factors for CHF, including myocardial
infarction, coronary heart disease, hypertension, diabetes, or pulmonary
disease. The median interval from the first dose of TNF antagonists to
CHF diagnosis or worsening was 3.5 months. Three patients died from CHF.
The cases included 10 patients aged \< 50 years old. Three of these 10
had risk factors for CHF. Echocardiography demonstrated a median
ejection fraction of 20% for 9 of these patients. All patients
discontinued TNF-blocking agents when CHF was diagnosed. Three had
complete resolution of CHF; 6 partially improved with therapy and one
died. CHF -- Remicade

Centocor investigated the use of infliximab in a phase 2 trial in NYHA
class III or IV CHF. Patients were randomized to receive placebo or
infliximab 5 or 10 mg/kg at 0, 2 and 6 weeks. No improvement was seen in
the clinical status of patients at 14 weeks with

infliximab. The study was stopped early for safety reasons when an
increased incidence of mortality and hospitalization for worsening heart
failure was observed in infliximab-treated patients, particularly those
treated at the higher dose. A Dear Doctor letter was issued warning
clinicians not to start infliximab in patients with CHF (see appendix E
for full study report).

As described above, a search of the AERS database revealed
post-marketing reports of CHF with infliximab. Some cases occurred in
patients under 50 years of age.

## Hepatoxicity - Remicade 

In the ATTRACT trial of infliximab used in combination with
methotrexate, elevations in transaminases (AST or ALT) were observed
more frequently than in patients receiving methotrexate alone. The
elevations observed were mild (\<2 times the upper limit of normal) or
moderate (≥ 2 times the upper limit of normal but \< 3 times the upper
limit of normal). These findings are reported in the package insert.

Elevations in transaminases were also observed in the ACCENT I trial of
Crohn's Disease, a study to evaluate the safety and efficacy of
maintenance Remicade. In this trial, 190 patients/arm received
infliximab 5 mg/kg initially and were then randomized to receive
maintenance with placebo or infliximab 5 or 10 mg/kg every 8 weeks.
Patients were receiving concomitant treatment with a variety of
immunomodulatory agents, including 6-MP, methotrexate or mycophenolate
mofetil. Most were not receiving methotrexate. Review of the ACCENT I
trial showed that patients randomized to receive 5 or 10 mg/kg
infliximab maintenance treatment were more likely to have moderate
elevations in AST than placebo-treated patients (8 in placebo arm, 14 in
5 mg/kg infliximab arm, 10 in 10 mg infliximab arm). None of the
patients with elevations in AST or ALT developed clinical liver
impairment. These data suggest that use of infliximab is associated with
mild to moderate elevations of transaminases even when used without
concomitant methotrexate.

## Humira Safety Review

The International Conference on Harmonisation Guidance document entitled
E1:"The Extent of Population Exposure Required to Assess Clinical Safety
for Drugs Intended for Long Term Treatment of Non-life-threatening
Conditions" sets forth a minimum set of standards for safety
evaluation[^1]. It recommends a minimum duration of exposure of at least
300-600 patients treated for at least 6 months and at least 100 treated
for 1 year, and a total exposure (at any dose) of approximately 1500
patients. At the end of Phase 2 meeting for adalimumab, CBER recommended
that the sponsor acquire a safety database larger than stated above to
be able to provide better estimates of adverse events related to the
potentially immunosuppressive properties of the product. The Agency
recommended that the sponsor study concomitant exposure with DMARDs and
other treatments typically used in clinical practice, and that the
safety data-base consist at least 1000 patients treated with the
recommended dose for at least one year. As a result of this shift in
thinking about extent of safety data at the time of a BLA, the Humira
safety database was larger than the safety databases available at the
time of approval for the other two TNF blocking agents and considerably
larger than the minimum ICH recommendations. The pre-marketing
experience included a total of 2334 patients; 2073 exposed for 6 months
and 1497 exposed for greater than one year. Humira was studied primarily
in placebo-controlled trials and in long-term follow up studies for up
to 36 months duration. Most patients received the recommended dose of 40
mg HUMIRA every other week.

The analysis of this safety database poses some specific challenges
given that 1) most of the patient exposure is from open-label extension
studies that lacked a concurrent control and 2) some serious events are
expected in the patient population under study, including some deaths,
serious infections, lymphomas, and other malignancies. The possible role
of adalimumab in increasing the risk of these events was assessed in a
number of ways including: a) comparison of event rates vs. placebo; b)
comparison to epidemiologic databases; c) examination of event rates as
a function of duration of exposure to adalimumab.

Table 11 summarizes events reported at a rate of at least 5% in patients
treated with HUMIRA 40 mg every other week compared to placebo and with
an incidence higher than placebo. Adverse event rates in patients
treated with HUMIRA 40 mg weekly were similar to rates in patients
treated with HUMIRA 40 mg every other week.

Table 11: Adverse Events Reported by ≥5% of Patients Treated with HUMIRA
During Placebo-Controlled Period of Rheumatoid Arthritis Studies

  --------------------------------- ------------------ ------------------
                                    HUMIRA             Placebo

                                    40 mg subcutaneous 

                                    Every Other Week   

                                    (N=705)            (N=690)

  Adverse Event (Preferred Term)    Percentage         Percentage

                                                       

  Respiratory                                          

  Upper respiratory infection       17                 13

  Sinusitis                         11                 9

  Flu syndrome                      7                  6

                                                       

  Gastrointestinal                                     

  Nausea                            9                  8

  Abdominal pain                    7                  4

                                                       

  Laboratory Tests\*                                   

  Laboratory test abnormal          8                  7

  Hypercholesterolemia              6                  4

  Hyperlipidemia                    7                  5

  Hematuria                         5                  4

  Alkaline phosphatase increased    5                  3

                                                       

  Other                                                

  Injection site pain               12                 12

  Headache                          12                 8

  Rash                              12                 6

  Accidental injury                 10                 8

  Injection site reaction\*\*       8                  1

  Back pain                         6                  4

  Urinary tract infection           8                  5

  Hypertension                      5                  3
  --------------------------------- ------------------ ------------------

\* Laboratory test abnormalities were reported as adverse events in
European trials

\*\* Does not include erythema and/or itching, hemorrhage, pain or
swelling

The most common adverse events associate with Humira included
mild-moderate injection site reactions and non-serious infections. In
the placebo-controlled trials, the rate of infection was 5 per patient
year in the HUMIRA treated patients and 4 per patient

year in the placebo-treated patients. The infections consisted primarily
of upper respiratory tract infections, bronchitis and urinary tract
infections. Most patients continued on Humira after the infection
resolved.

Serious adverse events include infections, malignancies, demyelinating
events, and lupus-like events. These types of events have been
previously described in the safety update in August 2001 for the other
TNF-blocking therapies.

### Serious Infections

The incidence of serious infections was 0.04 per patient year in HUMIRA
treated patients and 0.02 per patient year in placebo-treated patients.
The most common organs affected by serious infections among
adalimumab-treated patients were pulmonary, musculoskeletal, skin,
gastrointestinal, and genitourinary. Skin, musculoskeletal and urinary
infections were among those infections most frequently associated with
sepsis. The rate of serious infections did not increase with the longer
durations of exposure in the open label extension trials. Two patients
died and 13 patients withdrew from studies as a result of serious
infections. The serious infections observed included pneumonia, septic
arthritis, prosthetic and post-surgical infections, erysipelas,
cellulitis, diverticulitis, and pyelonephritis. The label includes a
bolded warning about not initiating Humira in patients with active
infections and caution with a history of recurrent infection or
predisposition to infection.

For both adalimumab and placebo-treated patients, the rate of serious
infections and deaths due to serious infections were lower among
patients \<65 years of age. Increasing age among adalimumab-treated
patients was associated with an increased occurrence of malignancies,
SAEs, AEs leading to withdrawals, and AEs resulting in dose interruption
compared to age-matched placebo-treated patients. The percentage of
patients with fatal AEs, which only occurred in the adalimumab--treated
group, was also higher with advancing age.

Thirteen cases of tuberculosis (TB), including miliary, lymphatic,
peritoneal, and pulmonary were reported in clinical trials. Most of the
cases of tuberculosis occurred within the first eight months after
initiation of therapy and may reflect recrudescence of latent disease.
Implementation of pre-treatment screening at the end of phase I with
intradermal PPD in the US, chest x-rays in Europe, and appropriate
prophylactic anti-tuberculosis treatment in accordance with CDC
Guidelines, was associated with a marked reduction in the rate of active
TB. However, other variables may have also contributed to the lower rate
of TB later in the clinical development program, including less exposure
to higher doses of adalimumab and possibly recruitment of fewer patients
at high risk of latent TB infection. While cases were observed at all
doses, the incidence of tuberculosis reactivations was particularly
increased at doses of Humira that were higher than the recommended dose.
All patients recovered after standard antimicrobial therapy. No deaths
due to tuberculosis occurred during the clinical trials. The label
includes a box

warning for patients to be evaluated for active or latent tuberculosis
infection with a tuberculin skin test prior to initiating treatment and,
if latent infection is diagnosed, appropriate prophylaxis in accordance
with the Centers for Disease Control and Prevention guidelines. The
label also recommends that patients be instructed to seek medical advice
if signs/symptoms (e.g., persistent cough, wasting/weight loss, low
grade fever) suggestive of a tuberculosis infection occur. In addition
to TB, six cases of invasive opportunistic infections caused by
histoplasma, aspergillus, and nocardia were also reported in clinical
trials.

### Malignancies

Among 2468 rheumatoid arthritis patients treated in clinical trials with
Humira for a median of 24 months, 48 malignancies of various types were
observed, including 10 patients with lymphoma. The Standardized
Incidence Ratio (SIR) (ratio of observed rate to age-, gender- and
race-adjusted expected frequency in the general population) for
malignancies was 1.0 (95% CI, 0.7, 1.3) and for lymphomas was 5.4 (95%
CI, 2.6, 10.0). An increase of up to several fold in the rate of
lymphomas has been reported in the rheumatoid arthritis patient
population, and may be further increased in patients with more severe
disease activity. [^2]^,^[^3] The other malignancies observed during use
of Humira were breast, colon-rectum, uterine-cervical, prostate,
melanoma, gallbladder-bile ducts, and other carcinomas. A more
comprehensive review of malignancies with particular emphasis on the
incidence of lymphoma, is discussed in section V.

### Demyelinating Events

Three cases of possible demyelinating disease were observed during the
clinical development program of adalimumab. One patient presented with
optic neuritis; one with paresthesias and one with lower extremity
numbness. Demyelinating disease has been observed in studies of many TNF
blockers, including etanercept, infliximab, and lenercept (see article
by Mohan *et al* in attachments). Two of the 3 subjects had complete
recovery, the other has residual leg numbness.

### Autoantibodies and Lupus Like Syndrome

In the controlled trials, 12% of patients treated with HUMIRA and 7% of
placebo-treated patients that had negative baseline ANA titers developed
positive titers at week 24. One patient out of 2334 treated with HUMIRA
developed clinical signs suggestive of new-onset lupus-like syndrome.
The patient improved following discontinuation of therapy. No patients
developed lupus nephritis or central nervous system symptoms. The impact
of long-term treatment with HUMIRA on the development of autoimmune
diseases is unknown. A few cases of isolated skin rash and serositis
with positive serologies were seen. A worldwide search of the safety
database (reported November 26, 2002) revealed sketchy descriptions of 4
cases of pleural effusion, 3 cases of pericarditis, and 1 case of
pericarditis and pleuritis among adalimumab-treated patients. Several of
these cases were evaluated for drug-induced lupus erythematosus, but no
evidence was found.

# Long-Term Safety

## Mortality

### Adalimumab

Eight patients (7 treated with adalimumab and 1 treated with placebo)
died as a result of AEs during the controlled portions of the randomized
trials. However, considerably more patients were treated with adalimumab
than with placebo in the controlled trials. Correcting for the different
exposures, deaths were calculated to have occurred at a rate of 0.3/100
patient-years (CI, 0.23, 0.82) among placebo-treated patients, 0.9/100
patient-years (CI, 0.23, 1.55) among all adalimumab-treated patients,
and 1.3/100 patient-years (CI, 0.16, 2.35) among patients receiving the
proposed recommended dose. Twenty-four deaths were observed overall
among the adalimumab-treated patients in the clinical development
program. Since the trials included a significant number of older
patients, 22% age 65 to 75 and 5% over age 75, some deaths were
expected. Even though the majority of patients enrolled in these studies
were females, the majority of the deaths occurred in male subjects. No
predominant cause of death was observed. The categories of deaths were
cardiovascular (7), malignancy (6), infections (5), gastrointestinal
(3), and respiratory, trauma, and hepatic necrosis (1 each).

Since most of the patient exposure was from open-label extension
studies, there are no concurrent controls for comparison. To provide an
estimate as to whether the mortality rate is higher than expected, the
mortality rate was compared to that predicted based on sex and
age-matched rates in the general US population. Determination of the
Standardized Mortality Rate (SMR) for comparison of the observed death
rate to the age-adjusted expected frequency of deaths for the whole
group of Humira-treated patients was 0.72 \[CI, 0.46, 1.05\]. These
data, based on relatively short-term exposure, do not indicate a higher
death rate with Humira treatment.

###  {#section-1 .unnumbered}

### 2. Etanercept {#etanercept .unnumbered}

Safety and efficacy data were recently reviewed by the agency for
patients treated with etanercept in long-term open-label clinical trials
for three years. As shown in Table 12, 546 patients have received
etanercept for at least 3 years and 427 for 4 years. A total of 14
deaths were observed in the clinical trials safety database. Of these, 5
(36%) were cardiovascular in nature, 4 (29%) were related to
malignancies, 2 (14%) were infectious, 1 (7%) was pulmonary and 2 (14%)
were unclassified (Table 13). Since there is no concurrent control
group, historical data were obtained from the Olmsted County database of
RA patients for comparison. As shown in Table 14, the percent of
patients dying of cardiovascular, infectious and pulmonary causes were
similar. A lower proportion of deaths were related to malignancies in
the Olmsted County database (10%) than in the etanercept database (29%).

To determine how the number of deaths observed in the etanercept
database compared with the number expected for a group of adults in the
general population, the expected number of deaths was calculated using
the National Vital Statistics Report (Kochanek, 2001) adjusting for age
and sex (Table 15). For all adults in the database, as well as for
adults participating in the MTX combination trial and for the children
with JRA, the observed number of deaths was lower than the expected
rate. No trends were seen to indicate an increase in the death rate with
longer exposure to etanercept.

Table 12: Duration of treatment of patients being following in
etanercept long-term safety studies

![](media/image2.png){width="5.9875in" height="2.9444444444444446in"}

Table 13: Deaths occurring among all adults in the long-term database

![](media/image3.png){width="5.429166666666666in"
height="4.753472222222222in"}

Table 14: Mortality in the etanercept long-term database compared to
population-based database

+--------------+--------------------------+----------------------------+
| Cause of     | Etanercept long-term     | Olmsted County MN database |
| death        | database                 |                            |
|              |                          | 279 deaths / 6350          |
|              | 14 deaths / 1819         | patient-years              |
|              | patient-years            |                            |
+--------------+--------------------------+----------------------------+
| Ca           | 36%                      | 39%                        |
| rdiovascular |                          |                            |
+--------------+--------------------------+----------------------------+
| Malignancy   | 29%                      | 10%                        |
+--------------+--------------------------+----------------------------+
| Infectious   | 14%                      | 15%                        |
+--------------+--------------------------+----------------------------+
| Pulmonary    | 7%                       | 11%                        |
+--------------+--------------------------+----------------------------+
| Cer          | 0%                       | 9%                         |
| ebrovascular |                          |                            |
+--------------+--------------------------+----------------------------+
| Other        | 14%                      | 16%                        |
+--------------+--------------------------+----------------------------+

Table 15: Expected number of deaths in the general population compared
to observed number of deaths in etanercept long-term database

![](media/image4.png){width="5.363194444444445in"
height="1.3763888888888889in"}

### Infliximab

Eleven deaths occurred during the 2 years of the ATTRACT trial: 4 deaths
in the placebo arm and 3, 2, 1 and 1 in the 3 mg/kg q8wk and q4wk and 10
mg/kg q8wk and q4wk arms, respectively. Three deaths occurred in the
second year of the study: 1 on placebo and 2 on infliximab. One death on
infliximab was due to a ruptured abdominal aortic aneurysm. The other
was a patient who developed a pneumothorax after their week-86 dose of
infliximab. The patient had a chest tube inserted, but developed a
bronchopleural fistula requiring surgical repair. He subsequently
developed ARDS and sepsis.

## Other Long-Term Safety Data

### Etanercept

As stated above, the FDA recently reviewed 3-year data from open-label
follow-up studies on patients receiving continued treatment with
etanercept. The 3-year data included 85 RA patients from a study of
methotrexate co-administration, 628 adult RA patients from other studies
involving etanercept monotherapy and 69 pediatric patients receiving
etanercept monotherapy from the JRA trial. The data on patients taking
etanercept for 3 years do not indicate any new safety concerns beyond
those identified at the time of initial approval and through spontaneous
post-marketing reports. In particular, there was no evidence of
increased mortality, or increases in the rate of malignancies compared
to the general population. Serious infections were observed, but the
rate is within the range reported in RA populations not receiving
etanercept. No increase was seen in the rate of SAEs, malignancies or
serious infections with increased duration of exposure.

### Infliximab

The agency recently reviewed safety data from the second year of the
ATTRACT trial. The rate of SAEs was similar in the infliximab and
placebo arms (29% vs. 33%, respectively). When SAEs that could be
ascribed to rheumatoid arthritis were excluded, there were 10 other SAEs
in the placebo arm, compared to 17, 7, 13, and 8 in the 4 infliximab
arms. The major non-RA-related category of SAE in the placebo arm was
infections, which accounted for 5 of 14 SAEs, compared to 3/17, 3/7,
4/13 and 2/8 in the 4 infliximab arms. Malignancies represented 2 of the
patients with SAEs in the placebo arm and 1, 0, 3 and 1 in each of the 4
infliximab arms. No other patterns of increase in individual SAEs were
observed in the infliximab-treated patients and no patterns of increase
in any category of SAEs were noted. No dose-related pattern of increase
in SAEs was observed with infliximab.

The number of patients experiencing an infection that required treatment
with antibiotics was analyzed. The duration of follow-up was 29% longer
for infliximab-treated patients than for those receiving placebo.
Overall the incidence of infections requiring antibiotics was 43% for
patients receiving placebo and 60% for those receiving infliximab, a 39%
higher rate. Infections occurring more frequently among
infliximab-treated patients than controls included sinusitis (12% vs.
6%), urinary tract infection (12% vs. 8%), pharyngitis (85 vs. 4%),
infection not-otherwise specified (6% vs. 2%), pneumonia (4% vs. 2%),
and cellulitis (4% vs. 1%). An analysis of the occurrence of treated
infections over time did not indicate that the incidence of infections
increased with longer durations of treatment.

Serious infections were defined as those which constituted a definite
hazard to the patient and included vital organ-system dysfunction or
physicochemical impairment that was irreversible or required treatment.
Any fatal, life-threatening, severely or permanently disabling infection
was categorized as serious as were any that led to initial or prolonged
hospitalization. Similar proportions of subjects developed serious
infections in placebo- and infliximab-treated groups during the 2 years
of the ATTRACT trial. No specific serious infection appeared at a
clearly higher frequency in infliximab-treated patients. Because of the
limited number of patients followed in the ATTRACT trial, one cannot
make definite conclusions about whether infliximab treatment is
associated with an increase in serious infections.

# MALIGNANCIES INCLUDING LYMPHOMAS 

## General comments/Considerations for labeling

Lymphomas have been observed in clinical trials of patients receiving
each of the approved TNF blocking agents. As more long-term data have
accumulated, it has become possible to calculate observed and expected
rates based on large databases in the general population to determine
the relative frequency of lymphomas in the treated population.
Standardized incidence ratios (SIRs) for lymphoma for each of the
approved TNF blocking agents are higher than that in the general
population. Interpretation of the comparative rates of lymphoma with the
TNF blocking agents is complicated by the observation in several reports
of approximately 2-fold higher lymphoma rates in the general RA
population. In addition, several reports have indicated that patients
with higher levels of disease activity/inflammation have several-fold
higher rates of lymphoma.[^4]^,^[^5] A 4-5 fold increased rate of
lymphoma has been observed in patients with moderately active RA and
higher rates in patients with highly active disease. Most of the
patients enrolled in trials of the TNF blocking agents had highly active
disease.

Since the standardized incidence ratio for lymphoma seen in the trials
of TNF blocking agents is in the range of that seen for patients with
the level of disease activity who enrolled in trials of TNF blockers, it
could be argued that the rates of lymphoma are not higher than expected.
However, the patient population for the two epidemiologic studies of
lymphoma incidence in RA patients with active disease is not identical
to the population in the trials of TNF blockers. Also the data collected
in those epidemiologic studies was from an earlier time when background
lymhoma rates were different and standard treatment of RA was different.

Because of the uncertainties surrounding the calculation of the expected
rate of lymphoma in the RA population studied in the trials of
adalimumab, the agency asked Abbott to include in the Humira label 1)
the number of lymphomas and malignancies seen; 2) the standardized
incidence ratio of malignancies and lymphomas compared to the general
population; 3) information on the estimates of lymphoma rates in RA
patients and in RA patients with highly active disease. The agency is
considering including similar language with analogous information in the
labels of the other approved TNF blocking agents as well as for other
potentially immunosuppressive biologic agents for RA where lymphomas
have been observed.

## Etanercept

To address the issue of the risk of lymphoma in patients receiving
etanercept, the agency recently reviewed all the data on cases of
lymphoma in patients in clinical trials and in post-marketing reports.
Lymphomas have been observed in rheumatoid arthritis patients receiving
etanercept. Among 3389 patients representing 7364 pt-yrs a total of 9
cases of lymphomas including 3 Hodgkin's diseases and 6 non Hodgkin's
lymphomas (NHL) have been reported from patients received one or more
doses of etanercept with median exposure of 2.2 years in either the
clinical trials or extension studies as of August, 2002. Of these 9
cases, 6 were observed in patients in clinical trials receiving
treatment with etanercept or during the prespecified follow-up period
following completion of their participation in the trial. An additional
3 cases were reported after the follow-up period. Two developed lymphoma
2 and 9 months after discontinuation of etanercept. The second of these
patients had received azathioprine for 9 months before lymphoma onset.
The third cases was a patient initially diagnosed with large granular
lymphocytic leukemia after 2 doses of etanercept.

If the number of 6 lymphomas is used in the calculations, then the
standardized incidence ratio (SIR) for lymphoma in etanercept RA trials
is 2.31 (expected =2.6, 95% CI 0.85, 5.03). If the larger number of 9
lymphomas is used, then an SIR of 3.47 is obtained (expected =2.6, 95%
CI 1.59, 6.59). The SIR is calculated from incident cases in the trials
divided by the expected incidence in the general population for an age,
gender and race- matched cohort, not a non-etanercept RA population. The
majority of population-based epidemiological analyses indicates that
patients with RA have a higher incidence of lymphoma compared to the
general population. The estimated risk of developing lymphoma in
patients with RA is reported in the range of 1.5 to 8.7 fold compared to
the general population. The observed SIR of 2.3-3.5 seen in etanercept
RA clinical trials falls within this range.

The characteristics of the 8 cases of lymphoma are as follows:

-   3 Hodgkin's disease and 5 NHL

-   Mean age 66.

-   4 are male and 4 are female.

-   Mean time to onset is 630 days (range, 4 days to 1403 days)

-   The majority of etanercept RA patients who developed lymphoma had
    significant disease activity prior to etanercept therapy.

The point estimate of the proportion of patients with Hodgkin's disease
from clinical trials is greater than expected, but the small number
(1-3) is associated with very broad confidence intervals.

­The number of lymphomas from post-marketing adverse event reports
through November 2, 2002 (4 years after initial product approval) is 70
(representing an estimated 205,923 pt-yrs in the US and 20,055 pt-yrs in
non U.S.). This yields a reporting rate of 0.03/100 pt-yrs. The expected
rate in the general population is 0.03 cases/100 pt-yrs (based on the
NCI/SEER database, 2001, adjusted for the age and gender distribution of
etanercept patients. It must be taken into account that the observed
reporting rate of 0.03/100 pt-yrs represents an underestimate of the
true incidence because of underreporting. The degree of underreporting
is unknown.

-   The mean age of patients receiving etanercept is 52 years with 50%
    receiving concurrent corticosteroids and 65% receiving concurrent
    methotrexate.

-   The median age of patients diagnosed with lymphoma while receiving
    etanercept is 61+/- 11 years (S.D.).

-   Majority of the patients with lymphomas are female (69%).

-   The average duration of treatment with etanercept at time of
    diagnosis of lymphoma is 14+/- 12 months (S.D.) (range 0.5 to 42
    months).

-   The time to onset ranges from 1.4 to 39.5 months without a distinct
    pattern emerging with analysis of different histological subtypes.

-   The most common indication for use of etanercept is RA (83%). Others
    include psoriatic arthritis, Still's disease and lupus.

-   Of patients with lymphoma, 60% have a history of concurrent or past
    exposure to methotrexate, 13% had received past or concomitant
    therapy with azathioprine, infliximab, or cyclosporine.

-   Most lymphomas are non-Hodgkin's lymphomas (NHL, 90%); 10% are
    Hodgkin's disease.

Among NHL cases, histology indicated: diffuse large B cell 44%; mantle
6%; peripheral T cell 8%; T cell chronic lymphocytic
leukemia/polylymphocytic leukemia 8%; follicular 11%; small lymphocytic
lymphoma/B cell chronic lymphocytic leukemia 17%; Waldenstrom's
macroglobulinemia 6%.

## Infliximab

The FDA recently reviewed all the reports of malignancies, including
lymphomas in the clinical trial experience with infliximab. In the
clinical development program up to and including the ATTRACT trial, 555
patients were observed in the studies in RA. Four cases of lymphoma were
observed in the RA patients and two in trials of Crohn's Disease
patients. Recently Centocor has completed a one year treatment phase of
the ASPIRE trial in early RA patients. The trial is still blinded. A
total of 1050 patients are enrolled in the ASPIRE trial, randomized to
receive placebo or infliximab in addition to background methotrexate. No
lymphomas have been observed in the ASPIRE trial.

A standardized incidence ratio for lymphomas and malignancies was
calculated as shown in Table 16. Because the ASPIRE trial has not been
unblinded, a worst-case-scenario was used to calculate the malignancy
rate, where all were attributed to infliximab. As shown in the table,
the SIR for malignancies did not exceed "1" for all RA patients.
However, the SIR for lymphomas was 6.35, with a lower limit of the 95%
confidence interval that excluded 1. The SIR for lymphoma was 8.7 for
Crohn's Disease patients.

Limited data are available for placebo-treated patients (Table 17). No
lymphomas were observed among the 430 placebo-treated subjects, although
the expected number based on the general US population was only 0.14. In
comparing the rate of lymphomas in infliximab-treated and
placebo-treated patients it should be kept in mind that the number of
patients observed on placebo were considerably smaller and the median
duration of exposure was relatively short.

Table 16: Malignancies in infliximab-treated patients in clinical
trials, adjusted for age, gender and race

+--------+----+-------+-------+----------+-------+-------+---+------+
| **     | N  | **    | **M   | **Mali   | **    | **    | * | SIR  |
| Popula |    | Total | edian | gnancy** | Obser | Expec | * | 95%  |
| tion** |    | Subje | Subje |          | ved** | ted** | S |      |
|        |    | ct-** | ct-** |          |       |       | I | *    |
|        |    |       |       |          | **    | **    | R | *Con |
|        |    | **    | **    |          | No.** | No.** | * | f.** |
|        |    | Yrs** | Yrs** |          |       |       | * |      |
|        |    |       |       |          | **ca  | **Ca  |   | **I  |
|        |    | **F   | **F   |          | ses** | ses** |   | nter |
|        |    | ollow | ollow |          |       |       |   | val^ |
|        |    | -up** | -up** |          |       |       |   | a^** |
+--------+----+-------+-------+----------+-------+-------+---+------+
| All    | 24 | 4148  | 1.00  | Lymphoma | 6     | .86   | 6 | \[2  |
| S      | 21 |       |       |          |       |       | . | .56, |
| tudies |    |       |       |          |       |       | 9 | 15.  |
|        |    |       |       |          |       |       | 8 | 19\] |
+--------+----+-------+-------+----------+-------+-------+---+------+
|        |    |       |       | All      | 27    | 23.55 | 1 | \[0  |
|        |    |       |       |          |       |       | . | .76, |
|        |    |       |       | Maligna  |       |       | 1 | 1.   |
|        |    |       |       | ncies^b^ |       |       | 5 | 67\] |
+--------+----+-------+-------+----------+-------+-------+---+------+
| All CD | 11 | 1     | 1.37  | Lymphoma | 2     | .23   | 8 | (1   |
|        | 06 | 646.2 |       |          |       |       | . | .05, |
| S      |    |       |       |          |       |       | 7 | 31.  |
| tudies |    |       |       |          |       |       | 0 | 41\] |
+--------+----+-------+-------+----------+-------+-------+---+------+
|        |    |       |       | All      | 10    | 4.84  | 2 | \[0  |
|        |    |       |       |          |       |       | . | .99, |
|        |    |       |       | Maligna  |       |       | 0 | 3.   |
|        |    |       |       | ncies^b^ |       |       | 7 | 80\] |
+--------+----+-------+-------+----------+-------+-------+---+------+
| All RA | 12 | 2458  | 0.8   | Lymphoma | 4     | 0.63  | 6 | \[1  |
|        | 98 |       |       |          |       |       | . | .73, |
| S      |    |       |       |          |       |       | 3 | 16.  |
| tudies |    |       |       |          |       |       | 5 | 26\] |
+--------+----+-------+-------+----------+-------+-------+---+------+
|        |    |       |       | All      | 17    | 18.62 | 0 | \[0  |
|        |    |       |       |          |       |       | . | .53, |
|        |    |       |       | Maligna  |       |       | 9 | 1.   |
|        |    |       |       | ncies^b^ |       |       | 1 | 46\] |
+--------+----+-------+-------+----------+-------+-------+---+------+

^a^Confidence intervals based on exact method

^b^All malignancies includes lymphomas and excludes nonmelanoma skin
cancers, which are not included in the SEER database.

Table 17: Malignancies in placebo-treated patients in clinical trials,
adjusted for age, gender and race

+--------+----+-------+-------+----------+-------+-------+---+------+
| **     | n  | **    | **M   | **Mali   | **    | **    | S | SIR  |
| Popula |    | Total | edian | gnancy** | Obser | Expec | I | 95%  |
| tion** |    | Subje | Subje |          | ved** | ted** | R |      |
|        |    | ct-** | ct-** |          |       |       |   | *    |
|        |    |       |       |          | **    | **    |   | *Con |
|        |    | **    | **    |          | No.** | No.** |   | f.** |
|        |    | Yrs** | Yrs** |          |       |       |   |      |
|        |    |       |       |          | **ca  | **Ca  |   | **I  |
|        |    | **F   | **F   |          | ses** | ses** |   | nter |
|        |    | ollow | ollow |          |       |       |   | val^ |
|        |    | -up** | -up** |          |       |       |   | a^** |
+--------+----+-------+-------+----------+-------+-------+---+------+
| All    | 4  | 691   | 0.32  | Lymphoma | 0     | 0.15  | 0 | \[   |
| S      | 89 |       |       |          |       |       |   | NC\] |
| tudies |    |       |       |          |       |       |   |      |
+--------+----+-------+-------+----------+-------+-------+---+------+
|        |    |       |       | All      | 4     | 4.31  | 0 | \[0  |
|        |    |       |       |          |       |       | . | .25, |
|        |    |       |       | Maligna  |       |       | 9 | 2.   |
|        |    |       |       | ncies^b^ |       |       | 3 | 38\] |
+--------+----+-------+-------+----------+-------+-------+---+------+
| All CD | 56 | 95    | 2.45  | Lymphoma | 0     | 0.01  | 0 | NC   |
|        |    |       |       |          |       |       |   |      |
| S      |    |       |       |          |       |       |   |      |
| tudies |    |       |       |          |       |       |   |      |
+--------+----+-------+-------+----------+-------+-------+---+------+
|        |    |       |       | All      | 2     | 0.19  | 1 | \[1  |
|        |    |       |       |          |       |       | 0 | .27, |
|        |    |       |       | Maligna  |       |       | . | 38.  |
|        |    |       |       | ncies^b^ |       |       | 5 | 02\] |
|        |    |       |       |          |       |       | 2 |      |
+--------+----+-------+-------+----------+-------+-------+---+------+
| All RA | 4  | 590   | 0.32  | Lymphoma | 0     | 0.14  | 0 | NC   |
|        | 30 |       |       |          |       |       |   |      |
| S      |    |       |       |          |       |       |   |      |
| tudies |    |       |       |          |       |       |   |      |
+--------+----+-------+-------+----------+-------+-------+---+------+
|        |    |       |       | All      | 2     | 4.10  | 0 | \[0  |
|        |    |       |       |          |       |       | . | .06, |
|        |    |       |       | Maligna  |       |       | 4 | 1.   |
|        |    |       |       | ncies^b^ |       |       | 9 | 76\] |
+--------+----+-------+-------+----------+-------+-------+---+------+

^a^Confidence intervals based on exact method

^b^All malignancies includes lymphomas and excludes nonmelanoma skin
cancers, which are not included in the SEER database.

## Adalimumab

In this clinical development program, malignancies (Table 18) were
observed at frequency rates approximating the expected rate in the
general population. The Standardized Incidence Ratio (SIR) was 1.00
\[95% CI, 0.7, 1.3\] (standard ratio of observed rate to age-adjusted
expected frequency) except for neoplasms of the immune system which were
observed at a greater rate than expected (Table 19). A total of ten
lymphomas, primarily Non Hodgkin's lymphoma, was observed in patients
treated with adalimumab. The observed SIR for all lymphomas was 5.4 (95%
CI, 2.6, 10.0) compared to the general population. The increased
incidence of lymphomas observed among these adalimumab-treated patients
raised concerns about whether adalimumab increases the risk of
development of lymphomas. Published literature suggests that RA patients
have an approximately 2-fold higher risk of lymphoma than the general
population.[^6] Furthermore, RA patients with highly active disease have
an even greater risk of lymphomas, in the same range as the SIR reported
for adalimumab-treated patients.[^7] Analysis of the time-to-onset of
the cases of lymphoma seen with adalimumab did not provide evidence of a
relationship to duration of adalimumab therapy (Table 20).

Table 18: Cancer Incidence Analysis in Clinical Development Program

+------------------+----------------+----------------+----------------+
| **Cancer Site**  | **Observed in  | **Observed     | **Observed     |
|                  | BLA ^1^**      | in**           | in**           |
|                  |                |                |                |
|                  |                | **Interim**    | **Final Safety |
|                  |                |                | Update ^3^**   |
|                  |                | **Safety       |                |
|                  |                | Update ^2^**   |                |
+------------------+----------------+----------------+----------------+
| **Exposure**     | **2334         | **2467         | **2468         |
|                  | patients**     | patients**     | patients**     |
|                  |                |                |                |
|                  | **median**     | **median**     | **median**     |
|                  |                |                |                |
|                  | **12 months**  | **19.3         | **24 months**  |
|                  |                | months**       |                |
+------------------+----------------+----------------+----------------+
| **All Sites**    | **30**         | **38**         | **48**         |
+------------------+----------------+----------------+----------------+
| **All            | **4**          | **8**          | **10**         |
| lymphomas**      |                |                |                |
+------------------+----------------+----------------+----------------+
| **NHL**          |                | **7**          |                |
+------------------+----------------+----------------+----------------+
| **Hodgkin's D**  |                | **1**          |                |
+------------------+----------------+----------------+----------------+
| **Breast**       | **4**          | **5**          | 7              |
+------------------+----------------+----------------+----------------+
| **Colon --       | **3**          | **4**          | **6**          |
| rectum**         |                |                |                |
+------------------+----------------+----------------+----------------+
| **Cervix --      | **3**          | **3**          | **5**          |
| Uteri**          |                |                |                |
+------------------+----------------+----------------+----------------+
| **Prostate**     | **4**          | **4**          | **5**          |
+------------------+----------------+----------------+----------------+
| **Melanoma**     | **2**          | **2**          | **3**          |
+------------------+----------------+----------------+----------------+
| **Gallbladder    | **1**          |                | **2**          |
| --**             |                |                |                |
|                  |                |                |                |
| **bile ducts**   |                |                |                |
+------------------+----------------+----------------+----------------+
| **               | **2**          |                | **2**          |
| Adenocarcinoma** |                |                |                |
|                  |                |                |                |
| **(unknown       |                |                |                |
| origin)**        |                |                |                |
+------------------+----------------+----------------+----------------+
| **Other**        | **7**          | **11**         | **8**          |
+------------------+----------------+----------------+----------------+
| **Non-melanoma   | **24**         | **32**         | **36**         |
| skin cancers**   |                |                |                |
+------------------+----------------+----------------+----------------+
| **Basal cell**   |                | **23**         |                |
+------------------+----------------+----------------+----------------+
| **Squamous       |                | **9**          |                |
| cell**           |                |                |                |
+------------------+----------------+----------------+----------------+

**1 Data available through August 31, 2001**

> **2 Data available through March 29, 2002**
>
> **^3^ Data available through August 31, 2002**

Table 19: Comparative Expected Cancer Incidence Rates In the Adalimumab
Clinical Development Program Through August 31, 2002

+-----------------------------+----------+---------+-------+----------+
| **Cancer Type** \*          | **Ob     | **Exp   | **    | **95%    |
|                             | served** | ected** | SIR** | CI**     |
+-----------------------------+----------+---------+-------+----------+
| **All Sites**               | 46       | 45.82   | 1.00  | (0.7 --  |
|                             |          |         |       | 1.3)     |
+-----------------------------+----------+---------+-------+----------+
| > **All Lymphomas**         | 10       | 1.85    | 5.42  | (2.6 --  |
|                             |          |         |       | 10.0)    |
+-----------------------------+----------+---------+-------+----------+
| > **NHL**                   | 9        | 1.70    | 5.28  | (2.4     |
|                             |          |         |       | --10.0)  |
+-----------------------------+----------+---------+-------+----------+
| > **Hodgkin's Disease**     | 1        | 0.14    | 7.09  | (0.1 --  |
|                             |          |         |       | 39.5)    |
+-----------------------------+----------+---------+-------+----------+
| **Breast**                  | 7        | 11.15   | 0.63  | (0.3 --  |
|                             |          |         |       | 1.3)     |
+-----------------------------+----------+---------+-------+----------+
| **Colon**                   | 5        | 4.75    | 1.05  | (0.3 --  |
|                             |          |         |       | 2.5)     |
+-----------------------------+----------+---------+-------+----------+
| **Lung**                    | 1        | 6.67    | 0.15  | (0.0 --  |
|                             |          |         |       | 0.8)     |
+-----------------------------+----------+---------+-------+----------+
| **Melanoma**                | 3        | 1.53    | 1.97  | (0.4 --  |
|                             |          |         |       | 5.7)     |
+-----------------------------+----------+---------+-------+----------+
| **Prostate**                | 5        | 4.45    | 1.12  | (0.4 --  |
|                             |          |         |       | 2.6)     |
+-----------------------------+----------+---------+-------+----------+
| **Uterine**                 | 4        | 2.30    | 1.74  | (0.5 --  |
|                             |          |         |       | 4.4)     |
+-----------------------------+----------+---------+-------+----------+
| **Other sites**             | 11       | 13.12   | 0.84  | (0.4 --  |
|                             |          |         |       | 1.5)     |
+-----------------------------+----------+---------+-------+----------+
| #### Non                    |          |         |       |          |
| -Melanoma Skin Cancers \*\* |          |         |       |          |
+-----------------------------+----------+---------+-------+----------+
| #### Basal Cell             | 23       | 20.12   | 1.14  | (0.7 --  |
|                             |          |         |       | 1.7)     |
+-----------------------------+----------+---------+-------+----------+
| **Squamous Cell**           | 9        | 3.79    | 2.37  | (1.1 --  |
|                             |          |         |       | 4.5)     |
+-----------------------------+----------+---------+-------+----------+

> \* Cancer rates used were 1992-1999 SEER rates

\*\* Skin cancer rates used were 1977-1978 NCI study rates

Table 20 : Lymphoma Incidence Rates by Duration of Treatment with
Adalimumab

+-----------------------+-----------------------+-----------------------+
| **Exposure Interval   | **Number/Total (%)**  | **N(N/100             |
| Until**               |                       | patient-years)**      |
|                       |                       |                       |
| **Time of Event -     |                       |                       |
| Months**              |                       |                       |
+-----------------------+-----------------------+-----------------------+
| 0 - \< 6              | 2/2468 (0.08)         | 2 (0.2)               |
+-----------------------+-----------------------+-----------------------+
| 6 -\< 12              | 1/2216 (0.05)         | 1 (0.1)               |
+-----------------------+-----------------------+-----------------------+
| 12 - \<18             | 1/1867 (0.05)         | 1 (0.1)               |
+-----------------------+-----------------------+-----------------------+
| 18 - \< 24            | 2/1395 (0.14)         | 2 (0.4)               |
+-----------------------+-----------------------+-----------------------+
| 24 - \< 30            | 1/619 (0.16)          | 1 (0.4)               |
+-----------------------+-----------------------+-----------------------+
| 30 - \< 36            | 0/375 (0.00)          | 0 (0.0)               |
+-----------------------+-----------------------+-----------------------+
| 36 - \< 42            | 0/321 (0.31)          | 1 (0.8)               |
+-----------------------+-----------------------+-----------------------+

summarizes the cases of lymphoma observed during the adalimumab clinical
development program by type and concomitant therapy. Lymphomas that have
occurred in the setting of impaired immune function have most often been
large B cell, Non Hodgkin's lymphomas.[^8] Similarly, the lymphoma type
most often reported in this clinical development program was the large B
cell, Non Hodgkin's lymphoma. Ninety percent of the lymphoma patients
had received MTX (seven were receiving concomitant MTX and two had
received prior MTX), and 80% were receiving concomitant corticosteroids.

Table 21: Summary of Lymphoma Cases By Type and Concomitant Therapy

+------------+-------------+----------+----------------+------+-------+
| **Subje    | **Type of   | **Family | **Concomitant  |      |       |
| ct/Study** | Lymphoma**  | H        | Therapy**      |      |       |
|            |             | istory** |                |      |       |
+------------+-------------+----------+----------------+------+-------+
|            |             |          | **A            | **M  | **C   |
|            |             |          | zathioprine/** | TX** | STD** |
|            |             |          |                |      |       |
|            |             |          | **Cycl         |      |       |
|            |             |          | ophosphamide** |      |       |
+------------+-------------+----------+----------------+------+-------+
| 2204/DE007 | Mantle zone | Sister-  |                | X    | X     |
|            | B cell      | leukemia |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 69/DE001   | Diffuse     |          |                | X    |       |
|            | Large B     |          |                | ^P^  |       |
|            | cell        |          |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 1414/DE011 | MALT cell B |          | X ^P^          | X    | X     |
|            | cell        |          |                | ^P^  |       |
+------------+-------------+----------+----------------+------+-------+
| 8911/DE019 | Follicular  |          |                | X    |       |
|            | B cell      |          |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 1          | Large B     |          |                |      | X     |
| 0509?DE031 | cell        |          |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 1705/De019 | Mixed small |          |                | X    |       |
|            | and large B |          |                |      |       |
|            | cell        |          |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 1          | T cell      |          |                | X    | X     |
| 1601/DE031 |             |          |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 8208/DE019 | Small and   |          |                | X    | X     |
|            | large B     |          |                |      |       |
|            | cell        |          |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 1          | Large B     |          |                | X    | X     |
| 4605/DE031 | cell        |          |                |      |       |
+------------+-------------+----------+----------------+------+-------+
| 4404/DE019 | Hodgkin's   |          |                | X    | X     |
+------------+-------------+----------+----------------+------+-------+
| Total = 10 |             | 1        | 1              | 9    | 8     |
+------------+-------------+----------+----------------+------+-------+

P = previous CSTD = Corticosteroids

Available data are insufficient to determine whether adalimumab
increases the incidence of lymphomas. Continued monitoring of
adalimumab-treated patients is necessary to quantify the role of
adalimumab, if any, in contributing to the observed higher incidence of
lymphomas than in the general population.

To reflect the observed higher rate of lymphomas compared to the general
population and the uncertainties in interpretation, the following
language was included in the **WARNINGS** section of the package insert:

###### Malignancies {#malignancies-1 .unnumbered}

> Lymphomas have been observed in patients treated with TNF blocking
> agents including HUMIRA. In clinical trials, patients treated with
> HUMIRA had a higher incidence of lymphoma than the expected rate in
> the general population (see **ADVERSE REACTIONS-Malignancies**). While
> patients with rheumatoid arthritis, particularly those with highly
> active disease, may be at a higher risk (up to several fold) for the
> development of lymphoma, the role of TNF blockers in the development
> of malignancy is not known^4,5^.

And the following in the Adverse Reactions section:

**Malignancies**

> Among 2468 rheumatoid arthritis patients treated in clinical trials
> with HUMIRA for a median of 24 months, 48 malignancies of various
> types were observed, including 10 patients with lymphoma. The
> Standardized Incidence Ratio (SIR) (ratio of observed rate to
> age-adjusted expected frequency in the general population) for
> malignancies was 1.0 (95% CI, 0.7, 1.3) and for lymphomas was 5.4 (95%
> CI, 2.6, 10.0). An increase of up to several fold in the rate of
> lymphomas has been reported in the rheumatoid arthritis patient
> population^4^, and may be further increased in patients with more
> severe disease activity^5^ (see **WARNINGS-Malignancies**)**.** The
> other malignancies observed during use of HUMIRA were breast,
> colon-rectum, uterine-cervical, prostate, melanoma, gallbladder-bile
> ducts, and other carcinomas.

# Data comparing TNF blockers to other DMARDs

In order to make reasoned decisions about treatment, physicians and
patients need data comparing the various available options.
Unfortunately, only limited data are available on the relative safety
and efficacy of the approved TNF blockers and other available DMARDs.
The agency has encouraged sponsors to conduct comparative trials to
address this important issue and hopefully, additional data will become
available in the future.

Only one randomized controlled trial has been reviewed by FDA comparing
a TNF blocking agent with another DMARD, the ERA trial of etanercept in
early RA. This study was reviewed at a meeting of the Arthritis Advisory
Committee in April 2000. The ERA trial enrolled approximately 600
patients with RA for under 3 years who had never

received MTX. Patients were randomized to receive etanercept 10 mg or 25
mg biw sc or MTX. MTX was begun at a dose of 7.5 mg weekly and increased
to 20 mg weekly unless patients experienced toxicity or had a complete
clinical response.

As shown in Table 22, 65% of patients receiving etanercept 25 mg had
ACR20 responses at 6 months, 40% had ACR 50 responses and 21% had ACR 70
responses at 6 months. Slightly higher proportions of subjects had ACR
20, 50 and 70 responses at 12 months. The point estimates for MTX
treated subjects were similar however, for each comparison, the response
rates for subjects receiving etanercept 25 mg was higher than for the
MTX comparator group. The difference in the proportion of patients with
an ACR20 response between etanercept and MTX was not statistically
significant. The area under the curve for ACR-N was higher for
etanercept 25 mg than for MTX (Figure 2).

Table 22: ACR 20, 50 and 70 responses at 3, 6 and 12 months

![](media/image2.wmf)

![](media/image2.wmf)

Figure 2: ACR-N over time during the study

During the course of trial 16.0012, two deaths occurred. There was one
death of lung cancer in a subject in the Enbrel 10 mg arm diagnosed
after two months of dosing. The other death was in the Enbrel 25 mg arm
and arose from non-infectious complications of an aortic aneurysm
repair.

A similar number of SAE's were observed in the MTX arm and the
etanercept 25 mg arms of the ERA trial (Table 23). A similar number of
infectious SAE's were seen with etanercept and MTX. Three malignancies
were seen in the etanercept 25 mg arm compared to 1 in the MTX arm.
Three cases of interstitial pneumonitis were seen in the MTX arm and
none in the two etanercept arms. Two cases each of thromboembolic SAE's
were seen in the etanercept arms and none in the MTX arms.

A higher proportion of subjects in the Enbrel 25 mg arm completed 12
months of dosing with assigned study drug than in the methotrexate arm.
A total of 21 subjects discontinued study drug in the methotrexate arm
compared to 10 in the Enbrel 25 mg arm and 9 in the Enbrel 10 mg arm (p
= 0.016, MTX vs. all Enbrel). The reasons for discontinuation due to
adverse events are shown in Table 24. The most common adverse events
leading to discontinuation were alopecia, oral/nasal ulcers and
vomiting, adverse events associated with methotrexate use. These events
occurred in 9 subjects in the methotrexate arm and none in the Enbrel
arms. Infection led to discontinuation in 3 subjects in the methotrexate
arm and 3 and 1 in the Enbrel 10 mg and 25 mg arms, respectively. A
diagnosis of a malignancy led to discontinuation in 1 subject in the
methotrexate arm and two each in the Enbrel arms. MTX pneumonitis was
observed in 3 subjects in the methotrexate and none in the Enbrel arms.
Finally, injection site reaction (ISR) led to discontinuation in one
subject in the Enbrel 25 mg arm. Other adverse events leading to
discontinuation were evenly distributed in the 3 arms of the trial.

Adverse events were reported by a higher proportion of subjects in the
methotrexate arm than the two Enbrel arms: 95% vs. 90% and 89% in the
Enbrel 10 mg and 25 mg arms respectively (p = 0.010, methotrexate vs
combined Enbrel arms). The ten most common adverse events were headache,
nausea, rash, rhinitis, diarrhea, bleeding at injection site, asthenia,
dyspepsia, abdominal pain and dizziness. Of these, the only adverse
event occurring at least 2% more commonly in the Enbrel 25 mg arm than
the methotrexate arm was bleeding at injection site (14% vs. 10%).

One laboratory abnormality, low absolute neutrophil count (ANC), was
seen more frequently in the subjects receiving Enbrel than subjects in
the methotrexate arm: 16% of subjects in the Enbrel 25 mg arm vs. 8% in
the methotrexate arm. The majority of these cases were grade 1 or 2.
Grade 3 cases (ANC of 500-1000 cells/mm^3^) of low ANC were seen in 3
subjects in the Enbrel 25 mg arm and 2 in the methotrexate arm. In none
of three cases of low ANC were there associated infectious adverse
events. Low ANC counts recovered spontaneously within 8 weeks while
continuing Enbrel. No grade 4 cases were observed.

Laboratory abnormalities observed at a higher frequency in the
methotrexate arm than the Enbrel arms of the trial are shown in Table
25. Elevated liver enzymes (SGOT, SGPT) were observed more frequently in
the MTX arm than in the Enbrel arms. However, there were 4 cases of
elevated liver enzymes in Enbrel-treated subjects, all in the 10-mg arm.
One subject, #0106, had mildly elevated liver enzymes at screening which
increased 1 week after beginning Enbrel. Study drug was discontinued.
Liver biopsy showed fatty liver ascribed to obesity and prednisone.
Another subject, #2001, had chronically elevated liver enzymes with
grade 2 and grade 1 elevation of SGOT and SGPT, respectively, at
baseline. During the study, liver enzymes increased to 5x the upper
limit of normal and study drug was discontinued. Elevated liver enzymes
were ascribed to autoimmune hepatitis or acetaminophen toxicity. A third
subject, #2088, had normal liver enzymes at baseline, but developed
elevations during the trial with an SGPT of 35 at 2 months, and at 9 mo
SGOT 53 and SGPT 80. Study drug was discontinued and liver enzyme
elevations returned to the normal range. The fourth subject, #6703, had
a single set of elevated liver enzymes, SGOT 43 and SGPT 178. Liver
enzymes 4 weeks before and 6 weeks after were within the normal range.

Table 23: SAEs occurring in trial 16.0012

![](media/image1.wmf)

Table 24: Adverse events leading to discontinuation of study drug

![](media/image1.wmf)

#  {#section-2 .unnumbered}

Table 25: Abnormal laboratory values

# ![](media/image1.wmf) {#section-3 .unnumbered}

#  {#section-4 .unnumbered}

# VI. Summary {#vi.-summary .unnumbered}

The three licensed TNF-blocking products have all been shown to be
effective in patients with rheumatoid arthritis; they have also been
associated with certain types of serious adverse events. As expected,
much of the information on serious events have accumulated during the
post-marketing period, where causality assignment and precise
quantification of the event rates are more difficult. Since the initial
product approvals, the agency has made frequent changes to product
labels and used other methods to communicate safety information to
health care professionals and patients. Long term follow up of patients
enrolled in registry studies is ongoing, where a particular emphasis is
on all reports of malignancies and serious infections. The safety
profile of these products will continue to be developed through use of
the registry, periodic safety updates from the passive surveillance
program, and safety data from controlled trials of TNF blocking therapy
for other diseases.

Because the clinical trial designs and patient populations studied
differ among the three approved TNF-blocking agents and have not been
studied in head to head trials, direct comparisons cannot be made among
the products and between the various studies. Nonetheless, certain
generalizations can be made. First, certain serious, but uncommon,
adverse events have been observed with all three products, including 1)
Serious

infections, including serious bacterial infections, TB and certain
opportunistic infections; demyelinating syndromes; and lupus-like
reactions. These data suggest that these adverse reactions may be
related to blockade of TNF-α and may, therefore represent class effects
of these agents. However, the severity and degree of risk may not be the
same with all three agents. Second, because these serious adverse
reactions are so uncommon, they were not fully appreciated in the
initial safety database available at the time of approval of Enbrel and
Remicade, even though those safety databases met minimum ICH guidelines.
However, all of these serious adverse events were observed in the safety
database submitted for approval of Humira. These findings indicate that
for agents of this type, a larger safety database than the minimum ICH
guidelines may be warranted.

The large size of the Humira database presented certain challenges in
interpretation of the data. Because the number of patients treated and
the duration of observation was extensive, it is expected that there
would be deaths and malignancies, as there were. Yet because much of the
period of exposure was in open-label extension studies, there is no
internal control to allow an objective assessment of risk attributable
to the study drug. Assessment of the deaths that were observed indicate
that the mortality rate with Humira was not increased over that expected
in the general population. This finding is reassuring, especially since
the rate of mortality has been reported to be increased in patients with
RA, including a recent study of patients diagnosed between 1955 and 1994
in Rochester MN.[^9]

More complicated is the interpretation of the malignancies observed in
the Humira database. While the rate of malignancies overall was not
found to be increased over that seen in the general US population, the
rate of lymphomas was increased, with a standardized incidence rate of
5.4. The rate of lymphomas has been reported to be increased in patients
with RA compared to the general population and the rate is reported to
be increased still further in patients with highly active disease, such
as the patients evaluated in the Humira clinical development program.
The standardized incidence ratio for lymphomas with Humira is in the
range reported for RA patients with moderately active disease. Analysis
of the rate of lymphomas relative to the general US population with the
other two approved TNF blockers indicates a rate that is in the same
range. It is difficult to reach firm conclusions about whether TNF
blockers increase the risk of lymphomas because the patient populations
studied are different from those studied in the epidemiologic studies
and because of the lack of a concurrent control for most of the data.

The agency addressed the issue of lymphomas observed in patients
receiving Humira by including all the available information in the
package insert and including a warning

about lymphomas. It could be argued that similar information should be
included in the package inserts of the other TNF-blocking agents. The
agency is interested in hearing discussion from the advisory committee
about the best approach to studying the issue of lymphomas with
TNF-blocking agents and the best way to report this information in
product labels.

#  Appendices

## Appendix A. Medical officer review of BLA STN #125057 -- Adalimumab for use in the treatment of Rheumatoid Arthritis.  {#appendix-a.-medical-officer-review-of-bla-stn-125057-adalimumab-for-use-in-the-treatment-of-rheumatoid-arthritis. .unnumbered}

## 

## Appendix B. {#appendix-b. .unnumbered}

# Other analyses for infliximab claim of improvement in physical function {#other-analyses-for-infliximab-claim-of-improvement-in-physical-function .unnumbered}

Table 26: Landmark analysis at one year: Improvement from baseline in
HAQ ≥ 0.3 at weeks 30 and 54

+--------------------+--------+---------+--------+---------+---------+
| **Methods of       | **Pla  | **3     | **3    | **10    | **10    |
| Handling Missing   | cebo** | mg/kg** | m      | mg/kg   | mg/kg   |
| Data**             |        |         | g/kg** | q8      | q4      |
|                    | **(N   | **q8    |        | wks**   | wks**   |
|                    | =88)** | wks**   | **q4   |         |         |
|                    |        |         | wks**  | **(     | **(     |
|                    |        | **(     |        | N=87)** | N=81)** |
|                    |        | N=86)** | **(N   |         |         |
|                    |        |         | =85)** |         |         |
+--------------------+--------+---------+--------+---------+---------+
| **[Missing as      | 20     | 31      | 41     | 48      | 33      |
| nonrespon          | (23%)  | (36%)   | (48%)  | (55%)   | (41%)   |
| der]{.underline}** |        |         |        |         |         |
|                    |        | 0.054   | \      | \<0.001 | 0.012   |
| #Improvement (%)   |        |         | <0.001 |         |         |
|                    |        |         |        |         |         |
| P-value vs.        |        |         |        |         |         |
| placebo            |        |         |        |         |         |
+--------------------+--------+---------+--------+---------+---------+
| **[Multiple        | 26     | 34(40%) | 4      | 49      | 35      |
| Imputatio          | (30%)  |         | 5(53%) | (56%)   | (43%)   |
| ns#]{.underline}** |        | 0.17    |        |         |         |
|                    |        |         | 0.002  | \<0.001 | 0.065   |
| #Improvement (%)   |        |         |        |         |         |
|                    |        |         |        |         |         |
| P-value vs.        |        |         |        |         |         |
| placebo            |        |         |        |         |         |
+--------------------+--------+---------+--------+---------+---------+
| **[Modified Worst  | 24     | 31      | 41     | 49      | 35      |
| Cas                | (27%)  | (36%)   | (48%)  | (56%)   | (43%)   |
| e\*]{.underline}** |        |         |        |         |         |
|                    |        | 0.213   | 0.004  | \<0.001 | 0.030   |
| #Improvement (%)   |        |         |        |         |         |
|                    |        |         |        |         |         |
| P-value vs.        |        |         |        |         |         |
| placebo            |        |         |        |         |         |
+--------------------+--------+---------+--------+---------+---------+
| **[Worst           | 33     | 31      | 41     | 48      | 33      |
| C                  | (38%)  | (36%)   | (48%)  | (55%)   | (41%)   |
| ase]{.underline}** |        |         |        |         |         |
|                    |        | 0.84    | 0.15   | 0.19    | 0.66    |
| #Improvement (%)   |        |         |        |         |         |
|                    |        |         |        |         |         |
| P-value vs.        |        |         |        |         |         |
| placebo            |        |         |        |         |         |
+--------------------+--------+---------+--------+---------+---------+

Table 27: Number of infliximab patients with HAQ improvement of ≥0.3 at
week 54 who also had improvement of ≥0.3 at week 102 (non-responder
imputation)

+---------------------+--------+--------+--------+--------+---------+
|                     | 3      | 3      | 10     | 10     | **All   |
|                     | mg/kg  | mg/kg  | mg/kg  | mg/kg  | Inf     |
|                     |        |        |        |        | liximab |
|                     | q 8    | q 4    | q 8    | q 4    | Reg     |
|                     | Wks    | Wks    | Wks    | Wks    | imens** |
+---------------------+--------+--------+--------+--------+---------+
| Pts randomized      | 86     | 86     | 87     | 81     | 340     |
+---------------------+--------+--------+--------+--------+---------+
|                     |        |        |        |        |         |
+---------------------+--------+--------+--------+--------+---------+
| All patients        |        |        |        |        |         |
+---------------------+--------+--------+--------+--------+---------+
| > Pts with          | 48     | 46     | 54     | 41     | 189     |
| > improvement at    |        |        |        |        |         |
| > week 54           |        |        |        |        |         |
+---------------------+--------+--------+--------+--------+---------+
| > Pts with          | 32     | 41     | 43     | 35     | 151     |
| > improvement ≥ 0.3 | (67%)  | (89%)  | (80%)  | (85%)  | (80%)   |
| > at week 102       |        |        |        |        |         |
+---------------------+--------+--------+--------+--------+---------+
| Pts blinded through |        |        |        |        |         |
| 102 weeks           |        |        |        |        |         |
+---------------------+--------+--------+--------+--------+---------+
| > Pts with          | 33     | 33     | 44     | 36     | 146     |
| > improvement at    |        |        |        |        |         |
| > week 54           |        |        |        |        |         |
+---------------------+--------+--------+--------+--------+---------+
| > Pts with          | 19     | 29     | 34     | 31     | 113     |
| > improvement ≥ 0.3 | (58%)  | (88%)  | (77%)  | (86%)  | (77%)   |
| > at week 102       |        |        |        |        |         |
+---------------------+--------+--------+--------+--------+---------+
| Pts unblinded at/or |        |        |        |        |         |
| prior to 102 weeks  |        |        |        |        |         |
+---------------------+--------+--------+--------+--------+---------+
| > Pts with          | 15     | 13     | 10     | 5      | 43      |
| > improvement at    |        |        |        |        |         |
| > week 54           |        |        |        |        |         |
+---------------------+--------+--------+--------+--------+---------+
| > Pts with          | 13     | 12     | 9      | 4      | 38      |
| > improvement ≥ 0.3 | (87%)  | (92%)  | (90%)  | (80%)  | (88%)   |
| > at week 102       |        |        |        |        |         |
+---------------------+--------+--------+--------+--------+---------+

Table 28: Landmark analysis at 2 years. Number of patients with
improvement in HAQ ≥0.3 units at weeks 30, 54, 78 and 102

+--------------------+--------+---------+--------+---------+---------+
| **Methods of       | **Pla  | **3     | **3    | **10    | **10    |
| Handling Missing   | cebo** | mg/kg** | m      | mg/kg   | mg/kg   |
| Data**             |        |         | g/kg** | q8      | q4      |
|                    | **(N   | **q8    |        | wks**   | wks**   |
|                    | =88)** | wks**   | **q4   |         |         |
|                    |        |         | wks**  | **(     | **(     |
|                    |        | **(     |        | N=87)** | N=81)** |
|                    |        | N=86)** | **(N   |         |         |
|                    |        |         | =85)** |         |         |
+--------------------+--------+---------+--------+---------+---------+
| **[Missing as      | 11     | 21      | 36     | 34      | 28      |
| nonrespon          | (13%)  | (24%)   | (42%)  | (39%)   | (35%)   |
| der]{.underline}** |        |         |        |         |         |
|                    |        | 0.043   | \      | \<0.001 | \<0.001 |
| #Improvement (%)   |        |         | <0.001 |         |         |
|                    |        |         |        |         |         |
| P-value vs.        |        |         |        |         |         |
| placebo            |        |         |        |         |         |
+--------------------+--------+---------+--------+---------+---------+
| **[Multiple        | 22     | 28      | 37     | 37      | 31      |
| Imputatio          | (25%)  | (33%)   | (44%)  | (43%)   | (38%)   |
| ns#]{.underline}** |        |         |        |         |         |
|                    |        | 0.27    | 0.010  | 0.014   | 0.063   |
| #Improvement (%)   |        |         |        |         |         |
|                    |        |         |        |         |         |
| P-value vs.        |        |         |        |         |         |
| placebo            |        |         |        |         |         |
+--------------------+--------+---------+--------+---------+---------+
| **[Modified Worst  | 22     | 21      | 36     | 34      | 28      |
| Cas                | (25%)  | (24%)   | (42%)  | (39%)   | (35%)   |
| e\*]{.underline}** |        |         |        |         |         |
|                    |        | 0.93    | 0.016  | 0.046   | 0.173   |
| #Improvement (%)   |        |         |        |         |         |
|                    |        |         |        |         |         |
| P-value vs.        |        |         |        |         |         |
| placebo            |        |         |        |         |         |
+--------------------+--------+---------+--------+---------+---------+
| **[Worst           | 31     | 21      | 36     | 34      | 28      |
| C                  | (35%)  | (24%)   | (42%)  | (39%)   | (35%)   |
| ase]{.underline}** |        |         |        |         |         |
|                    |        | 0.12    | 0.34   | 0.60    | 0.93    |
| #Improvement (%)   |        |         |        |         |         |
|                    |        |         |        |         |         |
| P-value vs.        |        |         |        |         |         |
| placebo            |        |         |        |         |         |
+--------------------+--------+---------+--------+---------+---------+

## Appendix C -- Briefing materials from August 17, 2001 Safety update on anti-TNF products {#appendix-c-briefing-materials-from-august-17-2001-safety-update-on-anti-tnf-products .unnumbered}

#  {#section-6 .unnumbered}

## Appendix D Medical Officer review of Etancercept in CHF  {#appendix-d-medical-officer-review-of-etancercept-in-chf .unnumbered}

## 

## Appendix E Medical Officer Review of Infliximab in CHF {#appendix-e-medical-officer-review-of-infliximab-in-chf .unnumbered}

##  Appendix F -- selected publications  {#appendix-f-selected-publications .unnumbered}

[^1]: International Conference on Harmonisation. "E1: Guideline on the
    Extent of Population Exposure Required to Assess Clinical Safety for
    Drugs. Available at http://www.fda.gov/cber/guidelines

[^2]: Baecklund E, Ekbom A, Sparen P, Feltelius N, Klareskog L. Disease
    activity and risk of lymphoma in patients with rheumatoid arthritis
    : nested case-control study. *BMJ* 1998; **517**: 180-1

[^3]: Abstract. Wolfe F. Inflammatory activity, but not methotrexate or
    prednisone use predicts Non-Hodgkin's lymphoma in rheumatoid
    arthritis: a 25-year study of 1,767 RA patients. *ACR Plenary II*
    1998: **931**

[^4]: Baecklund E, Ekbom A, Sparen P, Feltelius N, Klareskog L. Disease
    activity and risk of lymphoma in patients with rheumatoid arthritis:
    nested case-control study *BMJ* 1998; 517:180-181.

[^5]: Abstract. Wolfe F. Inflammatory activity, but not methotrexate or
    prednisone use predicts non-Hodgkin's lymphoma in rheumatoid
    arthritis: a 25-year stud7 of 1767 RA patients. *ACR Plenary II*
    1998: 931

[^6]: Baecklund E, Ekbom A, Sparen P, Feltelius N, Klareskog L. Disease
    activity and risk of lymphoma in patients with rheumatoid arthritis
    : nested case-control study. *BMJ* 1998; **517**: 180-1

[^7]: Abstract. Wolfe F. Inflammatory activity, but not methotrexate or
    prednisone use predicts Non-Hodgkin's lymphoma in rheumatoid
    arthritis: a 25-year study of 1,767 RA patients. *ACR Plenary II*
    1998: **931**

[^8]: Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM. Tumor
    necrosis factor antagonist therapy and lymphoma development:
    twenty-six cases reported to the FDA. *Arthritis and Rheumatism*
    2002;**46**: 3151-3158

[^9]: Gabriel, SE, Crowson CS *et al*. Arthritis & Rheumatism,
    48(1):54-58, 2003.