Investigation into Painkiller Vioxx

SUSAN DENTZER:

More than 80 million people worldwide took this medication: Vioxx, the blockbuster painkilling drug pulled off the market in late September. Vioxx was withdrawn after its manufacturer, Merck, conducted a study showing the drug doubled the risk of heart attacks and strokes. One of those affected may have been Lisa Williams.

She's a 48-year-old biochemist now undergoing cardiac rehabilitation therapy at a Maryland hospital. A one-time fitness enthusiast and recreational runner, Williams took Vioxx in 2000 to relieve a painful bone spur in her heel. After ten weeks on the drug, she had a heart attack. She's now suing Merck.

LISA WILLIAMS:

My doctor said that the current state of my heart is that of an 80-year-old person. I deplore the fact that profit was put ahead of human life.

SUSAN DENTZER:

And you feel that's what Merck did?

LISA WILLIAMS:

I do. I believe they did.

SUSAN DENTZER:

Ray Gilmartin is Merck's chairman and CEO.

RAY GILMARTIN:

Merck, at every step of the way, in terms of our conduct with Vioxx, basically reflected our values that we put patient safety first. So, we studied the drug in great detail with lots of clinical trials. We disclosed the results of those trials, and, within a week, we voluntarily withdrew the drug from the market.

SUSAN DENTZER:

Although Merck is mounting a vigorous defense, the company now faces a potential multi-billion dollar legal liability from hundreds of lawsuits like Williams.' And that's not all. Two separate federal investigations are under way into whether Merck violated criminal laws by covering up information about Vioxx's dangers and whether it misled company shareholders about the safety of the drug.

And tomorrow, a Senate Finance Committee panel will hold hearings as it investigates allegations of missteps at Merck, and failed oversight by the Food and Drug Administration. Dr. Janet Woodcock, the FDA's acting deputy for operations, rejects the charge of FDA failures.

DR. JANET WOODCOCK, U.S. Food and Drug Administration: We don't agree with that assessment. We felt we were right where the evidence was as far as what we knew about Vioxx at every point in time.

SUSAN DENTZER:

Vioxx is one of a huge class of non-steroidal anti-inflammatory drugs, or NSAIDS. These drugs, which also include over-the-counter preparations like ibuprofen, relieve the pain of inflammation that characterizes conditions like arthritis.

DOCTOR (to patient):

Let's take a look at the arthritis here.

SUSAN DENTZER:

That sounds simple, but, in fact, inflammation is a phenomenally complicated body process involving multiple enzymes and other chemicals. Dr. Robert Califf is a leading cardiologist who heads Duke University's clinical research institute.

DR. ROBERT CALIFF:

These are drugs that alter the inflammatory pathways that we have in our bodies that are natural defensive pathways against infections and irritation and all sorts of things that happen to us. So, when we perturb that inflammatory system, it could be either good or bad. And we don't… it's so complicated, we can't really tell which is which.

SUSAN DENTZER:

A case in point are conventional NSAIDS like ibuprofen. They block one enzyme involved in inflammatory pain, Cox-2, along with another enzyme, Cox-1. But Cox-1 also happens to protect the stomach from ulcers. As a result, conventional NSAIDS can produce severe problems.

DR. JANET WOODCOCK:

You can have bleeding, you can have perforation of stomach ulcers, you can have obstruction of the gastrointestinal tract, and there are quite a number, probably thousands of people who die every year as a result of this toxicity.

SUSAN DENTZER:

Vioxx, a new type of NSAID, blocked only Cox-2 and left Cox-1 intact. That spared people those stomach and intestinal dangers, but in doing so, it apparently tipped the enzyme balance in the other direction. That's because Cox-1 also has another property: It helps blood platelets come together to form blood clots. But when clots form in coronary arteries, the result can be a heart attack. Tom Kline, Lisa Williams' attorney, argues that's precisely how Vioxx wreaked havoc in her body.

TOM KLINE:

The drug was a bad actor. It was going to subject anyone who took it, minor or major ailments, to the risks of a heart attack and a stroke.

SUSAN DENTZER:

It's not clear how fully the FDA or Merck understood these complicated effects of Vioxx when the drug was approved for use in 1999. By that point, Merck says, it had submitted data from studies on 5,400 patients. Those showed no signs of unexpected cardiovascular problems.

A year later, though, one of Merck's own clinical trials did raise red flags. Dubbed the "vigor" study, it compared taking twice the usual dose of Vioxx to taking another anti-inflammatory drug, Naproxen, sold as preparations like Aleve. The trial showed that Vioxx reduced by half the number of ill effects on the stomach and intestine.

RAY GILMARTIN:

But that same trial also showed that Vioxx had a higher rate of cardiovascular events compared to our comparative drug Naproxen. The question was at that point: Was this chance, or did naproxen cause fewer cardiovascular events or did Vioxx cause more?

SUSAN DENTZER:

Gilmartin says the weight of the evidence was that Naproxen was protecting the heart, not that Vioxx was endangering it. Naproxen is similar to aspirin, which is well known to prevent heart attacks. But the FDA did not buy that theory, arguing there was no hard evidence to support it. So it convened an expert group of doctors to examine the vigor trial results.

DR. JANET WOODCOCK:

It was decided that we didn't know what was the cause of this observation in the vigor trial, and it was decided what should be done is put information in the label about these results as well as some precautions about use in people who are at risk for cardiovascular events.

SUSAN DENTZER:

In 2002, those warnings were added to Vioxx's label, the information about a drug that's given to physicians. Meanwhile, other studies continued to raise questions about Vioxx's cardiovascular risks. Woodcock says none were definitive.

DR. JANET WOODCOCK:

Some of those studies did not show an increased risk for Vioxx compared to the other NSAIDS. Some of them had a hint of an increased risk.

SUSAN DENTZER:

The FDA decided to await the results of another trial Merck had launched, dubbed "approve." That study was testing whether Vioxx could prevent recurrence of cancerous colon polyps, and was specifically designed to capture data about cardiovascular risks. But those results weren't due until sometime after 2004.

Then in September of this year, a special group monitoring the trial data noticed a troubling trend. Although the rate of cardiovascular events for patients in the trial was low, it was still double for patients taking Vioxx versus the patients on dummy pills. For reasons that still aren't understood, the elevated risks did not show up until patients had been on Vioxx more than 18 months. Those results are what finally prompted Merck to pull Vioxx off the market.

RAY GILMARTIN:

The important lessons from this are the fact that as a company such as ours continues to study these drugs, that as we come up with new findings and a surprising finding in this case about safety, how important it is to disclose that immediately to put that information into the public domain in a variety of ways.

SUSAN DENTZER:

Attorney Kline says the approve trial's implications are obvious.

TOM KLINE:

If you extrapolate from the study, it is clear that thousands of people suffered heart attacks and strokes and many of them died.

SUSAN DENTZER:

That's undoubtedly true, says Woodcock, but she adds that it will never be known how many others might have died from stomach and intestinal problems if people have been taking other nsaids because Vioxx was not the market.

DR. JANET WOODCOCK:

So, perhaps we were trading in this case one toxicity for another, and that's something we learned in the approve trial.

SUSAN DENTZER:

Experts like Califf says the Vioxx case points to a woefully out of date system of drug approval and oversight. They say that system has not kept pace with our growing scientific understanding of the body's complexity and of the complicated effects drugs can have on the body's systems.

DR. ROBERT CALIFF:

I believe the Vioxx episode was a signal to us that we have multiple drugs out there that may be doing a great amount of benefit or a great amount of harm that we just don't know about at this point.

SUSAN DENTZER:

Califf, in fact, was one of several experts who urged Merck to perform a study that gave Vioxx to patients with both arthritis and heart disease. They thought that would be the quickest way to determine whether Vioxx really did prompt more cardiovascular events. Merck decided not to do that study, believing its ongoing ones were sufficient. Now, Califf says the Vioxx case underscores the need for a completely new regulatory approach.

DR. ROBERT CALIFF:

We have a system which is very much geared toward getting approval from the FDA based on short-term studies. And what happens after that in terms of post-marketing studies for the most part is dictated by the companies themselves, because they have the responsibility of selling the drug and of measuring the outcomes related to that drug.

I believe we need a system where the design of the long-term study is a matter of public health, where consumers, physicians, the FDA and payers are involved in designing those studies.

SUSAN DENTZER:

Woodcock at the FDA agrees.

DR. JANET WOODCOCK:

Well, we may need to really consider doing trials, more trials in people who are taking drugs after the drugs have been marketed, trials in the real world situation to find out answers. But we have to look carefully at the side effects and especially the long-term consequences of taking these medicines.

SUSAN DENTZER:

As experts now debate how best to restructure drug oversight, it's possible this story will not end with Vioxx. Several other similar drugs are now undergoing close scrutiny to see whether they, too, carry cardiovascular risks.

Those include Celebrex and Bextra, made by Pfizer, and a second Merck drug, Arcoxia, not yet approved for sale in the U.S. Among other things, Pfizer now plans to test the safety of Celebrex in a study that will give it to patients at high risk for cardiovascular disease.