Agent: Valdecoxib

Indication: Analgesia, Dysmenorrhea Osteoarthritis, and Rheumatoid
Arthritis

Reviewer: Kent Johnson, MD

Date: November 7, 2001

NDA: 21,341

EXECUTIVE SUMMARY

1-RECOMMENDATIONS

A. Approval for the indications of osteoarthritis and rheumatoid
arthritis at a dose of 10mg/day and dysmenorrhea at a dose of 20-mg bid
as needed.

B. Nonapproval of the acute pain, including opiod-sparing and prevention
of operative pain. The only substantial multidose safety database is
found in the Coronary Artery Bypass Graft (CABG) Surgery study 035. This
study demonstrated an excess of serious adverse events including death
in association with the use of paracoxib and valdecoxib 40 mg bid when
added to ad lib parenteral narcotic analgesia. The allocation was 2:1
drug versus placebo and the population was highly enriched with patients
at high risk for

cardiovascular thromboembolic events. Therefore, interpretation of these
findings cannot be conclusive at this time. These finding warrants
further investigation before valdecoxib can be considered safe and
effective for the treatment of pain, particularly multidose therapy in
the perioperative setting. The dose used in the CABG trial was eightfold
higher than the dose proposed for approval for the treatment of
osteoarthritis and rheumatoid arthritis and twice the dose proposed for
the treatment of dysmenorrhea. In addition the proposed populations is
distinctly different than the post-operative setting. The extensive
safety database at 10-80mg daily in the arthritis safety database is
adequate to support approval of the chronic therapy at 10 mg/day for
arthritis and acute dose of 20 mg bid for short term use in
dysmenorrhea.

2-SUMMARY OF CLINICAL FINDINGS

a\) Adequate efficacy has been demonstrated in osteoarthritis and
rheumatoid arthritis at 10mg/d with no additional efficacy at 20mg/d.
The safety profile with chronic use in RA and OA is adequate at 10mg/d.
At higher total daily doses, the findings of more hypertension and edema
are frequently reproduced, and they are formally affirmed in a
prospective manner in Trial 47, which directly tested the hypothesis of
renal safety at 40 and 80 mg/day. In the analysis of older
subpopulations over the age of 65 years edema and hypertension appear to
be greater at 20 mg/day compared to 10 mg/ day.

b\) Single-dose analgesia has been demonstrated at 20mg and 40mg in the
dental, dysmenorrhea, with supportive data from other surgical models.

c\) Two studies (024, 037) evaluating prevention or pre-emption of
post-operative pain demonstrated the superiority of valdecoxib 20, 40
and 80 mg over placebo for the endpoints of time to rescue medication as
well as proportion of patients taking rescue medication. There was no
difference in pain intensity over the first 2 hours in study 024 and 4
hours in study 037. This finding raises concern over the value of
preoperative management of post-operative pain, particularly in regards
to the risk versus potential benefit.

Data from these two studies should not be considered for labeling until
the overall clinical value of such treatment is further defined as well
as the safety. Pre-operative dosing should be compared to post-operative
dosing to adequately characterize the value of pre-operative treatment
given the lack of differentiation in pain intensity between valdecoxib
and placebo treated subjects.

d\) Three studies of opioid sparing were submitted (Trials 35, 51, and
38). While mean opiod dose was lower in subjects treated with valdecoxib
40mg bid in the three studies, results were not replicated for 20-mg
bid. Decreases in peak pain intensity were demonstrated in two of the
three studies at 40 mg bid. This finding was not replicated for the
20-mg bid dose. Sparing of adverse events was not demonstrated in these
studies.

In study 035 there was a statistically significant excess of serious
adverse events associated with the use of valdecoxib 40-mg bid when
added to ad lib narcotic therapy compared with narcotic analgesia alone.
The value of "opioid sparing based on numeric differences in total
opioid requirement is of unclear and unproven clinical benefit.

e\) No efficacy advantage was demonstrated or suggested for valdecoxib
compared to:

i\. ibuprofen, naproxen and acetamenophen/oxycodone in anlagesic studies

ii\. naproxen, ibuprofen or diclofenac in osteoarthritis studies

iii\. naproxen in rheumatoid arthrits studies

3-OVERVIEW OF CLINICAL PROGRAM ANALGESIA:

This NDA consists of a program of analgesia trials to support a claim
for acute pain, and a number of trials in osteoarthritis and rheumatoid
arthritis to support a claim for chronic use in these conditions. The
analgesia program tended to follow drug development programs for acute
pain used in the past, relying heavily on single-dose demonstrations of
efficacy compared to placebo and active controls, plus PK support
demonstrating blood level stability over time and a satisfactory chronic
risk/benefit from different indications (osteoarthritis and rheumatoid
arthritis) to then *extrapolate* the safety for multiple-dose use in
acute pain. The following is the sponsor's request for claims:

*An indication for the treatment of acute pain and dysmenorrhea at
40mg/d, with an*

*additional 40mg on day one if needed, and an indication for chronic
treatment of the*

*signs and symptoms of osteoarthritis and rheumatoid arthritis at a dose
of 10mg/day,*

*with the proviso that "some may receive additional benefit at
20mg/day."*

It should be noted that there was the usual interaction with the sponsor
regarding the scope and content of their development program. These
interactions were more prescriptive in the case of OA and RA, as RA had
been recently addressed in a Guidance Document, and the former had been
the topic of a number of public meetings during which certain
fundamentals such as trial duration, primary endpoints, and statistical
methodology, were established. Thus, there was a priori agreement
regarding data assessment in OA and RA, but the same cannot be said of
analgesia. The agency, in collaboration with outside bodies, has been
and remains in the process of formulating current analgesia guidelines,
and, in particular, the nature of the evidence base needed to
demonstrate efficacy in analgesia. A weakness in the approach used in
the past is the extrapolation needed to assert multiple dose efficacy,
rather than having data directly supporting this. In the past, this
approach, although not ideal, was deemed acceptable given that agents
were drugs which were

administered orally and usually showed identical dosing in both the
analgesia and arthritis settings. Furthermore, pharmacokinetic
parameters would suggest higher rather than lower levels on remedication
in the acute multi-dose setting. In addition, in many to most acute pain
settings, pain intensity typically diminishes rather than increase over
time (suggesting that analgesia that is documented to be effective at
the time of maximum pain would continue to be adequate as time passed.

An area where extrapolation cannot be made is in the assessment of
dosing interval. Single dose efficacy data alone is less robust than
comparative multi-dose data in assessing the optimal dosing interval.
Although the division is exploring approaches which yields direct
multiple-dose evidence and so depends less on extrapolation, the
interactions for this NDA preceded this, so in this review the
single-dose to multiple-dose extrapolation will be accepted. It is of
note that supportive evidence of mulit-dose efficacy was submitted by
the sponsor although studies were not designed to rigorously assess the
multi-dose period.

The analgesia program consisted of nineteen trials \-- seven dental, two
dysmenorrrhea, and ten in various surgical settings. Only four were
designed as multiple-dose trials. The other fifteen all were explicitly
designed as single-dose, These trials could not provide multiple dose
evidence of efficacy or dosing interval because: (1) The election of a
very early time as the explicit, or de facto (as evidenced e.g. by its
use in the powering of the trial) time-point for the primary analysis
(ten trials using the 45 min PID for powering), and (2) the absence of
re-dosing of short duration, active controls (ibuprofen or
oxycodone/acetaminophen).

The dysmenorrhea trials were both 4-part crossover designs. Two surgery
trials were designed to test the use of valdecoxib in a pre-emptive
manner, given shortly before surgery. All trials were both placebo and
active controlled except three which were designed to test a
morphine-sparing hypothesis the pre-operative and the two pre-operative
dosing studies. The three morphine-sparing trials allowed ad lib
morphine use in both arms, so, in effect, they employed a
"standard-of-care" as the control arm. The inclusion criteria varied
widely across these designs, from patients undergoing the standard third
molar extraction in the dental trials, to patients undergoing various
modes of anaesthesia delivery (local, regional, spinal, general). This
diversity has always been encouraged, as pertinent to any claim is a
presumption of generalizability. In this NDA Trial 35 attempted to
capture patients with substantial co-morbidity by enrolling patients who
had undergone coronary artery bypass graft (CABG) surgery. This was an
efficacy as well as a safety trial. The "COX-2 hypothesis" relates to
organ specific safety; notably the upper gastrointestinal tract.

In discussions with the sponsor the division has emphasized the
importance of rigorously testing the overall safety as well as upper
gastrointestinal safety of valdecoxib. Given the evolving knowledge of
selective COX-2 inhibition, this issue is of growing concern. This trial
included a pre-defined basket of serious safety endpoints, called
clinically relevant adverse events (CRAEs), which were to be formally
adjudicated. In addition study 047 included renal safety endpoints in
addition to asymptomatic endoscopically ascertained gastroduodenal
ulcers as prespecified endpoints

ARTHRITIS:

The arthritis program consisted of early dose-ranging RCTs (Trials 15
and 16), followed by four standard efficacy trials (1 hip OA, 1 knee OA,
and 2 RA), one active control, non-inferiority trial in OA (trial 63),
and four formal safety trials -- Trial 47 (OA/RA), 62 (RA), 48 (OA), and
53 (knee OA), all using a similar endoscopic ulcer primary endpoint, and
one (47) also using a renal toxicity composite primary endpoint. These
safety trials also collected validated efficacy endpoints, although not
encompassing the full primary endpoint spectrum needed for formal
efficacy evidence in OA or RA.

4-EFFICACY ANALGESIA:

The analgesia trials were assessed by (1) the improvement in pain over
time, (2) the time to the onset of analgesia, and (3) the time to need
for re-dosing or rescue medication. All three of these should be
substantially inter-correlated, so all were tested at the p\<0.05 level,
and no adjusting for multiplicity was done. However, this threefold
endpoint approach was not appropriate for the morphine-sparing trials as
they did not collect time to onset of analgesia, nor did they allow
rescue medication. In these trials, two measures were used: (1) pain
relief, and (2) morphine spared.

By the endpoints noted above, the following number of trials
demonstrated efficacy (by either all three endpoints showing statistical
significance at a p\<0.05 or two endpoints, in the case of the
morphine-sparing trials): 10mg/d -- 4 trials (#5, 14, 35, 24), 20mg/d -
8 trials (#5, 14, 35, 58, 59, 11, 24, 37), 40mg/d -- 6 trials (35, 58,
59, 72, 24, 37). So few comparisons to active controls were
statistically significantly different, either superior or inferior, that
this evidence base is not further considered. Using the criteria of
replicated success in two of the three pain models -- dental pain,
dysmenorrhea, and post-surgical pain, and excluding

dosing at 80mg/d or 40mgbid -- given evidence to suggest an unacceptable
risk-benefit at these levels, the data support clear single-dose
efficacy of 20mg, and 40mg. There was no replication of the efficacy of
10 mg based on pain intensity differences.

The clinical relevance of opioid-sparing was not adequately
demonstrated. Pre-emptive administration of valdecoxib 20, 40 and 80 mg
was associated with longer time to rescue medication compared with
placebo in Trials 24 and 37 and number of patients who took rescue
medication. Pre-emptive versus post operative dosing efficacy was not
tested and peak pain intensity over 2 and 4 hours respectively in the
two studies did not differ between placebo and active treatment arms.
Therefore the benefit of pre-emptive treatment is not

clear, especially in view of the safety concerns in the post-operative
setting.

ARTHRITIS:

The trials performed for the demonstration of efficacy in RA and OA were
conventional and adequate in design. They included three formal efficacy
trials in OA (two placebo control trials and one non-inferiority trial
using only an active control, and two in RA, both placebo controlled.
There were also safety RCTs with safety parameters as primary endpoints
that also measured efficacy. These studies employed less standardized
athritis efficacy endpoints such as patient and investigator global
assessments and time to

dropout due to inefficacy.

The analysis of the efficacy results for RA and OA in this NDA were
relatively straightforward. Valdecoxib did demonstrate efficacy at the
10mg and 20mg/d dosages in replicated data by usual comparisons with
placebo arms, and there were no obvious threats (e.g. a differential
dropout pattern) to the validity of these conclusions. Although no
formal active control, non-inferiority evidence was pre-specified and
pre-agreed upon in this NDA, this NDA, like others in the past, included
numerous comparisons with active controls -- and these were within the
range of what has been seen with prior NDAs. There was no added benefit
at 20mg/d, compared to 10mg/d.

5-SAFETY

Note: The review proper contains numerous adverse event tables which are
supplied for reference, as the global safety experience of valdecoxib
will likely bear critically on approval and labeling. Review comments
are made in each section of these databases, but all relevant safety
considerations are captured in the discussions of safety and risk /
benefit here in the Executive Summary.

With two notable exceptions -- edema and hypertension, valdecoxib was
comparable to the standard non-steroidal agents used as active controls
in the trials, except for some evidence supporting fewer GI adverse
events, and some lessening of opiate side effects (e.g. constipation,
dizziness, etc.) in trials with those as active controls. These findings
will be reflected in the AE tables in the label. The finding of a
greater incidence of edema and hypertension at doses above 20 mg/day,
almost uniformly in the databases and clearly when prospectively
addressed in formal safety Trials 47 and 62, is of concern, The
relationship

between these events and the signal of more vascular events at 40mgbid
dosing in the predisposed population of Trial 35 (CABG) is unclear. The
excess of serious cardiovascular thromboembolic events in the valdecoxib
arm of the CABG trial (see analgesic safety table #12) is of note as the
entire study population received prophylactic low dose aspirin as part
of the standard of care in this setting to minimize just such events.
Given the emerging concern over a possible pro-thrombotic action of
certain agents in the COX2 class, these data are of concern. These
findings were seen at high dose in the peri-operative setting, not in
the chronic safety studies of similar high doses.

**REVIEW PROPER**

**SAFETY REREPORT ON TRIAL 35**

This analgesia study comparing paracoxib/valdecoxib and placebo in
patients undergoing CABG surgery was designed to test opioid-sparing, as
reported in the Analgesia Efficacy section of this review. This trial
was also specifically designed to test a safety hypothesis, using a
pre-defined basket of safety endpoints, called "clinically relevant
adverse events\" (CRAEs), which included many serious vascular
endpoints. The trial was powered using both a morphine sparing and a
CRAE event rate calculation. In the trial analysis, there were 80 such
events (25.7%) in the 311 paracoxib/valdecoxib patients, compared with
23 (15.2%) in the 151 placebo patients (p=0.012, by Fisher's Exact). The
patient numbers for the particular events are shown in Table 1 below.

> Note: The reader is also referred to an in depth analysis of this
> important trial in the Parecoxib Medical Review by James Witter M.D.
> PhD. It is attached *in toto* in the appendix.

Table 1: Clinically Relevant Adverse Events (CRAEs): Prespecified
Endpoint event placebo

para/valdecoxib

deaths 0 4

myocardial infarction 1 1

cerebrovascular accident 1 9

deep venous thrombosis 0 3

pulmonary embolism 0 2

congestive heart failure 1 4

renal dysfunction / failure 7 29

infection 11 29

pulmonary complication 4 19

pericarditis 1 4

GI event 0 4

major non-GI bleed 2 0

Discussion: These data, along with the other analyses in Dr. Witter\'s
review (appendix) are manifestations of an increase in vascular events
rates, which coupled with the signals seen elsewhere in this database
(for example, Trial 47 and the adverse event tables shown later in this
review) all contributes to the concern that there may be a component of
increased thrombogenicity associated with this agent.

**DEATHS**

A total of 22 deaths have been reported in the NDA and the 120-Day
Update. Fifteen occurred during a blinded trial, five in open
extensions, and two in an ongoing cancer pain trial (Trial 40) which
remains blinded.

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**Deaths**

The total double-blind exposure for all doses of valdecoxib is 1283
patient-years (107, 323,397,316, 142 patient-years for 1-5mg, 10mg,
20mg, 40mg, and 80mg valdecoxib total daily dose, respectively) ,
compared to 291 patient-years for naproxen, 248 patient-years for
diclofenac, 40 patient-years for ibuprofen, and 161 patient-years for
placebo. Thus, the crude death rate in the unblinded controlled studies
for valdecoxib is 0.9% (12/1283) compared to 0.52% (3/579) in comparator
NSAIDs (p=NS, by Fisher's Exact). Given the 2:1 (parecoxib/valdecoxib:
placebo) randomization in the CABG trial the 4 deaths in that study may
bias the rates. This study was in an enriched population for serious
cardiovascular adverse events and used a dose not proposed for chronic
use. The rates excluding this trial are 0.6% for valdecoxib compared to
0.5% for the NSAID comparators.

The rate of cardiovascular thromboembolic deaths ( including arrhythmia,
MI and PVD) in the controlled database was 0.5% (6/1283) for valdecoxib
and 0.3% (2/579) for the NSAID groups combined. Excluding the CABG study
the rates for such events was 0.3% (4/1283) for valdecoxib and 0.3% for
NSAID comparators. The number of events was small and there was no
pattern seen based on dose or duration of therapy. Excluding the CABG
trial there was no clear signal for differences in event rates between
valdecoxib and comparator NSAIDs. A large outcome study employing
chronic dose therapy would be needed to address this issue further. Such
as study would include overall safety including cardiovascular, renal
and GI endpoints as well as overall deaths and serious adverse events.

**Requested Cardiovascular Safety Analysis in High Risk Patients**

Concerns have been raised regarding COX-2 selective agents and
cardiovascular safety following outcome study (VIGOR) of one such agent.
Based on these concerns a subanalysis of cardiovascular events in high
risk patients was requested by the reviewer. The following tables do not
suggest a higher risk of cardiovascular events in an enriched population
of "high risk" or "at risk" patients for valdecoxib compared to the
NSAID comparators. The small number of patients exposed precludes robust
comparisons.

**HIGH RISK PATIENTS\*: Rates of Serious Thromboembolic Cardiovascular**

**Adverse Events\*\***

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