Conflicted Safety Panel Let Vioxx Study Continue Merck pulled its painkiller Vioxx from the market in 2004 after a study showed the drug caused heart problems, strokes and death. But documents obtained by NPR reveal that early results from a 1999 study showed similar problems. Yet Merck didn't stop that study and tell the public.

Conflicted Safety Panel Let Vioxx Study Continue

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In 2004, Merck & Company pulled its painkiller Vioxx from the market. The drug was causing heart problems, strokes and deaths among patients in a large study underway at the time. Merck stopped that study when those results became clear. Now documents obtained by NPR show that five years earlier, in 1999, during another large Vioxx study, patients had similar heart problems. That study was not stopped.

NORRIS: During those five years, millions of Americans took Vioxx. A U.S. Food and Drug Administration scientist has estimated that some 38,000 people who took the drug died. Thousands of former Vioxx patients and their families are now suing the company.

NPR's Snigdha Prakash reports on why the earlier study wasn't stopped and why the public was not warned earlier that Vioxx was unsafe.

The decision to stop a large study of new medicine involves complex scientific and ethical issues. To find out if Merck responded appropriately to the heart problems it saw back in 1999, NPR consulted with three scientists who are authorities on heart disease and clinical studies.

We showed each of them charts and graphs from the large Vioxx study called VIGOR. The charts and graphs showing the study's early results have never been made public before. The first of the three experts NPR consulted is cardiologist Eric Topol of Case Western Reserve University. He's been a leading critic of Merck's Vioxx research and was subpoenaed to testify in the Vioxx product-liability lawsuits.

Dr. ERIC TOPOL (Case Western Reserve University): This is the most compelling and worrisome data that's come out about the VIGOR trial. And it's amazing it's taken this long, from November 1999 to 2006, to come out.

PRAKASH: The data Topol's talking about show that as of December 1999, three and a half months before the VIGOR study ended, Vioxx patients had suffered twice as many strokes, heart attacks and deaths as patients on naproxen, the older painkiller to which Vioxx was being compared.

As in most large drug studies, patients in the study were being tracked by a panel of experts to make sure they weren't being harmed by the drug they were testing. The study's official safety panel was told about these heart attacks, but the minutes of the panel's December 1999 meeting show that the panel didn't stop the study. Cardiologist Eric Topol says the safety panel made the wrong decision.

Dr. TOPOL: You have a very dangerous situation. It was incumbent on the watchdog committee to stop the trial, to alert all the responsible parties and the public.

PRAKASH: Topol singles out a graph the safety panel saw. The graph has two lines. One line shows deaths in the Vioxx group, the other, deaths in the naproxen group. For the first few weeks of the study, the two lines rise gently because the number of deaths is small. And the lines move in tandem because the number of deaths is about the same in the Vioxx group as in the naproxen group.

Dr. TOPOL: Everything looks about the same to four to six weeks, and then around six weeks, one curve is going way apart from the other.

PRAKASH: That curve is the Vioxx line. It separates from the naproxen line and starts climbing and it keeps climbing every month for the next nine months. The naproxen line stays flat, hardly any of the naproxen patients are dying.

Dr. TOPOL: And so what you see is a highly divergent trend that implicates Vioxx of having a higher risk of death.

PRAKASH: We showed the same graph to the second expert we consulted, cardiologist Paul Armstrong of the University of Alberta. He's served on the safety panels of many large scientific studies. Armstrong points to that steadily climbing line on the graph, the one that shows the monthly total of Vioxx deaths in the study, and says it tells you something else about patients on Vioxx.

Dr. PAUL ARMSTRONG (University of Alberta): The longer the exposure, the greater the risk.

PRAKASH: Armstrong says had he served on the safety panel, he would have been in a hurry to stop the study after seeing that graph. The third expert NPR consulted is Curt Furberg. He's a former head of clinical trials at the National Heart, Lung and Blood Institute. He's now a professor at Wake Forest University and has served on the safety panels of some 50 studies. Furberg agrees with cardiologists Eric Topol and Paul Armstrong.

Dr. CURRENT FURBERG (Wake Forest University): A doubling in risk is quite remarkable. The committee, in my view, should have told the sponsor to stop the study and told the world this drug is harmful. Unfortunately, that was not done and I think that contributed to the tragedy with Vioxx.

PRAKASH: To find out why the Merck safety panel continued the study, we requested interviews with the panel's members. The safety panel, known officially as a Data and Safety Monitoring Board - or DSMB - declined NPR's interview request, but written answers to our questions.

First, the safety panel said, it didn't stop the study because there were several possible explanation for the differences in cardiovascular problems between the Vioxx and naproxen groups. An actor reads from the panel's statement.

Unidentified Man: The DSMB was unable to determine whether the differences were due to some adverse affect of Vioxx, the lack of the protective anti-platelet effects of naproxen or some combination of those factors.

PRAKASH: In other words, the safety panel said, it couldn't tell if Vioxx was causing the heart problems or if naproxen, acting like low-dose aspirin, protected people from them, making Vioxx just look risky by comparison.

Dr. ARMSTRONG: Whichever is true, it's immaterial to the patients who are dead and receiving Vioxx.

PRAKASH: Cardiologist Paul Armstrong.

Dr. ARMSTRONG: To continue the trial when you already see excess hazard seems to me to be unwise.

PRAKASH: Moreover, our expert Curt Furberg says the safety panel's reasoning is based on an assumption that's never been proven in any scientific study, that naproxen prevents heart attacks.

Dr. FURBERG: It comes across as a way of protecting the drug and protecting the company.

PRAKASH: The second point the safety panel makes is that the heart problems in the study were small in number and the diagnoses came from the patient's own doctors and could turn out to be wrong. Curt Furberg concedes the number of heart problems and deaths was small. But he says it's clear the results weren't due to chance. He says the patterns were the same in every population group in the study.

Dr. FURBERG: In old people, young people, those who have hypertension, those who don't, etcetera. And the findings were very, very consistent. So in my mind, this confirms that the findings are real.

PRAKASH: Another reason the safety panel says it didn't stop the study in December 1999 was because the study was nearing its end anyway. Curt Furberg says it does take time to stop a large, multinational study and only a few additional heart attacks or deaths could have been predicted to occur in the remaining time. But, he says -

Dr. FURBERG: I think we have obligations, ethical, moral obligations. You don't want to expose patients to a harmful drug in a drug study. They should not be treated like guinea pigs. They are human beings. And we need to respect their rights.

PRAKASH: The safety panel also emphasized that this was an important study for patients. Vioxx could save lives if the study showed that Vioxx caused less gastrointestinal bleeding. But cardiologist Paul Armstrong counters such bleeding isn't common.

Dr. ARMSTRONG: The frequency with which that occurs is minor and I would say unlikely to be counterbalanced by this excess in death and cardiovascular events.

PRAKASH: The experts NPR consulted say that by not stopping the VIGOR study after Vioxx's heart problems became clear, the safety panel failed not just the 4,000 Vioxx patients in the study, but the millions who would go on to take Vioxx, until it was taken off the market almost five years later.

NORRIS: In a moment, experts say the safety panel was too close to Merck.

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