Healthy Skepticism Library item: 5565

Warning: This library includes all items relevant to health product marketing that we are aware of regardless of quality. Often we do not agree with all or part of the contents.

Publication type: report

FDA
NDA 21-042 Vioxx (rofecoxib) tablets MACMIS ID # 9456 WARNING LETTER
: FDA 2001 Sep 21

Abstract:

Raymond V. Gilmartin
President and CEO
Merck & Co., Inc.
P.O. Box 1000, UG3BC-10
North Wales, PA 19454-1099

RE: NDA 21-042 Vioxx (rofecoxib) tablets MACMIS ID # 9456

WARNING LETTER

Dear Mr. Gilmartin:

This Warning Letter concerns Merck & Co. Inc.‘s (Merck) promotional
activities and materials for the marketing of Vioxx (rofecoxib)
tablets.
Specifically, we refer to promotional audio conferences given on behalf
of
Merck by Peter Holt, MD, a press release, and oral representations made
by
Merck sales representatives to promote Vioxx. As part of its routine
monitoring and surveillance program, the Division of Drug Marketing,
Advertising, and Communications (DDMAC) has reviewed your promotional
activities and materials and has concluded that they are false, lacking
in
fair balance, or otherwise misleading in violation of the Federal Food,
Drug, and Cosmetic Act (the Act) and applicable regulations. See 21
U.S.C.
§§ 331(a) and (b), 352(a), (f), and (n), and 355 (a).

You have engaged in a promotional campaign for Vioxx that minimizes the
potentially serious cardiovascular findings that were observed in the
Vioxx
Gastrointestinal Outcomes Research (VIGOR) study, and thus,
misrepresents
the safety profile for Vioxx. Specifically, your promotional campaign
discounts the fact that in the VIGOR study, patients on Vioxx were
observed
to have a four to five fold increase in myocardial infarctions (MIs)
compared to patients on the comparator non-steroidal antiinflarnmatory
drug
(NSAID), Naprosyn (naproxen).

Although the exact reason for the increased rate of MIs observed in the
Vioxx treatment group is unknown, your promotional campaign selectively
presents the following hypothetical explanation for the observed
increase in
MIs. You assert that Vioxx does not increase the risk of MIs and that
the
VIGOR finding is consistent with naproxen’s ability to block platelet
aggregation like aspirin. That is a possible explanation, but you fail
to
disclose that your explanation is hypothetical, has not been
demonstrated by
substantial evidence, and that there is another reasonable explanation,
that
Vioxx may have pro-thrombotic properties.

You have also engaged in promotional activities that minimize the Vioxx
/
Coumadin (warfarin) drug interaction, omit important risk information,
make
unsubstantiated superiority claims against other NSAIDs, and promote
Vioxx
for unapproved uses and an unapproved dosing regimen. In addition, in
misrepresenting the Vioxx / warfarin drug interaction you also
misrepresent
Vioxx’s safety profile by minimizing the potentially serious risk of
significant bleeding that can result from using Vioxx and warfarin
concomitantly.

Your minimizing these potential risks and misrepresenting the safety
profile
for Vioxx raise significant public health and safety concerns. Your
misrepresentation of the safety profile for Vioxx is particularly
troublesome because we have previously, in an untitled letter, objected
to
promotional materials for Vioxx that also misrepresented Vioxx’s safety
profile.

Background

Vioxx is a NSAID with selective cyclooxygenase 2 (COX-2) inhibitory
properties. It was approved on May 20, 1999, for the treatment of
primary
dysmenorrhea, for the management of acute pain in adults, and for
relief of
the signs and symptoms of osteoarthritis.

Prior to approval, endoscopy studies were submitted to the original NDA
database demonstrating that treatment with Vioxx 25 mg or 50 mg daily
was
associated with a significantly lower percentage of endoscopically
apparent
gastroduodenal ulcers than treatment with ibuprofen 2400 mg daily.
Because
the correlation between findings of endoscopic studies and the relative
incidence of clinically serious upper gastrointestinal (GI) events was
unknown, after approval, Merck sponsored the VIGOR study to obtain
information regarding clinically meaningful upper GI events and to
develop a
large controlled database for overall safety assessment.

The VIGOR study included approximately 4000 patients per treatment arm
(Vioxx 50 mg a day or naproxen 1000 mg a day) treated for a median time
of 9
months. The primary endpoint of the study was the relative risk of
confirmed PUBs (perforations, symptomatic ulcers, and GI bleeds) in
patients
with rheumatoid arthritis taking Vioxx 50 mg daily (two to four times
the
approved dosing regimen for Vioxx in osteoarthritis), compared to
patients
taking naproxen, 1000 mg daily. The. study also compared the safety
and
tolerability of the two treatments in patients with rheumatoid
arthritis.
The results of the study demonstrated that patients on Vioxx had a
significantly lower cumulative incidence of PUB’S compared to patients
on
naproxen (2.08% and 4.49% for Vioxx and naproxen, respectively).

Other important results from the VIGOR study included the unexpected
findings that investigator reported serious cardiovascular events
occurred
in 101 patients (2.5%) in the Vioxx treatment group compared to 46
patients
(1.1 %) in the naproxen treatment group, and MIs occurred in 20
patients
among 4047 in the Vioxx treatment group (0.5%), compared to four
patients
among 4029 in the naproxen treatment group (0.1%). These unexpected
findings were extensively discussed at the FDA Arthritis Advisory
Committee
Meeting on February 8, 2001. Although, the reason for these
differences is
not clear, possible explanations include both an ability of naproxen to
function as a cardioprotective agent and a pro-thrombotic property of
Vioxx.

Promotional Audio Conferences

We are aware of six promotional audio conferences, presented on behalf
of
Merck by Peter Holt, MD that are in violation of the Act and its
implementing regulations. These audio conferences were held on June 8,
2000, June 13, 2000, June 16, 2000, and three on June 21, 2000, and
were
moderated by Merck employees.

On December 12, 2000, we sent you a written inquiry about your
involvement
with and influence on the initiation, preparation, development, and
publication of audio conferences given by Dr. Holt. We also asked you
to
describe the nature of the relationship between you and Dr. Holt. In
your
response dated January 5, 2001, you stated that, “Dr. Holt entered into
a
speaker contract with Merck on June 22, 1999.” You also stated that,
“Merck
has determined that we arranged for Dr. Holt to speak at ten audio
conferences in 2000. Merck Business Managers provided him with the
topic for
the audio conferences and, for two of the audio conferences, asked him
to
address the safety profiles of Vioxx and other NSAIDs.”

The promotional audio conferences identified above, arranged by, and
presented on behalf of, Merck were false or misleading in that they
minimized the MI results of the VIGOR study, minimized the Vioxx /
Cournadin
drug interaction, omitted important risk information, made
unsubstantiated
superiority claims, and promoted Vioxx for unapproved uses and an
unapproved
dosing regimen. Our specific objections follow.

Minimization of MI Results

Statements made during the promotional audio conferences identified
above
minimize the potentially serious MI risk that may be associated with
Vioxx
therapy. For example, in your June 21, 2000, audio conference you
begin
your discussion of the MI rates observed in the VIGOR study by stating,
“When you looked at the MI rate the rate was different for the two
groups.
The MI rate for Vioxx was 0.4 percent and if you looked at the Naprosyn
arm
it was 0.1 percent, so there was a reduction in MIs in the Naprosyn
group.”
You then present your explanation as to why the Vioxx treatment arm had
an
increased rate of MIs compared to the naproxen treatment arm.
Specifically,
you state that,

Vioxx is a wonderful, effective, selective COX-2 inhibitor that
inhibits
COX-2 but at the doses used does not inhibit COX-1. So therefore
without
the COX-1 inhibition you don’t inhibit platelets, you don’t prolong
bleeding
time and therefore it cannot be used as a cardiovascular protective
drug.
Naprosyn on the other hand is a wonderful platelet inhibitor, prolongs
bleeding time and inhibits platelets identically to aspirin. Obviously
the
binding with Naprosyn is reversible and with aspirin is irreversible,
but
the effect on platelets and bleeding time is identical in terms of its
effect and therefore functions as a wonderful drug for cardiovascular
prophylaxis. So basically the MI rates are in sync with what we know
about
Vioxx and what we know about Naprosyn.

In fact, the situation is not at all clear. There are no adequate and
well-controlled studies of naproxen that support your assertion that
naproxen’s transient inhibition of platelet aggregation is
pharmocodynamically comparable to aspirin or clinically effective in
decreasing the risk of MIs. Therefore, your representation that
naproxen
prolongs bleeding time and inhibits platelets identically to aspirin is
misleading, and minimizes the potential seriousness of this finding. As
you
know, the reason for the difference between Vioxx and naproxen has not
been
determined; it is also possible that Vioxx has pro-thrombotic
properties.
Also, the MI rate that you report for Vioxx is inaccurate; the MI rate
for
Vioxx in the VIGOR study was 20 Mls among 4047 patients (0.5%), not
0.4%, as
you stated.

Your minimization of the seriousness of the MI rates observed in the
Vioxx
treatment arm of the VIGOR trial is further reinforced in your audio
conferences by your discussion of a retrospective analysis of this
trial.
For example, in your June 21, 2000, audio conference, you state that,

…Merck went and pulled out those patients that again were enrolled in
VIGOR and asked the question, who were those patients that really
needed
secondary cardiovascular prophylaxis from the get go, and that ended up
being four percent of the study group in VIGOR based on whether there
was a
prior MI, stroke, TIA, angina, CABG or PTCA…. Now if you look at the
remaining part of VIGOR, which is 96 percent of the VIGOR population,
and
once again looked for the MI rate between Naprosyn and Vioxx, there’s
no
statistically significant difference in the MI rate between Naprosyn
and
Vioxx. In fact, Naprosyn is 0.2 percent and Vioxx is 0.1 percent.

Your claim that the MI rate for naproxen was 0.2 percent and for Vioxx
was
0.1 percent is again. inaccurate. Contrary to your claim that there
was a
higher rate of MIs in the naproxen group compared to the Vioxx group,
the MI
rate for Vioxx in this subpopulation was 12 MIs among 3877 patients
(0.3%)
as compared to 4 MIs among 3878 patients (0.1%) for naproxen.

Moreover, you again minimize the Vioxx MI rate observed in the VIGOR
study
by your comparison of this rate to the rate of MIs observed for
Celebrex
(celecoxib) in the Celebrex Long-Term Arthritis Safety Study (CLASS).
For
example, in your June 21, 2000, audio conference you state, “Now if you
remember the crude MI rate of Vioxx in VIGOR that number was 0.4
percent
which is basically the same or in fact a little bit less then the crude
MI
rate of Celebrex in CLASS which is 0.5 percent.” Your claim that the
MI
rates of Vioxx compared to Celebrex were basically the same, “or in
fact a
little bit less” is misleading. You are comparing MI rates from two
different trials with different patient populations. For example,
patients
who had angina or congestive heart failure with symptoms that occurred
at
rest or minimal activity and patients taking aspirin, including
low-dose
(325 mg or less, daily or every other day) or other antiplatelet agents
(e.g., ticlopidine) were excluded from the VIGOR trial. The CLASS
trial in
contrast, did not exclude patients of this type. The CLASS trial thus
may
have included patients at a higher risk for MIs.

Minimization of Vioxx / Coumadin Interaction

Statements made during your promotional audio conferences also minimize
the
risk of Vioxx therapy in patients who are taking warfarin. For
example, in
your June 16, 2000, audio conference you stated that, “…if you look
at the
thromboembolic events it’s very clear that these selective COX-2
inhibitors
have the benefit of not having platelet aggregation and bleeding time,
and
therefore, can be used safely in terms of post-op and with Coumadin.”
Your
statement that Vioxx can be used safely with warfarin minimizes the
precaution in the PI that states that “…in post-marketing experience,
bleeding events have been reported, predominately in the elderly, in
association with increases in prothrombin time in patients receiving
Vioxx
concurrently with warfarin.” Your promotion minimizing the risk of
using
Vioxx and warfarin concurrently is particularly troublesome because
Merck
was aware of this potentially dangerous drug interaction in 1999, well
before these audio conferences occurred. In fact, Merck began
disseminating
a revised PI in October 1999, which included new information about this
risk.

The seriousness of this interaction is further minimized by your
suggestion
that COX-2 inhibitors, including Vioxx, can be used safely with
warfarin
because it “has the benefit of not having platelet aggregation and
bleeding
time.” This clam implies that Vioxx is safer than other NSAIDS used
in
combination with warfarin. However, Vioxx has not been studied in
head-to-head trials prospectively designed to assess this specific
endpoint.
Your superiority claim is therefore misleading.

We note that earlier in your June 16, 2000, promotional audio
conference you
state, “It can be used in people with Coumadin, although with Coumadin
you’ve got to check their INR three and four days after you add the Cox
inhibitor to the Coumadin because there may be a bump in the INR.”
This
disclosure does not correct the overall misleading message, however,
nor
does it correct your suggestion that Vioxx is safer than other NSAIDs
in
patients taking warfarin.

Omission of Important Risk Information

Your promotional audio conferences fail to present serious and
significant
risks associated with Vioxx therapy. For example, your promotional
audio
conferences fail to state that Vioxx is contraindicated in patients who
have
experienced asthma, urticaria, or allergic-type reactions after taking
aspirin or other NSAIDs. You also fail to present the gastrointestinal
(GI)
warning about the possibility of serious GI toxicity such as bleeding,
ulceration, or perforation in patients taking Vioxx. Moreover, you
fail to
present Vioxx’s precautions for use in patients who have liver and
kidney
disease, information about patient populations in which Vioxx’s use is
not
recommended, such as women in late pregnancy, and information about
Vioxx’s
most common adverse events.

Unsubstantiated Superiority Claims

You make several unsubstantiated superiority claims for Vioxx
throughout
your promotional audio conferences. For example, in your June 16,
2000,
audio conference, you claim that, “The importance of [VIGOR and CLASS]
is
that the data is going to really help change I believe the package
inserts
for [Vioxx and Celebrex] down the road because it really shows once
again
that they are safer than nonsteroidals.” Your suggestion that COX-2
inhibitors, including Vioxx, have an overall safety profile that is
superior
to other NSAIDs is misleading because such an advantage has not been
demonstrated. In fact, in the VIGOR study the incidence of serious
adverse
events was higher in the Vioxx treatment group than in the naproxen
treatment group (9.3% and 7.8% for Vioxx and naproxen, respectively).
The
results of safety analyses that were pre-specified in the protocol for
the
VIGOR trial, such as CHFrelated adverse events and discontinuations due
to
edema-related adverse events, hepatic-related adverse events,
hypertension-related adverse events, and renal-related adverse events
were
all numerically higher (in some cases statistically significantly
higher) in
the Vioxx treatment group than in the naproxen treatment group_
Furthermore,
your claim that the VIGOR and CLASS trials “show once again that they
are
safer than non-steroidals” is also misleading because it implies that
the
results of the VIGOR trial (i.e., patients on Vioxx had a significantly
lower cumulative incidence of PUBS than patients on naproxen) can be
applied
to the entire class of NSAIDs.

In your June 16, 2000, audio conference you state, “…if you look at
the
thromboembolic events it’s very clear that these selective COX-2
inhibitors
have the benefit of not having platelet aggregation and bleeding time,
and
therefore, can be used safely in terms of post-op and with Coumadin.”
This
claim suggests that Vioxx is safer, or has fewer side effects, than
other
NSAIDs used in the post-operative setting because COX-2 inhibitors do
not
affect platelet aggregation and bleeding time. Vioxx has not been
studied,
however, in head-to-head trials prospectively designed to assess its
safety
compared to other NSAIDS in the post-operative setting. Your
superiority
claim is therefore misleading.

Further examples of your unsubstantiated superiority claims include
your
claim that, “In terms of half life Vioxx has a half life of 17 hours
and is
truly a once a day drug, whereas Celebrex has a half life of 1 I hours
and
is a BID (twice a day) drug,” stated in your June 16, 2000, audio
conference. This claim is misleading because it suggests that Celebrex
must
be dosed twice a day for all of its approved indications. In fact,
Celebrex
is approved for use either twice a day, or once a day, for the
treatment of
osteoarthritis. Therefore, your claim that Celebrex is a “BID drug” is
misleading.

Promotion of Unapproved Uses

Your audio conferences are misleading because they promote Vioxx for
unapproved uses. For example, in your June 21, 2000, conference, you
claim
that in the VIGOR study, “…the Vioxx 50 milligrams a day and the
Naprosyn,
a gram a day, were absolutely equally effective in terms of treating
the
patients with rheumatoid arthritis.” Your claim is misleading because
it
suggests that Vioxx is effective for the treatment of rheumatoid
arthritis
when this has not been demonstrated. The VIGOR study was not designed
to
assess the efficacy of Vioxx for the treatment of rheumatoid arthritis.
Your claim that Vioxx is “absolutely equally effective” to naproxen in
treating patients with rheumatoid arthritis is also misleading because
this
has not been demonstrated by adequate and well-controlled clinical
studies,
and because the VIGOR study was not capable of assessing their
comparative
effectiveness.

Your promotional audio conferences are also misleading because they
suggest
that Vioxx is safe and effective for other unapproved uses such as the
prevention of cancer and invasive cancer, and for the treatment of
Alzheimer’s disease and gout. Examples of claims that promote Vioxx
for
unapproved uses, include, but are not limited to, your claims in your
June
16, 2000 audio conference that, “…COX-2 seems to be able to interfere
with
… programmed cell death. Therefore, you get this increased cell
growth
which allows polps to form, cancer and then invasive cancer. And by
blocking COX-2 you can actually prevent the development of colon
polyps,
cancer and invasive cancer.” Additional examples include your claims
that
“So we tried it [Vioxx] after Vioxx was released and really within one
or
two pills acute attacks o£ gout were being shut down,” and
“Specifically, if
you looked at potential uses of these drugs, the most exciting right
now I
guess in two areas, one is Alzheimer’s disease….”

Press Release

We have identified a Merck press release entitled, “Merck Confirms
Favorable
Cardiovascular Safety Profile of Vioxx,” dated May 22, 2001, that is
also
false or misleading for similar reasons stated above. Additionally,
your
claim in the press release that Vioxx has a “favorable cardiovascular
safety
profile,” is simply incomprehensible, given the rate of MI and serious
cardiovascular events compared to naproxen. The implication that
Vioxx’s
cardiovascular profile is superior to other NSAIDs is misleading; in
fact,
serious cardiovascular events were twice as frequent in the VIOXX
treatment
group (101 events, 2.5%) as in the naproxen treatment group (46 events,
1.1%) in the VIGOR study.

Oral Representations

Merck sales representatives have engaged in false or misleading
promotional
activities that also minimize the potentially serious MI results
observed in
the VIGOR trial. Specifically, Merck sales representatives made false
or
misleading statements to DDMAC reviewers at two different professional
meetings. At your exhibit booth during the 119th Annual Meeting of the
Maryland Pharmacists Association (MPhA), in Ocean City, Maryland, June
9 – June 12, 2001, your representative stated that the increased MI rate
seen in
patients on Vioxx in the VIGOR study is due to the fact that naproxen
works
just like aspirin (i.e., inhibits clotting and platelet aggregation).
In
addition, during the Annual Meeting of the American Society of
Health-Systems Pharmacists (ASHP), in Los Angeles, California, June 3 –
June
6, 2001, your representative stated that Vioxx had a greater MI rate in
the
VIGOR trial because naproxen is cardioprotective, having platelet
effects
similar to aspirin. These statements made by your sales
representatives are
misleading for the reasons stated above.

Conclusions and Requested Actions

The promotional activities and materials described above minimize the
potentially serious cardiovascular findings that were observed in the
VIGOR
study, minimize the Vioxx. / Cournadin drug interaction, omit crucial
risk
information associated with Vioxx therapy, contain unsubstantiated
comparative claims, and promote unapproved uses. On December 16, 1999,
we
also objected to your dissemination of promotional materials for Vioxx
that
misrepresented Vioxx’s safety profile, contained unsubstantiated
comparative
claims, and lacked fair balance.

Due to the seriousness of these violations, and the fact that your
violative
promotion of Vioxx has continued despite our prior written notification
regarding similar violations, we request that you provide a detailed
response to the issues raised in this Warning Letter on or before
October 1,
2001. This response should contain an action plan that includes a
comprehensive plan to disseminate corrective messages about the issues
discussed in this letter to the audiences that received these
misleading
messages. This corrective action plan should also include:

Immediately ceasing all violative promotional activities, and the
dissemination of violative promotional materials for Vioxx.
Issuing a “Dear Healthcare provider” letter to correct false or
misleading
impressions and information. This proposed letter should be submitted
to us
for review prior to its release. After agreement is reached on the
content
and audience, the letter should be disseminated by direct mail to all
healthcare providers who were, or may have been exposed to the
violative
promotion.
A written statement of your intent to comply with “I” and “2” above.
Your written response should be received no later than October 1, 2001.
If
you have any questions or comments, please contact Lesley Frank, Ph.D.,
JD,
by facsimile at (301) 594-6771, or at the Food and Drug Administration,
Division of Drug Marketing, Advertising and Communications, HFD-42, Rm.
1713-20, 5600 Fishers Lane, Rockville, MD 20857. We remind you that
only
written communications are considered official.

In all future correspondence regarding this particular matter, please
refer
to MACMIS ID #9456 in addition to the NDA number.

The violations discussed in this letter do not necessarily constitute
an
exhaustive list. We are continuing to evaluate other aspects of your
promotional campaign for Vioxx, and may determine that additional
remedial
messages will be necessary to fully correct the false or misleading
messages
resulting from your violative conduct.

Failure to respond to this letter may result in regulatory action,
including
seizure or injunction, without further notice.

Sincerely,

Thomas W. Abrams, R.Ph., MBA
Director
Division of Drug Marketing, Advertising, and Communications