Saturday, June 11, 2005

Vioxx: Betrayal of Trust

NPR recently broke the story that the vice president of Merck, makers of Vioxx, may have pressured the academic departments of physicians who were speaking out about the drug's potential (now known) cardiovascular side effects in 2000.

To fully understand the disappointing nature of this revelation, it helps to know the background that Merck is one of the oldest pharmaceutical firms, and perhaps the most respected among them, with a reputation for integrity. There is a sense of 'even Merck?' in the medical field. Without mentioning names, there are other companies this behavior would have been less surprising from.

So what exactly happened with Vioxx? Just to briefly review the history of this drug, in the early 90s a number of drug companies began a race for COX-2 inhibitors, a type of nonsteroidal pain medicine which, unlike the older generation (Motrin, Aleve) would not cause stomach upset and bleeding--a side effect which can be life threatening in patients taking large doses for long periods of time. When the COX-2 inhibitors Vioxx, Celebrex and Bextra were released, it was understood that they were designed as second-line drugs for those who needed nonsteroidal pain meds but had additional risk factors for gastrointestinal bleeding. Most people should be on Motrin or Aleve-like agents.

The first place the story gets fishy is when direct-to-consumer marketing campaigns (remember the Dorothy Hamill ads?) were released, implying that Vioxx was a first-line agent. The ensuing surge in requests to doctors, eager to make patients happy, resulted in Vioxx's launch as a 'blockbuster' drug with enormous sales. But remember, at this point thousands of people have been prescribed the drug off label, as first-line therapy.

In 1999, the VIGOR trial showed that patients on Vioxx had a statistically significant increase in heart attacks in comparison to naproxen (Aleve). For every 1000 patient-years, 8 stomach bleeds could be avoided, but 4 heart attacks were caused. The interesting thing here is that the investigators interpreted these results to mean that naproxen might be protective, not that Vioxx could be harmful. This is a dubious conclusion, since naproxen has been available for many years and there has never been any data supporting that conclusion.

Then, in 2004 the drug safety panel following the APPROVe study stopped the trial. This was an effort to show that Vioxx might protect against colon polyps. The panel had noted that the difference in cardiovascular events had just become statistically significant, and needed to unblind the groups to determine whether the drug was protective or harmful--and of course the rest is history. Merck volunarily decided to withdraw the drug from the market, but other COX 2 manufacturers continued to sell it.

A meta-analysis, or synthesis of multiple studies, recently found that significant information to withdraw the medication from the market in 2000 or 2001--check out the link, there's a telling graph.

What have we learned from this? Commentators have come up with many points, but here are a few I think are salient.

1. The FDA needs both teeth and eyes.
Currently, the FDA is not allowed to require additional safety studies once a medication has been approved, and it needs that authority. But what's less known is that they get much of their budget from drug companies--that's right, the companies they regulate--for the express purpose of expediting drug approvals. Their post-marketing monitoring budget is all from the Congress, and it's just not enough to keep track of all the drugs approved out there.

2. Drug marketing to consumers should be better regulated.
There's plenty of good reasons to use drugs off label, but patients shouldn't be basing that decision on an ad.

3. Doctors need an easy-to-use database of drug adverse effects.
Anyone who's looked at a Physicians' Desk Reference knows how difficult it is to know whether the side effects listed there are common, or spurious findings in one obscure study. The FDA's website just isn't as easy to use as, say, the CDC. A better FDA database online would be a big help.

4. When reading a medical study sponsored by a drug company, read the data, not the conclusions.

As this ongoing saga evolves, we will doubtless learn more about what really happened at the managerial level at Merck, and it's not going to be reassuring.


At 3:49 PM, Anonymous Anonymous said...

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