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FDA, Merck and Vioxx: Putting Patient Safety First?

November 18 , 2004, at 10:00 a.m. in 216 Hart Senate Office Building

Member Statements: 

Charles Grassley, IA

Max Baucus, MT

Witness Statements: 

Panel I

Dr. David J. Graham, MPH, Associate Director for Science, Office of Drug Safety, 

Center for Drug Evaluation and Research, U.S. Department of Health and Human 

Services, Food and Drug Administration, Washington, DC

Panel II

Dr. Gurkirpal Singh, Adjunct Clinical Professor of Medicine, Division of 

Gastroenterology and Hepatology, Department of Medicine, Stanford University School 

of Medicine, Stanford, CA

Dr. Bruce M. Psaty, PhD, Professor, Medicine & Epidemiology, University of 

Washington, Cardiovascular Health Research Unit, Seattle, WA

Panel III 

Dr. Sandra L. Kweder, Acting Director, Office of New Drugs, Center for Drug 

Evaluation and Research, U.S. Department of Health and Human Services, Food and 

Drug Administration, Washington, DC

Panel IV

Mr. Raymond V. Gilmartin, Chairman, President & Chief Executive Officer, Merck & 

Co., Whitehouse Station, NJ
Opening Statement of U.S. Senator Chuck Grassley of Iowa

Chairman, Senate Committee on Finance

Hearing – FDA Merck and Vioxx: Putting Patient Safety First?

Thursday, November 18, 2004

Good morning. We’re here today because Congress has a Constitutional duty to conduct

oversight of the executive branch of government. Congressional oversight can expose

wrongdoing in the federal bureaucracy and in the private sector. Congressional oversight can

shed disinfecting sunlight. It can result in accountability and necessary reforms for the public

good. Today’s hearing will consider allegations of mismanagement by the Food and Drug

Administration and the Merck pharmaceutical company regarding the safety of the painkiller

Vioxx.

On September 30th of this year, Merck withdrew Vioxx from the worldwide market. A

blockbuster drug became a blockbuster disaster. Before September 30th, Vioxx was the subject

of controversy in the scientific community behind closed doors. Today we will look out in the

open at the decisions made about Vioxx. Depending on the perspective you take, Vioxx either

changed lives for the better or ended lives prematurely.

Historically the Food and Drug Administration has met its charge to protect the health

and safety of the American people. Those who work at the agency are by and large committed to

doing no harm. Even so, the FDA has also stood watch over failures when it comes to drug

safety.

Likewise, the pharmaceutical industry in the United States has achieved extraordinary

advancements in medicine. Drug makers have helped to save lives and improve the quality of

life of people around the world. They’ve profited by doing so. At the same time, the industry

has contributed to the skyrocketing costs of health care and settled billions of dollars in false

claims against the government, including both civil and criminal actions.

Merck & Co. has a reputation for excellence in research and development. Yet today

Merck is faced with one of the worst drug disasters in history. Merck acknowledged that Vioxx

carried with it serious cardiovascular risks when it withdrew the drug from the market. During

today’s hearing we’ll hear about the red flags that were raised about those risks in the years

before and the years after Vioxx was approved by the FDA.

The Finance Committee has jurisdiction over the Medicare and Medicaid programs. 
Accordingly, the committee has a responsibility to the more than 80 million Americans who

receive health care coverage — including prescription drugs — under these programs. Of the 20

million Americans who reportedly took Vioxx, an untold number are Medicare and Medicaid

beneficiaries. I asked the Office of the Inspector General for the Department of Health and

Human Services how much the federal government reimbursed Merck for Vioxx. I was told that

the Medicaid program paid in excess of $1 billion for Vioxx while Vioxx was on the market. 

I’ve also seen a June 4, 1999 Merck document titled "IN IT TO WIN IT” that said: “As of

yesterday, Vioxx became reimbursable on Medicaid in 42 states with the other 8 states close

behind." The Medicaid market was clearly going to be a money maker for Merck, and Medicaid

has paid Merck well for Vioxx.

Last year Vioxx sales totalled $2.5 billion. Merck's marketing effort included $160

million for direct-to-consumer advertising. It’s been said that in the history of pharmaceutical

advertising, Vioxx was one of the most directly-marketed-to-consumers prescription drugs ever. 

In addition to targeting consumers directly, Merck reportedly spent more than that marketing

Vioxx to directly to physicians. There’s nothing wrong with either of these efforts. Such

marketing is part of the system, but today’s hearing will consider whether Merck followed the

letter and spirit of the law with its marketing of Vioxx.

The witnesses here today will help tell the Vioxx story. That story will continue to unfold

in the months ahead. It will affect public confidence. When the FDA approves a drug, it’s

considered a “Good Housekeeping Seal of Approval.” However, what’s come to light about

Vioxx since September 30th makes people wonder if the FDA has lost its way when it comes to

making sure drugs are safe. Today’s witnesses will describe how danger signals were ignored. 

They’ll offer perspective on how appropriate action wasn’t taken. We’ll see that the FDA failed

to heed the words of its own scientists.

It also looks like the FDA allowed itself to be manipulated by Merck on labeling changes

that became necessary after a review by Merck that’s known as the VIGOR trial. The VIGOR

trial found that heart attacks were five times higher for Vioxx patients than for patients on

another drug. Even so, nearly two years passed before any label change was made by the FDA. 

Merck completed the VIGOR trial in March 2000. It gave the findings to the FDA in June 2000. 

The trial was the subject of an advisory board meeting in February 2001. But it was April 11,

2002 before the Vioxx label was actually changed. During these 22 months, Merck aggressively

marketed Vioxx, knowing that consumers and doctors were largely unaware of the

cardiovascular risks found in the VIGOR trial.

One of my concerns is that the FDA has a relationship with drug companies that is too

cozy. That’s exactly the opposite of what it should be. The health and safety of the public must

be the FDA's first and only concern. I’m interested in changes inside the FDA that result in

greater transparency and openness at the Food and Drug Administration. One reform that may be

needed is an independent office of drug safety. It doesn’t make sense from an accountability

standpoint to have the office that reviews the safety of drugs that are already on the market to be

under the thumb of the office that put the drugs on the market in the first place.
The bottom line is, consumers should not have to second guess the safety of what's in

their medicine cabinets. The public should feel confident that when the FDA approves a drug,

you can bank on it being safe, and if a drug isn't safe, the FDA will take it off the market.

We have three panels of witnesses today. The first witness is Dr. David Graham. He is

an epidemiologist for the FDA. Dr. Graham recently completed a study involving Vioxx and

he’ll discuss his findings. Dr. Graham will also describe the environment where he works in the

FDA’s Office of Drug Safety. It’s this office that’s responsible monitoring the effect of a drug

once it’s on the market.

Our next witness is Dr. Gurkipal Singh. Dr. Singh will testify by video conference from

California where he is recovering from a heart attack. Dr. Singh is an Adjunct Professor of

Medicine at Stanford University. He is a former consultant to Merck on Vioxx. Dr. Singh will

describe how he was threatened by Merck in that capacity because of his concerns about Vioxx. 

Dr. Singh will also explain how drugs like Vioxx work, the information that was available about

the cardiac safety of Vioxx, and the labeling changes made to Vioxx. The committee will also

hear testimony from Dr. Bruce Psaty. Dr. Psaty is an epidemiologist, a practicing physician and a

drug safety expert. He will discuss the studies about Vioxx, the risks and benefits of such drugs,

and how similar drug disasters can be prevented. After these three witnesses, we will hear from

Dr. Sandra Kweder of the Food and Drug Administration, and Mr. Raymond Gilmartin, the Chief

Executive Officer of Merck & Co.

The record for this hearing will remain open for 10 days. Committee members should

submit remarks and questions for the record no later than November 29. In addition, a number of

documents will be discussed today. They have been made available to the committee members,

their staffs and the hearing witnesses. Many of these documents have been provided to the

committee by Merck and other parties to litigation involving Vioxx. As a result, they may be

considered confidential in the context of those court proceedings. I ask that committee members,

their staffs and the hearing witnesses not leave the room with their bound copies of these

documents during this hearing today. Committee staff will collect the exhibits from each

witness, committee member and from all committee staff at the close of the hearing.

I look forward to the opening remarks of the Ranking Member of the Finance Committee, 

my colleague, Senator Baucus.

Before the testimony begins, I will to respond to comments issued last night by the FDA’s

acting administrator, Dr. Crawford, about Dr. Graham, our first witness. News reports today say

the FDA is calling Dr. Graham a “a maverick who did not follow Agency protocols.”

Today’s hearing includes a lot of testimony about scientific findings. It’s not about

protocols or administrative “he said, she saids.” Dr. Graham completed an FDA-sponsored

three-year study under FDA guidance and with Drs. Campen, Levy, Shoor, Ray, Cheetham,

Spence and Hui. Dr. Graham’s immediate supervisor said the paper that formed the basis of the

study was “... an excellent study and analysis of a complex topic.” So the clarifications provided

last night by Dr. Crawford appear intended intimidate a witness on the eve of hearing. I want to

hear about Dr. Graham’s study today. In fact, just seven days ago — on November 9th — Dr.
Crawford met with Dr. Graham and acknowledged that there was a culture problem at the FDA

and a problem with drug safety. Dr. Crawford even asked Dr. Graham to consider helping with

an “internal FDA drug safety program and develop(ing) recommendations for improvements....” 

So Dr. Crawford knows there’s a problem and would better serve the FDA by spending time on

the problem rather than going after congressional witnesses who helped identify the problem in

the first place.
For Immediate Release Contact: Liz Fowler

Thursday, November 18, 2004 202-224-4515

Statement of U.S. Senator Max Baucus

“FDA, Merck and Vioxx: Putting Patient Safety First?” 

Thank you, Mr. Chairman, for holding this hearing. The withdrawal of the pain-killer 

Vioxx from the market has raised serious questions.

Two million patients were taking Vioxx in late September when Merck pulled it due to 

concerns about the increased risk of heart attacks and strokes. While we do not know the true 

extent of the risk, tens of thousands of patients potentially could have suffered a heart attack or 

stroke as a result of the drug. 

This hearing is an opportunity to take a hard look at what happened with Vioxx. But this 

hearing goes beyond Merck and Vioxx. We must think critically about the way we test and 

evaluate drugs to ensure their safety. 

In the weeks since Merck withdrew Vioxx, many questions have been raised. Questions 

like:

• When did Merck know about the potential dangers of Vioxx?

• And should the company have acted sooner to withdraw the drug?

• Why didn’t the FDA detect the risks associated with Vioxx during the initial approval 

process, or even in the 5 years since approval?

• Does the FDA have sufficient resources, authority and independence to ensure that the 

drugs it approves are safe?

• And should we be doing more to monitor drug safety after a drug has been approved?

These questions, and many others, must be answered so that medications do not pose a 

risk to Americans’ health. These issues are critical to Medicare and Medicaid beneficiaries. In 

the 5 years that Vioxx was on the market, Medicaid spent more than $1 billion on the drug. And 

Medicaid bears the cost of any additional medical care necessary when drugs cause injury.

Furthermore, in just over a year, Medicare will begin covering prescription drugs through 

the optional Part D benefit. We need to be certain that beneficiaries of the new program are not 

exposed to potentially harmful medications.
2

I am concerned that what happened with Vioxx may have been due, in part, to 

insufficient emphasis on complete, rigorous, and expansive clinical trials. Clinical trials focused 

on drug safety should not stop when the FDA approves a drug. We need to continue testing 

drugs to thoroughly evaluate the potential risks, not just the benefits.

Clinical trial results should be more transparent. The conduct and reporting of clinical 

trials is critical to approving a new drug. And we must continue to evaluate and monitor drugs 

even after they are approved to ensure their safety and effectiveness. 

In addition, I have encouraged drug manufacturers to expand the number of patients who 

participate in clinical trials, including patients in rural areas such as Montana. 

I also support greater use of studies that test the comparative effectiveness and safety of 

drugs in similar therapeutic classes. The Medicare bill that passed last year designated $50 

million for these studies. And I have supported raising the level of funding to $75 million. But 

the current Senate appropriations bill only includes $15 million. We should do more.

Finally, the Vioxx situation raises serious concerns about the broad implications of the 

medical malpractice reform bill currently being considered by the Congress. 

Liability restrictions in this bill apply not just to doctors and hospitals. They also include 

pharmaceutical and medical product manufacturers, such as Merck. And the legislation creates 

new protections for products approved by the FDA, like Vioxx. 

Given the events we are discussing today, I think the Congress and the public need to 

take a hard look at this legislation. I hope that today’s hearing will shed light on recent events. 

And I look forward to hearing from our witnesses. Thank you, Mr. Chairman.

###
Testimony of David J. Graham, MD, MPH, November 18, 2004

Mr. Chairman and members of the Committee,

Introduction. Good morning. My name is David Graham, and I am pleased to come before you 

today to speak about Vioxx, heart attacks and the FDA. By way of introduction, I graduated from the 

Johns Hopkins University School of Medicine, and trained in Internal Medicine at Yale and in adult 

Neurology at the University of Pennsylvania. After this, I completed a three-year fellowship in 

pharmacoepidemiology and a Masters in Public Health at Johns Hopkins, with a concentration in 

epidemiology and biostatistics. Over my 20 year career in the field, all of it at FDA, I have served in a 

variety of capacities. I am currently the Associate Director for Science and Medicine in FDA’s Office of 

Drug Safety. 

During my career, I believe I have made a real difference for the cause of patient safety. My 

research and efforts within FDA led to the withdrawal from the US market of Omniflox, an antibiotic that 

caused hemolytic anemia; Rezulin, a diabetes drug that caused acute liver failure; Fen-Phen and Redux, 

weight loss drugs that caused heart valve injury; and PPA (phenylpropanolamine), an over-the-counter 

decongestant and weight loss product that caused hemorrhagic stroke in young women. My research also 

led to the withdrawal from outpatient use of Trovan, an antibiotic that caused acute liver failure and 

death. I also contributed to the team effort that led to the withdrawal of Lotronex, a drug for irritable 

bowel syndrome that causes ischemic colitis; Baycol, a cholesterol-lowering drug that caused severe 

muscle injury, kidney failure and death; Seldane, an antihistamine that caused heart arrhythmias and 

death; and Propulsid, a drug for night-time heartburn that caused heart arrythmias and death. I have done 

extensive work concerning the issue of pregnancy exposure to Accutane, a drug that is used to treat acne 

but can cause birth defects in some children who are exposed in-utero if their mothers take the drug 

during the first trimester. During my career, I have recommended the market withdrawal of 12 drugs. 

Only 2 of these remain on the market today-Accutane and Arava, a drug for the treatment of rheumatoid 

arthritis that I and a co-worker believe causes an unacceptably high risk of acute liver failure and death. 

Vioxx and heart attacks. Let me begin by describing what we found in our study, what others 

have found, and what this means for the American people. Prior to approval of Vioxx, a study was 

performed by Merck named 090. This study found nearly a 7-fold increase in heart attack risk with low 

dose Vioxx. The labeling at approval said nothing about heart attack risks. In November 2000, another 

Merck clinical trial named VIGOR found a 5-fold increase in heart attack risk with high-dose Vioxx. The 

company said the drug was safe and that the comparison drug naproxen, was protective. In 2002, a large 

epidemiologic study reported a 2-fold increase in heart attack risk with high-dose Vioxx and another 

study reported that naproxen did not affect heart attack risk. About 18 months after the VIGOR results 

were published, FDA made a labeling change about heart attack risk with high-dose Vioxx, but did not 

place this in the “Warnings” section. Also, it did not ban the high-dose formulation and its use. I believe 

such a ban should have been implemented. Of note, FDA’s label change had absolutely no effect on how 

often high-dose Vioxx was prescribed, so what good did it achieve? 

In March of 2004, another epidemiologic study reported that both high-dose and low-dose Vioxx 

increased the risk of heart attacks compared to Vioxx’s leading competitor, Celebrex. Our study, first 

reported in late August of this year found that Vioxx increased the risk of heart attack and sudden death 

by 3.7 fold for high-dose and 1.5 fold for low-dose, compared to Celebrex. A study report describing this 

work was put on the FDA website on election day. Among many things, this report estimated that nearly 

28,000 excess cases of heart attack or sudden cardiac death were caused by Vioxx. I emphasize to the 

Committee that this is an extremely conservative estimate. FDA always claims that randomized clinical 

trials provide the best data. If you apply the risk-levels seen in the 2 Merck tria ls, VIGOR and 

APPROVe, you obtain a more realistic and likely range of estimates for the number of excess cases in the 

US. This estimate ranges from 88,000 to 139,000 Americans. Of these, 30-40% probably died. For the 

survivors, their lives were changed forever. It’s important to note that this range does not depend at all on 
2

the data from our Kaiser-FDA study. Indeed, Dr. Eric Topol at the Cleveland Clinic recently estimated 

up to 160,000 cases of heart attacks and strokes due to Vioxx, in an article published in the New England 

Journal of Medicine. This article lays out clearly the public health significance of what we’re talking 

about today.

So, how many people is 100,000? The attached Tables 1 and 2 show the estimated percentage of 

the population in your home State and in selected cities from your State that would have been affected 

had all 100,000 excess cases of heart attack and sudden cardiac death due to Vioxx occurred only in your 

State or city. This is to help you understand how many lives we’re talking about. We’re not just talking 

numbers. For example, if we were talking about Florida or Pennsylvania, 1% of the entire State 

population would have been affected. For Iowa, it would be 5%, for Maine, 10% and for Wyoming, 27%. 

If we look at selected cities, I’m sorry to say, Senator Grassley, but 67% of the citizens of Des Moines 

would be affected, and what’s worse, the entire population of every other city in the State of Iowa.

But there is another way to put this range of excess cases into perspective. Imagine that instead 

of a serious side-effect of a widely used prescription drug, we were talking about jetliners. Please ignore 

the obvious difference in fatality rates between a heart attack and a plane crash, and focus on the larger 

analogy I’m trying to draw. If there were an average of 150 to 200 people on an aircraft, this range of 

88,000 to 138,000 would be the rough equivalent of 500 to 900 aircraft dropping from the sky. This 

translates to 2-4 aircraft every week, week in and week out, for the past 5 years. If you were confronted 

by this situation, what would be your reaction, what would you want to know and what would you do 

about it?

Brief history of drug disasters in the US. Another way to fully comprehend the enormity of the

Vioxx debacle is to look briefly at recent US and FDA history. The attached figure shows a graph 

depicting 3 historical time-points of importance to the development of drug safety in the US. In 1938, 

Congress enacted the Food, Drug and Cosmetic Act, basically creating the FDA, in response to an 

unfortunate incident in which about 100 children were killed by elixir of sulfanilamide, a medication that 

was formulated using anti-freeze. This Act required that animal toxicity testing be performed and safety 

information be submitted to FDA prior to approval of a drug. In 1962, Congress enacted the KefauverHarris Amendments to the FD&C Act, in response to the thalidomide disaster in Europe. Oversees, 

between 1957 and 1961, an estimated 5,000 to 10,000 children were born with thalidomide-related birth 

defects. These Amendments increased the requirements for toxicity testing and safety information preapproval, and added the requirement that “substantial evidence” of efficacy be submitted. Today, in 

2004, you, we, are faced with what may be the single greatest drug safety catastrophe in the history of this 

country or the history of the world. We are talking about a catastrophe that I strongly believe could have, 

should have been largely or completely avoided. But it wasn’t, and over 100,000 Americans have paid 

dearly for this failure. In my opinion, the FDA has let the American people down, and sadly, betrayed a 

public trust. I believe there are at least 3 broad categories of systemic problems that contributed to the 

Vioxx catastrophe and to a long line of other drug safety failures in the past 10 years. Briefly, these 

categories are 1) organizational/structural, 2) cultural, and 3) scientific. I will describe these in greater 

detail in a few moments.

My Vioxx experience at FDA. To begin, after publication of the VIGOR study in November 

2000, I became concerned about the potential public health risk that might exist with Vioxx. VIGOR 

suggested that the risk of heart attack was increased 5-fold in patients who used the high-dose strength of 

this drug. Why was the Vioxx safety question important? 1) Vioxx would undoubtedly be used by 

millions of patients. That’s a very large number to expose to a serious drug risk. 2) heart attack is a fairly 

common event, and 3) given the above, even a relatively small increase in heart attack risk due to Vioxx 

could mean that tens of thousands of Americans might be seriously harmed or killed by use of this drug. 

If these three factors were present, I knew that we would have all the ingredients necessary to guarantee a 

national disaster. The first two factors were established realities. It came down to the third factor, that is, 

what was the level of risk with Vioxx at low- and high-dose.
3

To get answers to this urgent issue, I worked with Kaiser Permanente in California to perform a 

large epidemiologic study. This study was carefully done and took nearly 3 years to complete. In early 

August of this year, we completed our main analyses and assembled a poster presentation describing 

some of our more important findings. We had planned to present these data at the International 

Conference on Pharmacoepidemiology, in Bordeaux, France. We concluded that high-dose Vioxx 

significantly increased the risk of heart attacks and sudden death and that the high doses of the drug 

should not be prescribed or used by patients. This conclusion triggered an explosive response from the 

Office of New Drugs, which approved Vioxx in the first place and was responsible for regulating it postmarketing. The response from senior management in my Office, the Office of Drug Safety, was equally 

stressful. I was pressured to change my conclusions and recommendations, and basically threatened that 

if I did not change them, I would not be permitted to present the paper at the conference. One Drug 

Safety manager recommended that I should be barred from presenting the poster at the meeting, and also 

noted that Merck needed to know our study results.

An email from the Director for the entire Office of New Drugs, was revealing. He suggested that 

since FDA was “not contemplating” a warning against the use of high-dose Vioxx, my conclusions 

should be changed. CDER and the Office of New Drugs have repeatedly expressed the view that ODS 

should not reach any conclusions or make any recommendations that would contradict what the Office of 

New Drugs wants to do or is doing. Even more revealing, a mere 6 weeks before Merck pulled Vioxx 

from the market, CDER, OND and ODS management did not believe there was an outstanding safety 

concern with Vioxx. At the same time, 2-4 jumbo jetliners were dropping from the sky every week and 

no one else at FDA was concerned.

There were 2 other revelatory milestones. In mid-August, despite our study results showing an 

increased risk of heart attack with Vioxx, and despite the results of other studies published in the 

literature, FDA announced it had approved Vioxx for use in children with rheumatoid arthritis. Also, on 

September 22, at a meeting attended by the director of the reviewing office that approved Vioxx, the 

director and deputy director of the reviewing division within that office and senior managers from the 

Office of Drug Safety, no one thought there was a Vioxx safety issue to be dealt with. At this meeting, 

the reviewing office director asked why had I even thought to study Vioxx and heart attacks because FDA 

had made its labeling change and nothing more needed to be done. At this meeting a senior manager 

from ODS labeled our Vioxx study “a scientific rumor.” Eight days later, Merck pulled Vioxx from the 

market, and jetliners stopped dropping from the sky.

Finally, we wrote a manuscript for publication in a peer-reviewed medical journal. Senior 

managers in the Office of Drug Safety have not granted clearance for its publication, even though it was 

accepted for publication in a very prestigious journal after rigorous peer review by that journal. Until it is 

cleared, our data and conclusions will not see the light of day in the scientific forum they deserve and

have earned, and serious students of drug safety and drug regulation will be denied the opportunity to 

consider and openly debate the issues we raise in that paper.

Past experiences. My experience with Vioxx is typical of how CDER responds to serious drug 

safety issues in general. This is similar to what Dr. Mosholder went through earlier this year when he 

reached his conclusion that most SSRIs should not be used by children. I could bore you with a long list 

of prominent and not-so-prominent safety issues where CDER and its Office of New Drugs proved to be 

extremely resistant to full and open disclosure of safety information, especially when it called into 

question an existing regulatory position. In these situations, the new drug reviewing division that 

approved the drug in the first place and that regards it as its own child, typically proves to be the single 

greatest obstacle to effectively dealing with serious drug safety issues. The second greatest obstacle is 

often the senior management within the Office of Drug Safety, who either actively or tacitly go along 

with what the Office of New Drugs wants. Examples are numerous so I’ll mention just a few. 

With Lotronex, even though there was strong evidence in the pre-approval clinical trials of a 

problem with ischemic colitis, OND approved it. When cases of severe constipation and ischemic colitis 

began pouring into FDA’s MedWatch program, the reaction was one of denial. When CDER decided to 
4

bring Lotronex back on the market, ODS safety reviewers were instructed to help make this happen. 

Later, when CDER held an advisory committee meeting to get support for bringing Lotronex back on the 

market, the presentation on ways to manage its reintroduction was carefully shaped and controlled by 

OND. When it came to presenting the range of possible options for how Lotronex could be made 

available, the list of options was censored by OND. The day before the advisory meeting, I was told by 

the ODS reviewer who gave this presentation that the director of the reviewing office within OND that 

approved Lotronex in the first place came to her office and removed material from her talk. An OND 

manager was “managing” an ODS employee. When informed of this, ODS senior management ignored 

it. I guess they knew who was calling the shots.

Rezulin was a drug used to treat diabetes. It also caused acute liver failure, which was usually 

fatal unless a liver transplant was performed. The pre-approval clinical trials showed strong evidence of 

liver toxicity. The drug was withdrawn from the market in the United Kingdom in December 1997. With 

CDER and the Office of New Drugs, withdrawal didn’t occur until March 2000. Between these dates, 

CDER relied on risk management strategies that were utterly ineffective and it persisted in relying on 

these strategies long after the evidence was clear that they didn’t work. The continued marketing of 

Rezulin probably led to thousands of Americans being severely injured or killed by the drug. And note, 

there were many other safer diabetes drugs available. During this time, I understand that Rezulin’s 

manufacturer continued to make about $2 million per day in sales.

The big picture. The problem you are confronting today is immense in scope. Vioxx is a terrible 

tragedy and a profound regulatory failure. I would argue that the FDA, as currently configured, is 

incapable of protecting America against another Vioxx. We are virtually defenseless.

It is important that this Committee and the American people understand that what has happened 

with Vioxx is really a symptom of something far more dangerous to the safety of the American people. 

Simply put, FDA and its Center for Drug Evaluation and Research are broken. Now, I’m sure you have 

read the recent proposal to have the Institute of Medic ine perform a review of CDER and its drug safety 

program and make recommendations for fixing things up. Don’t expect anything meaningful or effective 

from this exercise. Over the history of CDER’s drug safety program, a number of similar reviews have 

been done. In the late 1970’s, I believe that a blue ribbon panel recommended that there be an entirely 

separate drug safety operation in FDA with full regulatory authority. It wasn’t implemented. During the 

1980’s and early 1990’s, CDER organized its own “program reviews” of drug safety. The basic premise 

underlying each of these reviews was that the “problem” was with the drug safety group; it didn’t fit into 

the Center. So, the charge given to the review panel members was always framed as “figure out what’s 

wrong with drug safety, and tell us what to do to get it to fit in.” There was and is an implicit expectation 

that the status quo will remain unaltered.

The organizational structure within CDER is entirely geared towards the review and approval of 

new drugs. When a CDER new drug reviewing division approves a new drug, it is also saying the drug is 

“safe and effective.” When a serious safety issue arises post-marketing, their immediate reaction is 

almost always one of denial, rejection and heat. They approved the drug so there can’t possibly be 

anything wrong with it. The same group that approved the drug is also responsible for taking regulatory 

action against it post-marketing. This is an inherent conflict of interest. At the same time, the Office of 

Drug Safety has no regulatory power and must first convince the new drug reviewing division that a 

problem exists before anything beneficial to the public can be done. Often, the new drug reviewing 

division is the single greatest obstacle to effectively protecting the public against drug safety risks. A 

close second in my opinion, is an ODS management that sees its mission as pleasing the Office of New 

Drugs. 

The corporate culture within CDER is also a barrier to effectively protecting the Americ an people 

from unnecessary harm due to prescription and OTC drugs. The culture is dominated by a world-view 

that believes only randomized clinical trials provide useful and actionable information and that postmarketing safety is an afterthought. This culture also views the pharmaceutical industry it is supposed to 
5

regulate as its client, over-values the benefits of the drugs it approves and seriously under-values, 

disregards and disrespects drug safety. 

Finally, the scientific standards CDER applies to drug safety guarantee that unsafe and deadly 

drugs will remain on the US market. When an OND reviewing division reviews a drug to decide whether 

to approve it, great reliance is placed on statistical tests. Usually, a drug is only approved if there is a 

95% or greater probability that the drug actually works. From a safety perspective, this is also a very 

protective standard because it protects patients against drugs that don’t work. The real problem is how 

CDER applies statistics to post-marketing safety. We see from the structural and cultural problems in 

CDER, that everything revolves around OND and the drug approval process. 

When it comes to safety, the OND paradigm of 95% certainty prevails. Under this paradigm, a 

drug is safe until you can show with 95% or greater certainty that it is not safe. This is an incredibly high, 

almost insurmountable barrier to overcome. It’s the equivalent of “beyond a shadow of a doubt.” And 

here’s an added kicker. In order to demonstrate a safety problem with 95% certainty, extremely large 

studies are often needed. And guess what. Those large studies can’t be done. 

There are 2 analogies I want to leave you with to illustrate the unreasonableness of CDER’s 

standard of evidence as applied to safety, both pre- and post-approval. If the weather-man says there is an 

80% chance of rain, most people would bring an umbrella. Using CDER’s standard, you wouldn’t bring 

an umbrella until there was a 95% or greater chance of rain. The second analogy is more graphic, but I 

think it brings home the point more clearly. Imagine for a moment that you have a pistol with a barrel 

having 100 chambers. Now, randomly place 95 bullets into those chambers. The gun represents a drug 

and the bullets represent a serious safety problem. Using CDER’s standard, only when you have 95 

bullets or more in the gun will you agree that the gun is loaded and a safety problem exists. Let’s remove 

5 bullets at random. We now have 90 bullets distributed across 100 chambers. Because there is only a 

90% chance that a bullet will fire when I pull the trigger, CDER would conclude that the gun is not 

loaded and that the drug is safe.
6

Table 1. The percentage of each State’s population age 18 years or older that would be affected if an 

estimated 100,000 excess cases of heart attack and sudden cardiac death due to Vioxx had all occurred in 

that State. The States are presented alphabetically. These are the States represented by members of the 

Senate Finance Committee.

State

Estimated % of population

age 18 years or older

Arizona 2

Arkansas 5

Florida 1

Iowa 5

Kentucky 3

Louisiana 3

Maine 10

Massachusetts 2

Mississippi 5

Montana 14

New Mexico 7

North Dakota 21

Oklahoma 4

Oregon 4

Pennsylvania 1

South Dakota 18

Tennessee 2

Utah 6

Vermont 22

West Virginia 7

Wyoming 27
7

Table 2. The percentage of the population age 18 years or older from selected cities in the US that would 

be affected if an estimated 100,000 excess cases of heart attack and sudden cardiac death due to Vioxx 

had all occurred in that city. The cities chosen were from the more highly populated States shown in 

Table 1. These cities are in States represented by members of the Senate Finance Committee.

State and city

Estimated % of population

age 18 years or older

Arkansas

 Little Rock 73

Arizona

 Scottsdale

 Tuscon

66

27

Florida

 Orlando

 Tallahassee

 Tampa

72

89

44

Iowa

 Des Moines

 All other cities

67

100

Kentucky

 Louisville 52

Louisiana

 New Orleans 27

Oklahoma

 Oklahoma City 26

Oregon

 Portland 25

Pennsylvania

 Pittsburgh

 Lancaster

40

100

Tennessee

 Nashville 23

Utah

 Salt Lake City 73
8

Figure. A brief history of drug safety disasters in the US.

0

20000

40000

60000

80000

100000

120000

1920 1940 1960 1980 2000 2020

Year

Number harmed

Sulfanilamide,

FD&C Act

Thalidomide,

Kefauver-Harris

Rofecoxib,

???
9

References

1. Census data for major US cities, 2000 census. Available at: URL: 

http://www.infoplease.com/ipa/A0108676.html. Accessed November 14, 2004.

2. Census data for states in the US, 2003. Available at URL: 

http://www.infoplease.com/ipa/A0004986.html. Accessed November 14, 2004.
Gurkirpal Singh, MD

Adjunct Clinical Professor of Medicine

Department of Medicine, Division of Gastroenterology and Hepatology

Stanford University School of Medicine

Stanford, CA 

 and

Chief Science Officer 

Institute of Clinical Outcomes Research and Education (ICORE)

175 Eleanor Drive, Woodside, CA 94062

gsingh@stanford.edu

Chairman Grassley, Senator Baucus, Senators, and Ladies and Gentlemen:

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 swelling 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.
We have not always agreed with the interpretation of data, but to the best of my knowledge, 

nothing has been hidden, suppressed or falsified by any Merck scientist since this episode. All my 

requests for scientific information are handled promptly and courteously, and for this, I thank 

Merck in general, and Dr. Alise Reicin in particular.

Publication of VIGOR data 

Scientific publications in a medical journal are the most credible way to disseminate data 

about a medication. VIGOR data was published in the New England Journal of Medicine in 

November, 2000. A few weeks ago, Merck announced that the published VIGOR data was 

“preliminary” and that the “final” data was presented to the FDA. In my view, and all of my 

colleagues that I have consulted with, it is inappropriate to publish “preliminary” or incomplete 

data without clearly stating that the data are preliminary. This is especially true if the favorable 

data are complete but the unfavorable data are “preliminary” and likely to get worse. To the best 

of my knowledge, the VIGOR paper did not indicate anywhere that the data were preliminary or 

incomplete. Nor, did I ever see a correction or erratum indicating this fact subsequently – up 

until a few weeks ago, almost 4 years later.

The VIGOR publication minimized the significance of heart attacks. While it 

prominently discussed the reduction of stomach bleeds in patients taking Vioxx, it did not 

mention that in spite of this, patients on Vioxx had more serious adverse events, and more 

hospitalizations than patients on Naproxen. The true rates for cardiovascular thrombotic adverse 

events (a prespecified study endpoint in the protocol), hypertension and congestive heart failure –

which were all higher in the Vioxx group - were not shown in the paper at all.

The FDA review of VIGOR correctly pointed out that the explanation advanced by the 

authors – that naproxen reduced the risk of hear attacks – could not explain the 500% difference 

between Vioxx and naproxen. The reviewers also highlighted data from many other studies 

showing that this was not an isolated finding in VIGOR. However, Merck continued to claim 

“favorable cardiovascular safety profile” of Vioxx in multiple press releases and Companysponsored lectures and conferences. In September 2001, in a Warning Letter to Merck, the FDA 

Division of Drug Marketing, Advertising, and Communications (DDMAC) called the press 

releases claiming a “favorable cardiovascular safety profile” for VIOXX “simply 

incomprehensible”, and pointed out that the naproxen explanation was merely “hypothetical” 

rather than factual. These facts had previously been discussed by FDA reviewers as well (7).

.
Post-VIGOR Label Change

The VIGOR data were first made public in May 2000. However it was not until almost 2 

years later that the FDA requested Merck to revise Vioxx’s product label to reflect the heart 

attack risks observed in the VIGOR trial. These revisions were added to the “Precautions” 

section, under “Cardiovascular Effects”, instead of being prominently displayed as a “Warning”. 

While the stomach bleed safety data was added in a prominent fashion, the heart attack 

information seemed to support Merck’s contention that Vioxx did not increase the risk by adding 

statements such as “Because of its lack of platelet effects Vioxx is not a substitute for aspirin for 

cardiovascular prophylaxis”. Was there a single physician in the world who had prescribed 

Vioxx for cardiovascular prophylaxis? Why not also say “Because of its lack of anti-tumor 

effect, Vioxx is not a treatment for brain cancer” or “Do not use Vioxx for erectile dysfunction or 

depression”? The favorable data for Alzheimer’s disease studies was included at Merck’s 

insistence, but no unfavorable data from studies such as 085 or 090 as added. Even the 

Alzheimer’s disease studies data was favorably biased – while the label showed that there was no 

difference in heart attacks between Vioxx and placebo in these studies, it did not mention that the 

mortality rate of patients on Vioxx was almost twice that of those on placebo. Negotiations 

certainly succeeded for Merck.

Many people claim that the heart attack – stomach bleed data trade off was a favorable 

one, since there are many more stomach bleeds prevented than heart attacks caused by Vioxx. As 

the FDA review of VIGOR data pointed out, this was simply not true (7). Attachment 9 is selfexplanatory.

No long-term safety studies

More importantly, there were no attempts to design and carry out large safety studies to 

prove or disprove the link of Vioxx to heart attacks. Apparently, a 30,000 patient study had been 

announced in November, 2001 but never started. Last week, New York Times reported that 

Merck had considered a cardiovascular outcome study, but decided that it would send the 

“wrong” marketing and public relations signal. "At present, there is no compelling marketing 

need for such a study," said a slide prepared for a meeting of senior executives. "Data would not 

be available during the critical period. The implied message is not favorable." It is regrettable that 

scientific decisions on patient safety are influenced by perceived marketing and public relations 

concerns. In my opinion, it is better to kill a drug than kill a patient.

It is important to note that the APPROVe study which conclusively proved the increased 

risk of Vioxx was not a safety study – it was an efficacy study, designed to add another indication 
for Vioxx treatment. It was not large enough to detect a heart attack risk – that it did find a risk 

was a lucky break for patients, but this is not what it was designed to do.

The failure to conduct large long-term safety studies subjected millions of patients over 4 years 

to a drug whose safety had been questioned by the FDA even before its approval. This is not the 

proudest chapter in drug approval in the US.

Recommendations

What can we do to prevent this from happening again? First, we must find out exactly what went 

wrong.

1. A public enquiry should be conducted by an independent group of scientists with free 

access to all Merck internal documents to study all aspects of safety data surrounding 

Vioxx, with a particular emphasis on (a) if earlier, better studies could have shown the 

heart attack risk, (b) if such studies had indeed been suppressed by marketing and public 

relations worries, and (c) if a discussion of this heart attack risk was suppressed in an 

unethical fashion.

2. A public discussion of the role of FDA in approving drugs and labels. As the delay in 

Vioxx label shows, the current process of labeling is one of negotiations – if the 

“sponsor” does not agree with what the FDA wants, it can continue to stall or worse. It 

took 2 years for the label change of Vioxx to take effect, and even then, the label change 

supported mostly Merck’s position, not the one advanced by FDA’s own reviewers in 

public hearings. This process needs to be fixed, if need be, by new legislation. The FDA 

should be given the authority that is accorded to our judicial system – to make unilateral 

decisions on issues of public health safety, without having to negotiate and reach 

agreement with drug companies. The FDA should regulate the drug companies, not 

collaborate or negotiate with them if there is any question of public safety.

3. The FDA approval process needs to be more open and subject to public scrutiny. Once a 

drug is approved, all the data supporting such approval should be put in the public 

domain. If this had been done with Vioxx, perhaps independent scientists would have 

been able to spot early signals. Similarly, all clinical study data submitted to the FDA 

should be available to the public after the drug is approved. Claims of “trade secrets” 

should not take precedence over public health and safety. Pharmaceutical companies 

should not be allowed to selectively disseminate only positive data.
4. On drugs that need further safety data, a system of conditional or time-limited approvals 

should be instituted. For example, since the FDA reviewer had concerns about heart 

attacks before the approval of Vioxx, but there was not enough data to decide the issue 

one way or other, the FDA could have provided a conditional approval (if any) that 

would have required Merck to complete large safety studies within a certain time period.

5. An independent office of drug safety which does not report to the FDA new drug 

approval section should be established. Safety data on all new drug approvals must be 

vetted through this office. This office should have an independent authority to conduct 

safety studies on approved drugs, or require that such studies be conducted if there are 

safety signals. Only then will be able to adhere to the principle of “Primum, Non 

Nocere” – First, Do No Harm. 

Thank you.

References

1. Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy.

Am J Med 1998; 105(1B):31-38.

2. Singh G and Triadafilopoulos G. Epidemiology of NSAID-induced GI complications.

J Rheumatol 1999; 26 Suppl 26:18-24.

3. Singh G, Mithal A, Triadafilopoulos G. Decreasing hospitalizations due to complicated 

gastric and duodenal ulcers in the United States: 1998-2001. Gastroenterology 2004; 

126 (4 Suppl. 2): A97-98.

4. Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal antiinflammatory drugs and risk of serious coronary heart disease: an observational cohort 

study. Lancet 2002;359:118-123.

5. Muliner T. Anticipated consequences of NSAID antiplatelet effects on cardiovascular 

events and effects of excluding low-dose aspirin use in the Cox-2 GI Outcomes

Megatrial. Letter of November 21, 1996 to B Friedman, A Nies, and R Spector.
6. Villalba ML. FDA Medical Officer Review of VIOXX (rofecoxib), NDA 21-042 

(capsules) and NDA 21-052 (oral solution). Http://www.fda.gov/

cder/drug/infopage/vioxx/default.htm.

7. Targum SL. Consultation on NDA 21-042, S-007; Review of cardiovascular safety 

database [on Vioxx or rofecoxib). FDA Memorandum, Feb 1, 2001.

Http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.doc; last accessed

on June 5, 2001.
Bruce M. Psaty, MD, PhD 

Professor, Medicine, Epidemiology and Health Services 

Co-director, Cardiovascular Health Research Unit 

University of Washington 

1730 Minor Avenue, Suite 1360 

Seattle, WA 98101 

Mr Chairman and members of the Committee, 

Thank you for the opportunity to testify before the Committee on the cardiovascular risks 

associated with VIOXX. Let me introduce myself briefly, describe several key scientific issues, 

and summarize some of the studies of VIOXX and their findings. Finally, I will make 

recommendations about how to prevent similar problems in the future. 

 Introduction. I am a practicing general internist at Harborview Medical Center, Seattle 

WA, and a cardiovascular disease epidemiologist with an interest and expertise in 

pharmacoepidemiology, pharmacogenetics, and drug safety. I have experience in the design, 

conduct, analysis and interpretation of clinical studies, and I am currently the principal 

investigator on 4 large epidemiologic studies funded by the National Institutes of Health (NIH) 

or the American Heart Association (AHA). I have major roles in several multi-center NIHfunded epidemiologic studies and clinical trials, including the Cardiovascular Health Study, the 

Multi-Ethnic Study of Atherosclerosis, and the Women's Health Initiative. Regularly, I review 

research in several capacities. As a public-health scientist, I serve as chair of the Group Health 

Cooperative Research Committee and am currently a member of the NIH Epidemiology of 

Chronic Disease Study Section. I have chaired or participated in various committees and review 

groups constituted by the AHA, the NIH, and the World Health Organization. I also teach and 

mentor students, fellows and junior faculty in medicine and epidemiology. I have no financial 

interest in this matter. In 1991, the Society of Epidemiological Research selected me for a career 

development award for a pilot study of the risks of stroke associated with the use of progestins 

by post-menopausal women. This 3-year award was funded by the Merck Company Foundation. 

 Epidemiology. Epidemiology is the study of patterns and causes of disease in human 

populations. One of the primary purposes of studying the causes of disease is to identify 

approaches or treatments that can prevent disease. Epidemiologic studies, for instance, have 

identified high blood pressure and cholesterol as risk factors for heart attack and stroke. 

Subsequently, major prevention efforts based on proven therapies have reduced the burden of 

cardiovascular disease in the United States. My comments today are directed toward prevention. 

 For the purposes of our discussion today, the primary question is: what are the health 

outcomes associated with the use of a medicine such as VIOXX? Implicit in this question is the 

notion of a comparison group, who may receive a placebo (no medicinal effects) or another 

active treatment. The two basic types of studies in humans are the clinical trial and the 

observational study. In a clinical trial, patients are assigned randomly to receive the active or the 

comparison treatment, and they are followed for the health outcomes of interest. The clinical 

trial is the optimal method of assessing the health effects of medications, and the design of the 

clinical trial varies according to the question to be answered. For instance, trials that evaluate the 
 Psaty-2 

relief from the pain of arthritis can be conducted in a few hundred patients who are followed for 

6 weeks. But such a study is too small to evaluate the effects of a medication on health outcomes 

such as heart attack or stroke. Studies of thousands of patients followed for several years are 

often needed to provide confidence in the evaluation of these cardiovascular outcomes. 

 In observational studies, investigators examine the associations between risk factors and 

health outcomes that occur naturally in the community. The adverse health effects of smoking--

lung cancer, heart disease and stroke--are one example. Pharmacoepidemiologic studies assess 

the association between the use of medications as risk factors and various health outcomes. The 

key distinction between clinical trials and observational studies involves the allocation of the use 

of the medication. In large clinical trials, randomization creates groups that are on average 

balanced in terms of their baseline risk for the health outcome of interest with the result that the 

treatment-control comparison represents a fair test. In observational studies, patients and their 

physicians select the medication, and the factors associated with this selection rather than the 

medication itself may affect the risk. In some observational studies, appropriate design and 

analysis can eliminate or minimize the potential biases. In the absence of evidence from clinical 

trials, however, observational studies often provide the best available evidence for the health 

effects of medications widely used in the population. These two approaches--clinical trials and 

observational studies--are complementary. 

 

 Duty to patients. In order to make recommendations about drug therapies, physicians 

must have information about both the benefits and the risks so that patients can make informed 

decisions. This duty to obtain and provide information about risks and benefits of drug therapies 

or other interventions devolves to all who work in medicine, including the pharmaceutical 

industry (1). 

 Blood clots, heart attacks, and strokes. Clotting is important to stop the loss of blood 

from a cut or an injury (2,3). At the site of an injury, platelets stick together and with other 

proteins form a gel-like plug. Under normal conditions, a delicate balance between the forces 

that promote clotting and the forces that prevent clotting maintains the flow of blood and 

prevents the loss of blood from injuries. In a heart attack or a stroke, a blood clot forms, often at 

the site of an injury, in a vessel that brings oxygen and nutrients to the heart or the brain. When 

the flow of blood is stopped by the clot, a part of the heart or the brain is injured or dies. 

 Aspirin and COX-2 inhibitors. Aspirin, which prevents platelets from clumping, is 

well known to prevent heart attacks in patients who are at moderate to high risk of heart disease. 

COX-2 inhibitors such as VIOXX do not disable platelets as aspirin does. In November 1996, 

Merck scientists hypothesized that patients taking VIOXX would have higher rates of heart 

disease than those taking an aspirin-like comparison treatment (4). By April 1998, Merck 

scientist knew of evidence that COX-2 inhibitors such as VIOXX reduce the production of 

prostacyclin, which prevents platelet aggregation (5-7). In other words, VIOXX not only lacks 

the anti-platelet effects of aspirin, but it also disables one the blood vessel’s main defenses 

against the clumping of platelets. On the basis of this biologic evidence, it would be reasonable 

to hypothesize that the treatment of patients with VIOXX might increase the risk of heart attack 

and stroke compared with either an aspirin-like treatment or with placebo (no active treatment). 

For VIOXX to be used safely, the potential cardiovascular risks need to be defined clearly so that 
 Psaty-3 

physicians and patients can be informed about the risks as well as the benefits of therapy. 

 Underlying causes of the VIOXX problem. From the point of view of prevention, three 

interventions would help to avert a VIOXX-like problem in the future. First, large long-term 

clinical trials to define key risks and benefits should be done early in the approval process. 

Second, high-risk patients likely to use medication should be included in these clinical trials in 

adequate numbers. Third, specific pro-active post-marketing trials or studies should be 

conducted and completed soon after approval. The optimal balance among the three approaches 

will depend on the specific medication under review. The following narrative highlights some of 

these issue in relation to VIOXX. 

Studies of VIOXX. As part of the FDA drug-approval process, Merck conducted a 

number of small short-term clinical trials of VIOXX. Patients taking aspirin were excluded from 

many of these studies. The review by the FDA medical officer describes 58 studies that included 

5771 patients, 3629 of whom received VIOXX (8). Most of the use was short-term [page 7]. 

Only 371 and 381 patients had received doses of 12.5 mg or 25 mg for more than one year, and 

272 had received doses of 50 mg for at least 6 months [page 74]. These studies were adequate to 

evaluate relief from pain as well as some of the more common adverse effects such as high blood 

pressure, fluid retention, and abnormal laboratory tests for kidney function. 

 These same studies were not adequate to evaluate the effects of VIOXX on less common 

but important health outcomes such as heart attack and stroke. The FDA medical officer, aware 

of the possibility that VIOXX might promote clotting and thus increase the risk of cardiovascular 

disease, observed that in the 6 week studies, “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%). Especially 

in view of the known effects of COX-2 inhibitors on clotting, this three-fold difference 

represents a basis for concern. Before VIOXX was ever approved, the FDA medical officer 

noted: “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]. In 

May 1999, VIOXX was approved for several indications. 

The VIGOR trial. All non-steroidal anti-inflammatory drugs (NSAIDs) reduce pain to a 

similar degree. Epidemiologic studies had shown that NSAIDs were also associated with an 

increased risk of stomach ulcers and gastrointestinal (GI) bleeding. The novelty of the COX2 

inhibitors such as VIOXX was the possibility that they would treat pain effectively and spare 

patients the risk of stomach ulcers and bleeding. Although small studies that evaluated ulcers by 

invasive measures such as endoscopy had suggested the possibility of a reduced risk, the effects 

of VIOXX on major upper-GI clinical events such as bleeding, perforation or obstruction were 

not known. 

The VIGOR trial, which was started in January 1999, included patients 40 years and 

older with rheumatoid arthritis. Patients with recent cardiovascular events and patients taking 

aspirin were excluded. The investigators randomized 4047 patients to VIOXX 50 mg daily and 
 Psaty-4 

4029 to naproxen 500 mg twice daily. In this active-comparison trial, the primary health 

outcome was the occurrence of major upper-GI clinical events, and patients were followed for an 

average of 8 months. Cardiovascular events were not identified as a safety outcome at the start 

of the trial. 

Complete results for the cardiovascular events in the VIGOR trial were not available for 

the publication in the New England Journal of Medicine (9), but they were described in the 

report by the FDA medical officer for the hearing in February 2001 (10). Patients assigned to 

receive VIOXX had lower rates of GI events than naproxen patients (2.1 versus 4.5 events per 

100 person years of therapy). For the combined outcome of all cardiovascular deaths, heart 

attacks and strokes, VIOXX patients had higher rates than naproxen patients (1.30 versus 0.67 

events per 100 person years). For the outcome of heart attack alone, the rate was five times 

higher in VIOXX patients than in naproxen patients (0.74 vs 0.15 per 100 person years). In 1000 

patients followed for one year, VIOXX treatment would likely be associated with 24 fewer GI 

events (about 8 of them complicated or severe) and 6 more heart attacks than naproxen 

treatment. Because VIGOR excluded high risk patients taking aspirin, the balance of GI benefit 

and heart-disease risk in these patients is not known. 

 The FDA medical officer also noted trends toward higher rate of cardiovascular events in 

her comments on studies 085 and 090 [page 34]. The FDA medical officer correctly concluded: 

“there is an increased risk of cardiovascular thrombotic events, particularly myocardial infarction 

[heart attack], in the VIOXX group compared with the naproxen group” [page 34]. The size of 

the VIGOR trial was large enough to exclude chance as a credible explanation for the differences 

in the rates of GI and cardiovascular events. 

 These findings--GI benefit and cardiovascular harm--present patients, physicians, 

regulators and industry with an exceedingly difficult choice. On the one hand, GI events are 

more common than cardiovascular events in the population included in VIGOR; although they 

are potentially serious, they are not usually fatal, and recovery is generally complete. On the 

other hand, about 25% of heart attacks are fatal. For persons who survive an initial heart attack 

or stroke, the quality of life and the duration of survival are usually compromised. The VIGOR 

trial results were available in December 1999. If these safety results had been available to the 

FDA seven months earlier, it is possible that VIOXX might not have been approved in May 

1999, at least not without additional studies. 

 On the basis of the VIGOR trial, some physicians and scientists did not think that the 

benefits of VIOXX outweighed their risks. The Pharmacy and Therapeutics Committee of 

Group Health Cooperative, a health plan where I conduct many of my studies, reviewed these 

data and chose not to add VIOXX to their formulary. The cumulative review of VIOXX studies 

by Juni and colleagues suggests that, shortly after the results of the VIGOR trial were available, 

“an increased risk of myocardial infarction [heart attack] was evident from 2000 onwards” (11). 

 VIOXX is not the first instance of mixed findings. Some years ago, clofibrate was 

evaluated as a treatment for patients with high cholesterol levels. Compared with placebo, 

clofibrate treatment was associated with lower rates of heart attack but higher rates of death (12). 

This experience encouraged the FDA to insist on large long-term trials of cholesterol lowering 
 Psaty-5 

agents such as the “statins.” As a result of this approach, we now have excellent evidence from 

large long-term clinical trials about the substantial health benefits of lovastatin, pravastatin, 

simvastatin, and atorvastatin. Although these trials were expensive to conduct, the high quality 

of the evidence and the expanding indications for these effective medicines has helped to 

promote the health of the public as well as the pharmaceutical industry. The importance of 

conducting these large long-term trials early in the evaluation of drugs that will be used by 

millions of patients for many years cannot be overemphasized. 

Because the VIGOR trial included active treatment with naproxen for the control group, 

there are three potential interpretations of the cardiovascular findings. VIOXX increases risk, 

naproxen decreases risk, or both. From the point of view of public health and medicine, this 

question is an open one that deserves careful scrutiny of the design and conduct of additional 

studies of VIOXX. In the original publication and in other materials, Merck settled on the 

hypothesis that naproxen had decreased the risk of heart attacks. Oddly, the authors called for 

confirmation of their naproxen findings “in larger studies” (9). This naproxen explanation is 

highly unlikely for several reasons. First, the five-fold difference in the risk of heart attacks is 

too large to be explained by an aspirin-like effect of naproxen. In 1996, Merck scientists had 

hypothesized an effect size of 25 to 30% for aspirin (4). Second, observational studies suggest 

that the beneficial effect of naproxen on the risk of heart attack are probably about 15% or 20% 

rather than 500% (11,13,14). In September 2001, the FDA Division of Drug Marketing, 

Advertising, and Communications (DDMAC) concluded that some of Merck’s promotional 

activities and materials were “false, lacking in fair balance, or otherwise misleading.” The letter 

specifically notes that the naproxen explanation is merely “hypothetical” rather than factual, and 

calls the press release claiming a “favorable cardiovascular safety profile” for VIOXX “simply 

incomprehensible.” 

I would like to focus for a moment on the issue of extrapolation of the results of clinical 

trials. Trial results are directly generalizable to patients who were eligible for the study and who, 

if asked, would have enrolled. Generalization to other patients must be done with caution. As I 

have indicated, patients with cardiovascular disease and patients taking aspirin were often 

excluded from the clinical trials of VIOXX. The major indication for low-dose aspirin is the 

prevention of cardiovascular disease in patients who are at moderate to high risk (2,3). In most 

of the early studies, VIOXX was not evaluated adequately for the large number of Americans at 

especially high risk of cardiovascular disease. In one observational study, 42% of the VIOXX 

users had a clinical history of major cardiovascular disease (15). Among naproxen users in the 

community, the heart attack rate was about 8 times higher than the rate for naproxen users in 

VIGOR (1.16 per 100 person years vs 0.15 per 100 in VIGOR). In a population with a moderate 

to high rate of heart attacks, in other words, VIOXX might cause more heart attacks than the 

number GI events prevented. 

 It is not at all clear whether or how either the GI benefits or cardiovascular harms of 

VIOXX might be influenced by the use of low-dose aspirin (16,17). For instance, the results of 

Merck protocol 136 (18) suggest that the cumulative incidence of gastroduodenal ulcers >= 3 

millimeters as assessed by GI endoscopy was similar in patients who took ibuprofen (17.1%) and 

in patients who took both low-dose aspirin and VIOXX (16.1%), but higher than in patients who 

took low-dose aspirin (7.3%) or in patients who took placebo (5.8%). VIOXX was not 
 Psaty-6 

adequately studied in the large numbers of high-risk patients who would eventually take it. 

The FDA did request that Merck revise the product label to reflect the cardiovascular 

risks observed in the VIGOR trial. While the FDA public review of the VIGOR trial results 

occurred in February 2001, the revisions to the VIOXX product label were not completed until 

April 11, 2002. These revisions were added to the “Precautions” section, under “Cardiovascular 

Effects” (19). No black-box warning about adverse cardiovascular effects, the most prominent 

warning, was added to the VIOXX product label. In contrast, black-box warnings about an 

increased risk of cardiovascular events were added to estrogens and progestins after the results of 

the NIH-funded Women’s Health Initiative were published (20). The public health rationale for 

the two different approaches remains unclear. 

 Post-marketing surveillance studies. After approval, aggressive direct-to-consumer 

marketing of VIOXX led to increased sales, and soon, large numbers of Americans were using 

VIOXX. This high level of use permitted various investigators to conduct observational studies 

of the association between VIOXX and the risk of heart attack. For assessing this association, 

the FDA MedWatch system is not adequate (21). 

 Some observational studies have found no increase in the heart-attack risk associated 

with VIOXX (22). Others report an increase risk, especially for patients taking high-dose 

VIOXX (15,23). One of the best-designed observational studies was conducted by Dr Graham 

and colleagues (24). In this study, users of VIOXX were compared with users of CELEBREX 

(celecoxib, another COX-2 inhibitor). The analysis was adjusted for potential confounding 

factors. VIOXX at doses of 25 mg or less daily was associated with a 50% increase in the risk of 

heart attack; and doses of greater than 25 mg daily were associated with a 370% increase in the 

risk of heart attacks. These risk estimates from this observational study are consistent with the 

findings from the randomized trials, VIGOR and APPROVe. 

 APPROVe Trial. In this clinical trial, patients aged 40 years or older with benign 

tumors (adenomas) in the large intestine were randomly assigned to receive VIOXX 25 mg daily 

(n=1287) or placebo (n=1299). The purpose of the trial was to evaluate whether VIOXX 

prevented the recurrence of the adenomas. Patient enrollment began in February of 2000. 

Initially, patients taking low-dose aspirin were not eligible; but in June 2000 as a result of the 

VIGOR findings, the APPROVe protocol was amended to allow up to 20% of patients taking 

low-dose aspirin into the trial. After 18 months of follow-up, the cardiovascular event rates for 

the two groups diverged. VIOXX patients had higher rates of heart attack or stroke than placebo 

patients (1.08 versus 0.48 events per 100 person years of therapy; rate ratio [RR] = 2.25; 95% 

confidence interval [CI] = 1.24 to 4.08). This risk of heart attack or stroke was lower in patients 

taking aspirin (RR = 1.29; 95% CI = 0.28 to 6.50) than in patients not taking aspirin (RR = 2.57; 

95% CI = 1.31 to 5.06) although there was no significant difference between the two strata 

(interaction p-value = 0.37). On the basis of these data, the Data Safety and Monitoring Board 

recommended stopping the clinical trial, and Merck withdrew VIOXX from the market in 

September 2004. 

 In 1000 patients who have a baseline risk of 5 heart attacks or strokes over a one-year 

period, VIOXX treatment would likely increase the number of heart attacks or strokes to a total 
 Psaty-7 

of 11 . For patients with a higher baseline risk, the number of additional heart attacks or strokes 

would be larger. As commentators have pointed out (19), tens of thousands of patients may have 

had heart attacks or strokes that are attributable to the use of VIOXX. 

 The Merck-sponsored reviews of the early pre-existing small short-term clinical-trial data 

could provide only limited information (25,26). Importantly, it was the results of a large longterm clinical trial, APPROVe, that convinced Merck to remove VIOXX from the market. The 

failure to conduct large long-term randomized trials in a more timely fashion permitted millions 

of Americans to use a drug whose cardiovascular safety profile was in question. 

 In the development of VIOXX, Merck had invested a enormous amount of time and 

money. In the evaluation of whether and when to withdraw VIOXX, Merck has an almost 

insurmountable conflict of interest. To protect the health of the public, this sort of decision 

should be referred to an independent group of reviewers. 

Recommendations. Attention to the following recommendations may help prevent 

future VIOXX-like problems. 

1. Large long-term trials to assure patient safety. Arthritis is a chronic condition, and 

treatment is often required for many years. Medicines for common chronic conditions have large 

potential markets with the result that even small increases in risk can affect tens of thousands of 

people. Medicines that will be used by large numbers of Americans for long periods of time are 

best evaluated in large long-term clinical trials that are started as early as possible in the approval 

process. The clinical trial of lumiracoxib is a recent example of a large trial (16,17). This 

approach, used for the statin drugs, has benefited patients, physicians and the pharmaceutical 

industry. If the VIGOR trial results had been available in May 1999 rather than December 1999, 

it is possible that VIOXX might not have been approved by the FDA, at least not without 

additional studies. 

 2. Evaluation of medicines in patients who are likely to use them and may be 

especially vulnerable to adverse effects. Initially, Merck excluded patients with recently 

diagnosed cardiovascular disease and patients taking aspirin. This approach maximized the 

possibility of finding a GI benefit and, at the same time, minimized the possibility of uncovering 

convincing evidence about cardiovascular harm. It also provides physicians and patients taking 

aspirin with no information about the risks and benefits of VIOXX therapy. For a large number 

of patients, it was not clear whether VIOXX was, at the time of approval, safe and effective for 

the intended use. 

 3. Improvements in post-marketing surveillance by the FDA. In the last decade, with 

the emphasis on rapid drug-approvals, new drugs (new molecular entities) often first appear on 

the US market. Perhaps because of the attention devoted to the speed of the review, less 

emphasis has been placed on attention to patient safety. The FDA should reorient priorities and 

devote more attention and resources to patient safety. The recognition of new adverse effects--

those that are not recognized prior to approval--will require the monitoring of patients who take 

these drugs. The FDA MedWatch data can only provide information about rare and serious side 

effects that are unrelated to the indication of the drug, so other means of evaluating safety must 
 Psaty-8 

be employed for newly marketed drugs. Specific pro-active post-marketing trials or studies 

should be designed, conducted and completed in a timely fashion (27). The optimal balance 

between clinical trials and observational studies will depend on the specific drug and the safety 

questions that may remain or arise. Moreover, new post-marketing surveillance systems and 

approaches should be developed or enhanced. For instance, Coordinated Clinical Studies 

Network, which was just recently funded as part of the NIH Roadmap Initiative, includes 4% of 

the US population and is moving toward the use of a coordinated system of electronic medical 

records: an almost on-line assessment of risk may be possible in the near future. 

4. Independent Office of Drug Safety and conditional approval of new medications. 

To implement improvements in post-marketing surveillance, the FDA needs a new Independent 

Office of Drug Safety that can pursue potential “signals” or “biologic hypotheses” in a pro-active 

way. This new office should be separate from the FDA office that originally approved the drug. 

A system of conditional approvals for new medications (or regular re-review of all medications) 

would provide the FDA the authority and the opportunity to insist on timely revisions to labels, 

to assure that post-marketing commitments have been completed, and to compel new postmarketing commitments when they may be indicated. Finally, to balance the interests of patients 

and industry, decisions about label changes, new studies, suspension of sales or withdrawal of 

drugs might best be made by the new Independent Office of Drug Safety in consultation with an 

outside group of disinterested reviewers. 

rfc6.doc 

Nov 15, 2004 
 Psaty-9 

References 

1. Berwick D, Davidoff F, Hiatt H, Smith R. Refining and implementing the Tavistock 

principles for everybody in health care. BMJ 2001;323:616-620. 

2. US Preventative Services Task Force. Aspirin for the primary prevention of cardiovascular 

events: recommendation and rationale. Ann Intern Med 2002;136:157-160. 

3. Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of 

cardiovascular events: a summary of the evidence for the US Preventive Services Task Force. 

Ann Intern Med 2002;136:161-172. 

4. Muliner T. Anticipated consequences of NSAID antiplatelet effects on cardiovascular events 

and effects of excluding low-dose aspirin use in the Cox-2 GI Outcomes Megatrial. Letter of 

November 21, 1996 to B Friedman, A Nies, and R Spector. 

5. McAdams BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. 

Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of 

a selective inhibitor of COX-2. Proc Natl Acad Sci 1999;96:272-277. 

6. Buerkle MA, Lehrer S, Sohn HY, Conzen P, Pohl U, Krotz F. Selective inhibition of 

cyclooxygenase-2 enhances platelet adhesion in hamster arterioles in vivo. Circulation 

2004;110:2053-9. 

7. FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004;351:1709-11. 

8. Villalba ML. FDA Medical Officer Review of VIOXX (rofecoxib), NDA 21-042 (capsules) 

and NDA 21-052 (oral solution). Http://www.fda.gov/cder/drug/infopage/vioxx/default.htm. 

9. Bombardier C, Laine L, Reicin A, et alia for the VIGOR Study Group. Comparison of upper 

gastrointestinal toxicity of Rofecoxib and Naproxen in patients with rheumatoid arthritis. N Engl 

J Med 2000;343:1520-1528. 

10. Targum SL. Consultation on NDA 21-042, S-007; Review of cardiovascular safety database 

[on Vioxx or rofecoxib). FDA Memorandum, Feb 1, 2001. 

Http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.doc; last accessed on June 

5, 2001. 

11. Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular 

events and rofexocib: cumulative meta-analysis. Lancet 2004; epud. 

12. Report from the Committee of Principal Investigators. A co-operative trial in the primary 

prevention of ischaemic heart disease using clofibrate. Br Heart J 1978;40:1069-1118. 

13. Solomon DH, Glynn RJ, Levin R, Avron J. Nonsteroidal anti-inflammatory drug use and 

acute myocardial infarction. Arch Intern Med 2002;162:1099-1104. 

14. Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal anti-inflammatory 

drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 

2002;359:118-123. 

15. Ray WA, Stein CM, Daugherty JR, Hall K, Arbogast PG, Griffin MR. COX-2 selective 

non-steroidal anti-flammatory drugs and risk of serious coronary heart disease. Lancet 

2002;360:1071-1073. 

16. Schnitzer TJ, Burnester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and 

ibuprofen in the Therapeutic Arthritis Research and Gastrointestingal Event Trail (TARGET), 

reduction in ulcer complications: randomised controlled trial. Lancet 2004;364:665-674. 

17. Farkauh ME, Kirshner H, Harrington RA, et al. Comparison of lumiracoxib with naproxen 

and ibuprofen in the Therapeutic ARthritis Research and Gastrointestinal Event Trial 

(TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 2004;364:675-684. 
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18. Louie D. Revised Confidential Information Brochure for IND 55,269 VIOXX (rofecoxib). 

Accompanied letter of May 12, 2004 from Diane Louie to Brian E Harvey. 

19. Topol EJ. Failing the public health--rofecoxib, Merck, and the FDA. N Engl J Med 

2004;351:1707-1709. 

20. Writing group for the Women's Health Iniative. Risks and benefits of estrogen plus 

progestin in healthy postmenopausal women principal results from the Women's Health Initiative 

randomized controlled trial. JAMA 2002;288:321-333. 

21. Kessler DA. Introducing MEDWatch: a new approach to reporting medication and device 

adverse effects and product problems. JAMA 1993;269:2765-2767. 

22. Mamdani M, Rochon P, Juurlink DN, et al. Effect of selective cyclooxygenase-2 inhibitors 

and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med 

2003;163:1481-1486. 

23. Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective 

cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 

2004;109:2068-2073. 

24. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden 

cardiac death in patients treated with COX-2 selective and non-selective NSAIDs. Lancet 2004; 

in press. 

25. Konstam MA, Weir MR, Reicin A, Shapiro D, Sperling RS, Barr E, Gertz BJ. 

Cardiovascular thrombotic events in controlled clinical trials of rofecoxib. Circulation 

2001;104:2280-2288. 

26. Weir MR, Perling RS, Reicin A, Gertz BJ. Selective Cox-2 inhibition and cardiovascular 

effects: a review of the rofecoxib development program. Am Heart J 2003;146:591-604. 

27. Ray WA, MacDonald TM, Solomon DH, Graham DJ, Avorn J. COX-2 selective nonsteroidal anti-inflammatory drugs and cardiovascular disease. Pharmacoepidemiol Drug Saf 

2003;12:67-70. 
DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

Food and Drug Administration

Rockville MD 20857

STATEMENT 

OF

SANDRA KWEDER, M.D

DEPUTY DIRECTOR, OFFICE OF NEW DRUGS

CENTER FOR DRUG EVALUATION AND RESEARCH

U.S. FOOD AND DRUG ADMINISTRATION

BEFORE THE

COMMITTEE ON FINANCE

UNITED STATES SENATE

November 18, 2004

Release Only Upon Delivery
1

INTRODUCTION

Mr. Chairman and Members of the Committee, I am Dr. Sandra Kweder, Deputy Director of 

the Office of New Drugs at the Center for Drug Evaluation and Research (CDER), U.S. Food 

and Drug Administration (FDA or the Agency). We appreciate the opportunity to participate 

in this hearing regarding drug safety and the worldwide withdrawal by Merck & Co., Inc. of 

Vioxx.

I. BACKGROUND ON DRUG SAFETY

Modern drugs provide unmistakable and significant health benefits. It is well recognized that 

FDA's drug review is a gold standard. Indeed, we believe that FDA maintains the highest 

worldwide standards for drug approval. FDA grants approval to drugs after a sponsor 

demonstrates that they are safe and effective. Experience has shown that the full magnitude 

of some potential risks do not always emerge during the mandatory clinical trials conducted 

before approval to evaluate these products for safety and effectiveness. Occasionally, serious 

adverse effects are identified after approval either in post-marketing clinical trials or through 

spontaneous reporting of adverse events. That is why Congress has supported and FDA has 

created a strong post-market drug safety program designed to assess adverse events identified 

after approval for all of the medical products it regulates as a complement to the pre-market 

safety reviews required for approval of prescription drugs in the United States. Monitoring 

the drug safety of marketed products requires close collaboration between our clinical 

reviewers and drug safety staff to evaluate and respond to adverse events identified in 

ongoing clinical trials or reported to us by physicians and their patients. The most recent 

actions concerning the drug Vioxx (rofecoxib) illustrates the vital importance of the ongoing 

assessment of the safety of a product once it is in widespread use. 

It is important to understand that all approved drugs pose some level of risk, such as the risks 

that are identified in clinical trials and listed on the labeling of the product. Unless a new 

drug's demonstrated benefit outweighs its known risk for an intended population, FDA will 

not approve the drug. However, we cannot anticipate all possible effects of a drug during the 

clinical trials that precede approval. An adverse drug reaction can range from a minor, 

unpleasant response to a drug product, to a response that is sometimes life-threatening or 

deadly. Such adverse drug reactions may be expected (because clinical trial results indicate 

such possibilities) or unexpected (because the reaction was not evident in clinical trials). It 

may also result from errors in drug prescribing, dispensing or use. The issue of how to detect 

and limit adverse reactions can be challenging; how to weigh the impact of these adverse drug 

reactions against the benefits of these products on individual patients and the public health is 

multifaceted and complex, involving scientific as well as public policy issues.
2

II. VIOXX 

The Vioxx Approval 

FDA approved Vioxx in May 1999 for the reduction of signs and symptoms of osteoarthritis, 

as well as for acute pain in adults and for the treatment of primary dysmenorrhea. Vioxx 

received a six-month priority review because the drug potentially provided a significant 

therapeutic advantage over existing approved drugs due to fewer gastrointestinal side effects, 

including bleeding. A product undergoing a priority review is held to the same rigorous 

standards for safety, efficacy, and quality that FDA expects from all drugs submitted for 

approval. 

As with many other new molecular entities, this product was taken before the Arthritis 

Advisory Committee, April 20, 1999, prior to its approval. It was the second of a new class 

(COX-2 selective) of non-steroidal anti-inflammatory drugs (NSAIDs) approved by FDA. 

The original safety database for this product included approximately 5,000 patients on Vioxx 

and did not show an increased risk of heart attack or stroke. 

In the clinical trials conducted before approval, the risk of gastrointenstinal (GI) side effects 

was determined through the use of endoscopy. At the time that FDA approved Vioxx , the 

available evidence from these endoscopy studies showed a significantly lower risk of 

gastrointestinal ulcers, a significant source of serious side effects such as bleeding and death, 

in comparison to ibuprofen. 

The VIGOR Study 

After Vioxx was approved in 1999, Merck continued studies of Vioxx designed to look at 

clinically meaningful GI effects, such as stomach ulcers and bleeding (VIOXX 

Gastrointestinal Outcomes Research, or VIGOR study). This study was designed to provide 

longer term clinical outcome data to confirm the shorter term endoscopy findings and to 

evaluate overall safety. The VIGOR study was a large (8,000-patient) study designed to 

evaluate the GI safety of Vioxx as compared to naproxen. This study was done in a 

rheumatoid arthritis population who typically require a higher dose (50 mg was used) of antiinflammatory medication.

VIGOR did not have a placebo group because to do so would have meant patients with 

rheumatoid arthritis would have been randomized to receive no pain relief. Use of a placebo 

would have been intolerable, because untreated patients would have suffered and left the 

study. The study also excluded subjects taking low dose aspirin for cardiovascular (CV) 

prevention because use of aspirin might have contributed to increased rates of GI bleeding in 

the study and confound the results. However, the exclusion of patients on low dose aspirin 

may have influenced CV events in the study, since low dose aspirin has been shown to reduce 

CV risk. 
3

In April 2002, FDA approved extensive labeling changes to reflect the findings from the 

VIGOR study. FDA also approved a rheumatoid arthritis indication at the 25 mg dose based 

on separate efficacy trials. The new label provided additional information to the Clinical 

Studies, Precautions, Drug Interactions and Dosage and Administration sections to reflect all 

that was known at the time about the potential risk of cardiovascular effects with Vioxx.

These labeling changes included detailed information about the increase in risk of 

cardiovascular events relative to naproxen, including heart attack. It also included data from 

the ongoing placebo controlled Alzheimer's study at the 14 month time point which did not 

show an increase in CV risk. The new labeling change also noted that Vioxx 50 mg was not 

recommended for chronic use.

Other Vioxx Studies

In the years following the 1999 FDA approval of Vioxx, Merck began conducting a series of 

clinical trials exploring other potential indications of this product. All trials for chronic use 

were designed to monitor carefully for CV safety and included data safety monitoring 

committees as well as blinded experts to assess all CV events in the trials. Some of these 

studies included placebo-controlled studies of Vioxx in Alzheimer's disease, prostate cancer, 

and colon polyps. Following the 2001 Advisory Committee meeting and the 2002 labeling 

changes, FDA focused on ensuring that all clinical trials conducted with Vioxx were designed 

to include careful monitoring of CV risk, and required that Merck submit all available CV 

data in ongoing trials.

In the period following the 2002 Vioxx labeling changes, FDA also continued to monitor the 

scientific literature reviewing several retrospective epidemiologic studies. Some of these 

studies suggested an increased risk for CV events with Vioxx, primarily with the 50 mg dose, 

while others did not. Epidemiologic studies in real world populations of conditions such as 

heart attack or stroke are difficult to conduct and interpret because of the need to carefully and 

adequately account for the many known powerful risk factors for these diseases. Merck, or 

Pfizer, the manufacturer of Celebrex (another COX-2 inhibitor), sponsored, directly or 

indirectly, many of these epidemiology studies.

Given the need for data to distinguish the impact of the use of these drugs on cardiovascular 

risk from factors such as smoking, hypertension, diabetes, low dose aspirin use, high 

cholesterol and others, the long-term, placebo-controlled trials that were being conducted 

offered the best opportunity to carefully assess both the existence of and the magnitude of 

these cardiovascular effects.

III. MERCK'S WORLDWIDE WITHDRAWAL OF VIOXX

Merck contacted FDA on September 27, 2004, to request a meeting to discuss with the 

Agency the Data Safety Monitoring Board's decision to halt Merck's long-term study of 

Vioxx in patients at increased risk of colon polyps. Merck and FDA officials met the next 

day, September 28, and during that meeting the company informed FDA of its decision to 

remove Vioxx from the market voluntarily. The data presented demonstrated an increase in
4

risk in cardiovascular risk and stroke starting at the eighteen month time point compared to 

placebo. This was the first demonstration of a difference in comparison to a placebo group 

and supported the previous signal seen in the VIGOR trial and some of the epidemiologic 

studies.

IV. THE KAISER STUDY ON VIOXX 

In follow up to the VIGOR findings, FDA worked with Kaiser Permanente California HMO 

as part of a collaborative agreement to provide an alternative means of evaluating the CV 

safety signal using a managed care database. In 2001, the forerunner of the Office of Drug 

Safety (ODS) and Dr. David Graham began informal discussions with Kaiser Permanente 

about projects of mutual interest. At the same time, FDA's Arthritis Advisory Committee was 

reviewing the cardiovascular risk observed in clinical trials for Vioxx and recommended the 

need to collect additional information regarding this risk. Dr. Graham indicated that Kaiser 

was interested in the CV safety of the COX-2 agents in general and in pursuing a scientific 

collaboration with ODS on this topic even if Agency funding were not available for the full 

study. FDA provided funding to partially support this pilot scientific collaboration in August 

2001 and again in August 2002. A protocol for the study was developed to study the risk of 

myocardial infarction among users of selective (COX-2) and non-selective non-steroidal antiinflammatory agents (NSAIDs). Dr. Graham was designated the ODS project officer for this 

study to work with his counterparts at Kaiser Permanente. Dr. Wayne Ray, an epidemiologist 

at Vanderbilt University and a cooperative agreement grantee of FDA, was added to the study 

team during the course of the study. Dr. Graham periodically discussed his work with his 

supervisors to provide updates on the progress of the study.

In February 2004, Dr. Graham and his coauthors submitted an abstract to the International 

Society for Pharmacoepidemiology (ISPE) for possible presentation at the August 2004 

meeting in Bordeaux, France. No study results were included in this abstract, which was 

accepted for a poster presentation in August 2004. In May 2004, Dr. Graham and his 

coauthors submitted an abstract of their study findings to the American College of 

Rheumatology (ACR) for possible presentation at their October 2004 meeting in San Antonio. 

The deadline for submitting abstracts for the San Antonio meeting was May 13, 2004. Dr. 

Graham informed his supervisor about his authorship role in the ACR abstract in early 

September 2004.

On August 11, 2004, David Graham first shared a draft of his ISPE poster presentation with 

his supervisors to obtain their review and clearance, as is required of any FDA author or 

presenter. At that time, Dr. Graham's supervisors in ODS informed him of the importance of 

this work and the need to promptly complete a study report for circulation within the Agency 

and for broader dissemination in a scientific journal. In reviewing the poster presentation, 

scientists within ODS and within the Office of New Drugs with specific expertise in COX-2s 

provided comments and raised questions regarding the study design and statistical modeling, 

which were not detailed in the poster. The conclusion that high dose Vioxx should never be 

used was questioned, as the label for the drug already recommended limiting high dose use to 

no more the five days based on the cardiovascular risks identified in clinical trials. A concern
5

was expressed that the data presented in the poster and in the medical literature did not 

support the recommendation of never using high dose Vioxx. These comments and concerns 

were shared with Dr. Graham who chose to revise his conclusions voluntarily. A disclaimer 

was placed on the poster to reflect that some of the conclusions and statements in the poster 

were those of the authors and did not necessarily reflect Agency policy.

Dr. Graham presented his poster in Bordeaux, France, on August 23-24, 2004, and 

participated in press coverage that discussed the findings. (Graham et al. at the International 

Conference on Pharmacoepidemiology and Therapeutic Risk Management, August 2004 

reporting an elevated cardiovascular risk for the 50 mg dose of Vioxx). 

Upon Dr. Graham's return from Bordeaux in late August, given the data's potential application 

to regulatory actions, Dr. Graham was asked to submit a draft report for Agency review 

within two weeks. He asked for a September 30, 2004, deadline and on that date, Dr. Graham 

provided a first draft of his report to his supervisors. Discussions concerning the report are 

ongoing between Dr. Graham and his supervisors. Dr. Graham has meanwhile submitted a 

manuscript version of the report to Lancet for publication. 

V. FDA INITIATIVES TO STRENGTHEN DRUG SAFETY 

At FDA, we are constantly searching for ways to improve our processes and methods, and 

thereby better serve the public health. On November 5, 2004, FDA announced a five-step 

plan to strengthen its drug safety program. First, CDER will sponsor an Institute of Medicine 

(IOM) study on FDA's drug safety system. An IOM committee will study the effectiveness 

of the United States' drug safety system, with an emphasis on the post-market phase, and 

assess what additional steps could be taken to learn more about the side effects of drugs as 

they are actually used. We will ask IOM to examine FDA's role within the health care 

delivery system and recommend measures to enhance the confidence of Americans in the 

safety and effectiveness of their drugs.

Second, CDER will implement a program for addressing differences of professional opinion.

Currently, in most cases, free and open discussion of scientific issues among review teams 

and with supervisors, managers and external advisors, leads to an agreed course of action. 

Sometimes, however, a consensus decision cannot be reached, and an employee may feel that 

his or her opinion was not adequately considered. Such disagreements can have a potentially 

significant public health impact. 

In an effort to improve the current process, CDER will formalize a program to help ensure 

that the opinions of dissenting scientific reviewers are formally addressed and transparent in 

its decision-making process. An ad hoc panel, including FDA staff and outside experts not 

directly involved in disputed decisions, will have 30 days to review all relevant materials and 

recommend to the Center Director an appropriate course of action.
6

Third, CDER will conduct a national search to fill the currently vacant position of Director of 

the Office of Drug Safety, which is responsible for overseeing the post-marketing safety 

program for all drugs. The Center is seeking a candidate who is a nationally recognized drug 

safety expert with knowledge of the basic science of drug development and surveillance, and 

has a strong commitment to the protection of public health. 

Fourth, in the coming year, CDER will conduct workshops and Advisory Committee 

meetings to discuss complex drug safety and risk management issues. These consultations 

may include emerging concerns for products that are investigational or already marketed. 

Examples of areas where FDA may seek input include:

* Whether a particular safety concern alters the risk-to-benefit balance of a drug; 

* Whether FDA should request a sponsor to conduct a particular type of study to further 

address an issue; 

* What types of studies would best answer safety questions; 

* Whether a finding is unique to one product or seems to be a drug class effect; 

* Whether a labeling change is warranted and, if so, what type; and 

* How to otherwise facilitate careful and informed use of a drug.

These consultations will include experts from FDA, other federal agencies, academia, the 

pharmaceutical industry, and the healthcare community. 

Finally, by the end of this year, FDA intends to publish final versions of three guidances that 

the agency developed to help pharmaceutical firms manage risks involving drugs and 

biological products. These guidances should assist pharmaceutical firms in identifying and 

assessing potential safety risks not only before a drug reaches the market and but also after a 

drug is already on the market. These guidances will rely on the use of good 

pharmacovigilance practices and pharmacoepidemiologic assessment. These documents are:

* “Premarketing Guidance,” which covers risk assessment of pharmaceuticals prior to

their marketing; 

* “RiskMAP Guidance,” which deals with the development and use of riskminimization action plans; and 

* “Pharmacovigilance Guidance,” which discusses post-marketing risk assessment, good

pharmacovigilance practices and pharmacoepidemiologic assessment. 

VI. CONCLUSION

In summary, FDA worked actively and vigorously with Merck to inform public health 

professionals of what was known regarding CV risk with Vioxx, and to pursue further 

definitive investigations to better define and quantify this risk. FDA also reviewed and 

remained current on new epidemiologic studies that appeared in the literature. Indeed, the 

recent study findings disclosed by Merck, leading to its decision to voluntarily withdraw 

Vioxx from the marketplace, resulted from FDA's vigilance in requiring these long-term 

outcome trials to address our concerns.
7

Detecting, assessing, managing and communicating the risks and benefits of prescription and 

over-the-counter drugs is a highly complex and demanding task. FDA is determined to meet 

this challenge by employing cutting-edge science, transparent policy, and sound decisions 

based on the advice of the best experts in and out of the agency. We are confident that the 

additional activities discussed above will strengthen the agency's program to greater ensure 

the safety of medical products that make a major contribution to the health and quality of life 

of millions of Americans. Medicines that receive FDA approval are among the safest in the 

world, and the measures we are taking are designed to strengthen this quality, as well as 

consumer confidence that FDA's processes ensure the highest protection of the public health.















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