Senate Hearing on Worldwide Withdrawal of
Vioxx
Event: Committee
Hearing: “FDA, Merck, and Vioxx: Putting Patient Safety First?”
Date/time: Thursday, Nov. 18, 2004, at 10 a.m.
Location: 215 Dirksen
Senate Office Building, Washington, D.C.
Description: In the past year, Sen. Chuck
Grassley, chairman of the Committee on Finance, has been examining whether the
Food and Drug Administration has made fundamental mistakes in managing public health risks with antidepressants in
children and, most recently, with
Vioxx, the pain medication for arthritis just withdrawn from the market
over concerns that it increases the risk for heart attack and stroke. Grassley
is concerned that the American public has
been kept in the dark. With more Americans relying on prescription drugs than ever before, and with federal
programs Medicare and Medicaid poised to pay for more prescription drugs
than in history, Grassley feels a critical
look at drug safety and the worldwide withdrawal of Vioxx is overdue.
The hearing will mark the first time the leaders of the FDA and Merck, maker of
Vioxx, will testify on Capitol Hill about Vioxx’s safety problems.
“Like most Americans,
I’ve always thought that when the FDA approves a drug, it’s like the
good housekeeping seal of approval,” Grassley said. “If the drug’s not safe,
the FDA would know and take it off the market. The alarming revelations about Vioxx make me a whole lot more skeptical. It looks
like the FDA and Merck saw a lot of red flags from the beginning. The
agency must address what looks like systemic
problems when it comes to putting public health and safety first and public
relations second. And Merck must stand up
and set the record straight about what it knew about cardiovascular risks associated with Vioxx and when the company
knew it. It appears that life-and-death decisions are being made behind
closed doors. The American people should never be the last to know that their
lives are at risk when taking a prescription drug.”
Principal Witness: Gurkirpal
Singh, MD, Adjunct Clinical Professor of Medicine, Division of Gastroenterology
and Hepatology, Department of Medicine, Stanford University School of Medicine,
Stanford, Calif. (via videoconference) – Dr. Singh is a former Merck
consultant with extensive knowledge and expertise on Vioxx. Chief
Science Officer of Institute of Clinical Outcomes Research and Education
(ICORE).
Dr. Singh, (testifying by
videoconference):
Thank you
for inviting me to testify before the Senate Finance Committee. I apologize for
not appearing in person, and giving this testimony by a video conference. I am
unable to travel because exactly two weeks ago today, I had a heart attack –
and before the plaintiff’s attorneys rush out of this room to call me - no, I
was not taking Vioxx.
I have been asked to review the
science of Cox-2 inhibitors, the link of rofecoxib to
heart attacks, the timeline of different studies, and my own role in teaching
physicians about these issues. Hindsight is always 20/20, and I do not intend
to be a Monday morning quarterback today. Instead, I will try to highlight the learnings and knowledge that we can derive from this
episode so that early signals are not missed again with another drug. At the
end of my presentation, I will make recommendations that I believe are essential
to avoid a repetition of this unfortunate incident where millions of Americans
were unknowingly subjected to serious harm.
I am a
rheumatologist by clinical training with research interests and expertise in
drug safety and epidemiology. My group and I were instrumental in pointing out
the risks of painkillers such as motrin and aleve (a class of drugs called NSAIDs),
identification of patients who have a risk of serious stomach bleeding from
such drugs and potential ways to avoid such risks. I have been working in the
research area of drug safety and outcomes research for almost 15 years, and
have published extensively in the medical literature. I am currently working
with large public datasets such as Medicare and Medicaid to study early safety
signals of medications. I lecture medical students, residents and other
physicians, both at Stanford, and in conferences worldwide, on many of these
issues.
Science of specific Cox-2 inhibitors
There are
2 enzymes in the human body – cox-1 and cox-2 (attachment 1). Cox-1 enzyme is
needed for the normal functioning of stomach and platelets. Cox-2 enzyme, on
the other hand, is thought to be responsible for pain and sweling
of arthritis. Traditional painkillers such as ibuprofen (the chemical in motrin) inhibit both cox-1 and cox-2. This means that while
these drugs are effective in reducing pain, they increase the risk of stomach
bleeding. A few years ago, my colleagues and I estimated that there are over
103,000 hospitalizations and 16,500 deaths every year from the stomach bleeding
complications of these drugs (1, 2). The specific cox-2 inhibitor drugs such as
Vioxx and Celebrex, were developed to inhibit only
cox-2, and not cox-1. It was hoped that these drugs would relieve pain but not
have any stomach problems. Indeed, this seems to be the case. In May 2004, I
presented data that showed a significant reduction in the number of stomach
bleeds in the US after the launch of these drugs (3). However, it is important
to remember that drugs such as Vioxx do not cure arthritis – they are used only
for control of pain, and are medicines for convenience and quality-of-life
improvement rather than for savings lives or preventing disabilities. There are
many other ways to effectively control pain as well.
Heart Attacks
It is
believed that most heart attacks occur when the blood vessels supplying blood
to the heart become narrowed because of cholesterol deposits (attachment 2),
and a blood clot forms at this narrowing, stopping the flow of oxygen to the
heart muscle. The blood clot is formed by cells called platelets, and it is the
cox-1 enzyme in the platelets that is responsible for this function. Aspirin
destroys this enzyme in a permanent fashion and prevents blood from clotting in
the heart blood vessels, thus helping reduce the risk of heart attacks. Other
painkillers such as ibuprofen and naproxen also inhibit the enzyme in the
platelets, but only temporarily and incompletely. While it is possible that
these non-aspirin painkillers may also reduce the risk of heart attacks, this
has never been shown in any randomized clinical trial, despite claims to the
contrary (4). These drugs are not used for preventing heart attacks since even
if they were to be effective, the effect of temporary and incomplete inhibition
of platelet would be much less beneficial than the complete and permanent
inhibition caused by aspirin.
Vioxx
and Risk of Heart Attacks
The Senate Finance Committee provided me with information on events
surrounding the approval and withdrawal of Vioxx, and the
supporting documents attached to my testimony. I have been asked to comment on
this with the specific purpose of identifying key events that should have
alerted scientists and public to the potential problems with Vioxx so that a similar
problem can be avoided in the future with another drug.
Before I
review the attachments, I wish to reiterate that the fundamental principle of
medicine – one that every physician swears by is - Primum,
Non Nocere – First, Do No Harm. A second principle is
a careful evaluation of risk-benefit ratio of any treatment. It is easier to
accept a more serious side-effect such as heart attack in a drug that cures
cancer, for example, than in one that is used to treat skin rash.
We now know that by November of
1996, Merck scientists (5) were seriously discussing a
potential risk of Vioxx – association with heart attacks (attachment 3). At
that time, it was not known that Vioxx may itself cause heart attacks. Rather,
the discussion focused on the issue that other painkillers by inhibiting
platelets may protect against heart attacks. Vioxx has no such
effect
on platelets, and thus may seem to increase the risk of heart attacks in
studies comparing it to other painkillers. This was a serious concern because
the entire reason for the development of Vioxx was safety – please note, once
again, that it is no more effective than older NSAIDs.
If the improved stomach safety of the drug was negated by a risk of heart
attacks, patients may not be
willing to
make this trade-off. Merck scientists, considered by many to be the best and
brightest in the pharmaceutical industry, were among the first to recognize
this. At this point in time, scientists should have started a public discussion
about this potential trade-off, and designed studies that would more carefully
evaluate the risk-benefit ratio of the drug.
It appears
from the internal Merck e-mails provided to me (attachment 4), that in early
1997, Merck scientists were exploring study designs that would exclude people
who may have a weak heart so that the heart attack problem would not be
evident. The discussion also focused on the fact that if aspirin were permitted
in these trials, there may not be any significant safety advantage of Vioxx on
the stomach. On the other hand, as one scientist pointed out, if aspirin was
excluded, patients on Vioxx may have more heart attacks and this would “kill
the drug”. He also points out that in the real world, “everyone is on it”.
Clinical trials should be designed to test a drug under “real world”
circumstances – on patients who are most likely to use the drug. Clinical
trials should not be designed to selectively favor one outcome over another by
excluding people similar to those who would take the drug after its approval.
Certainly, clinical trials should not be designed to put marketing needs in
front of patient safety – we need to know how a
drug
behaves in people who are going to take it, even if it “kills the drug”. It is
better to kill a drug than a kill a patient.
According
to documents provided to me by the Senate Committee, there were many other
internal discussions within Merck on these concerns of heart attack-stomach
bleed trade-offs, although the practicing physician did not learn of any of
this till many years later. In 1998, Dr. Doug Watson, a Merck scientist
presented an analysis of serious heart problems with Vioxx compared to patients
enrolled in studies of other Merck drugs. This analysis (attachment 5)
concluded that men taking Vioxx had a 28% greater risk (not statistically
significant), but in women, the risk was more than double (216%, statistically
significant) compared to people not taking any drug in other Merck studies. To
the best of my knowledge, these data were never made public. This is when a
public scientific discussion of the pros and cons of the medication should have
started.
By
1999, an even more serious problem was emerging. By the time Merck had filed
for the approval of Vioxx, there were several small studies evaluating the
efficacy and safety of Vioxx in patients with pain and arthritis. None of these
studies were large enough to study the risk-benefit trade offs of stomach
bleeds versus heart attacks. But a careful FDA review of Merck’s new drug
application for Vioxx, Dr. Villalba (attachment 6)
noticed that “thomboembolic events [such as heart
attack and stroke] are more frequent in patients receiving VIOXX than placebo…”
[page 105]. Among 412 patients taking placebo, 1 had a cardiovascular event
(0.24%); and among the 1631 patients receiving 12.5 mg or more of VIOXX daily,
12 had a cardiovascular event (0.74%) (6). This meant that not only did VIOXX
not inhibit the platelets, but for some reason, it was likely to promote heart
attacks directly. Many scientists would consider this three-fold difference as
an early warning sign. But there were no adequate data to make a firm
conclusion one way or another. In fact, the FDA reviewer went on to point out
that: “With the available data, it is impossible to answer with complete
certainty whether the risk of cardiovascular and thromboembolic
events is increased in patients on rofecoxib. A
larger database will be needed to answer this and other safety comparison
questions” [page 105]. It is my opinion that at this point in time, larger and
more definitive studies should have been done before the drug was approved.
After all, the drug was no more effective than any other available pain-killer
– and there were nearly 30 such drugs available in the US. Another drug (celebrex) that had no such signal had also been available
in the market for 6 months prior. A combination of two older drugs – a
pain-relieving drug such as motrin with a drug that
protects the stomach such as prilosec – is as
effective and almost as safe on the stomach as Vioxx, with no heart attack risk.
There was certainly no emergent need to approve Vioxx without further studies
if there
were lingering safety concerns. The trade -off of heart attacks for the rare
instances of stomach bleeds is not a reasonable one. Remember, primum non nocere – first, do no
harm. Instead, the drug was approved by the FDA in a priority review within 6
months – with no discussion on the heart attack trade-off. The prescribing
physicians remained unaware of any of these data or discussions, till much
later – with the new label change in April, 2002.
VIGOR Trial and my interaction with Merck
The VIGOR
trial, which will be discussed in detail later, was the first public release of
heart attack-stomach bleed trade-off concerns. At the time VIGOR study results
were announced, I was actively involved in research and teaching in this area.
Some of my medical education lectures were sponsored by Merck and other drug
companies. I was strongly in favor of this new class of drugs, and before the
VIGOR trial, was unaware of any significant heart attack issues. The results of
the VIGOR trial – a 500% increase in the risk of heart attacks with Vioxx –
stunned me. Clearly, the trade-off of 500% increase in heart attacks for a 50%
reduction in stomach bleeds did not seem attractive – at least, not without a
further discussion of data. Merck’s press release on this issue and a brief
mention of the heart attack data were not enough for me to continue to educate
physicians in my lectures. I asked Merck for more detailed data, including
information on high blood pressure and heart failure rates. When I was unable
to obtain this data after multiple requests, I added a slide to my
presentations that showed a man --representing the missing data -- hiding under
a blanket (attachment 7). Up until this point in time, Merck had responded to
all my requests promptly and in a scientific fashion. With VIGOR, suddenly it
was as if the Company had to think what questions to answer. I persisted in my
enquiries – and I was warned that if I continued in this fashion, there would
be serious consequences for me. I was told that Dr. Louis Sherwood, a Merck
senior vice-president, and a former Chief of Medicine at a medical school, had
extensive contacts within the academia and could make life “very difficult” for
me at Stanford and outside. But as a research scientist, I felt that it was
unethical for me not to discuss my concerns in public. An open scientific
debate was important – it is only through open debate and discussion that we
advance science. Dr. Sherwood called several of my superiors at Stanford to
complain (attachment 8). Subsequently, I learnt that this was a persistent
pattern of intimidation by Dr. Sherwood. Professor Fries too felt that this
suppression of scientific discussion was unethical and complained to Mr.
Raymond Gilmartin (attachment 9). Mr. Gilmartin and Mr. David Anstice
took immediate action, and the threats stopped immediately. From then onwards
till today, Merck scientists and officials have treated me and my colleagues
with appropriate respect and have always shared scientific data promptly.