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March 31, 2005
Did Merck decide to "see no evil" in Vioxx?
Developing pharmaceuticals is a tough job. And designing and conducting tests for a drug's safety and efficacy is quite complicated. You must carefully identify the study questions you want to answer, because everything from the type of people you enroll, to the study length, the analysis, and how you interpret the results depends upon a careful framing of the question. With all of these complexities, it's natural to expect some mistakes and missteps. But an excellent article by Robert Burton at Salon.com calls into question whether Merck's failure to recognize deadly heart-related side effects of its pain drug, Vioxx, were simple mistakes or a calculated decision not to directly investigate.
The story, "How Merck stacked the Vioxx deck" lays out how Dr. Burton sees it: that Merck knew there were heart risks with Vioxx but conducted studies "designed to avoid finding out how serious they were."
To check out the article, Salon offers non-members a 'Free Site Pass' that allows you access to their site after watching a short ad from their sponsors. For those of you don't want to bother, no worries, I've excerpted some key parts for you:
Given the enormous intellectual investment in the design of a drug like Vioxx, it is reasonable to presume that all potential outcomes were seriously entertained. I must presume that Merck would factor in what might happen to Vioxx sales with each study result. And so it's hard to escape the sadly cynical conclusion that the company consciously crafted its tests to avoid exposing the risks of Vioxx to the public.
[snip]
As far back as 1984, Garret FitzGerald and his colleagues at the University of Pennsylvania, writing in the New England Journal of Medicine, showed that the COX enzyme might prevent arterial blood clot formation. FitzGerald suggested that this side effect might mean little in healthy persons but could be dangerous to patients with severe atherosclerosis.
[snip]
Merck responded to FitzGerald's research by re-analyzing all of its Vioxx clinical data, and included FitzGerald's potentially worrisome lab data in its FDA application. (This data was published in 1999 in the Journal of Pharmacology and Experimental Therapeutics.) Merck also declared that it had adopted the standard procedure for "facilitating rigorous scientific analysis, on an ongoing basis, of all competing hypotheses about potential CV [cardiovascular, or heart-realted] risks or benefits from Vioxx."
Was this a sufficient evaluation of a potentially serious side effect of Vioxx? Or should more have been done? Given that it is standard practice to assess all serious potential risks of new drugs, FitzGerald's concern should have been directly addressed.
But rather than design a study focused on the C.V. risks of Vioxx, Merck created the VIGOR (Vioxx Gastrointestinal Outcomes Research) study in 2000. It compared the incidence of G.I. complications of Vioxx to naproxen, another conventional NSAID, whose most popular brand is Aleve. The goal was to prove that Vioxx was an equally effective but safer drug than an over-the-counter NSAID. Unfortunately, the study, published in the New England Journal of Medicine, revealed a twofold increase in C.V. risk for patients who took Vioxx. Of course, Merck acted surprised. What Merck didn't tell us is that it had stripped the deck of patients at high risk for heart disease.
Burton goes on to explain that the VIGOR study... (By the way, isn't that a great name for an efficacy trial? I don't need to see the results, I can just tell that Vioxx must work from that great name.) ...sorry, that the VIGOR study's participants were predominantly women, the mean age was 58, and the study duration was a little less than a year. Given that women tend to develop heart disease an average of 10 years later than men, it would be hard to draw conclusions about heart side-effects from this study group over the study time period. Meanwhile, other studies continued to raise questions about the heart risks of COX-2 inhibitor drugs, the class of drugs that includes Vioxx. And Merck looked like it was going to investigate...
According to an article in the New York Times earlier this year, the company planned to initiate a major C.V. risk study called VALOR [another great name!] in 2002. But just days before company researchers were to submit the study's protocol to the FDA, the project was abruptly halted. Merck did not explain why. It issued a general statement, saying that as it was designing the study, "we continued to ask ourselves and our consultants whether this was the right way to definitely answer" the question of whether Vioxx posed C.V. risks. "We ultimately decided not to conduct that particular study."
[snip]
To further distance Merck from any responsibility for those who had recently begun taking Vioxx, Kim added, "While the cause of these results is uncertain at this time, they suggest an increased risk of confirmed CV events beginning after 18 months of continuous therapy."
No, the risk didn't begin after 18 months. This would be analogous to saying that daily sunbathing for 18 months poses no risk for melanoma if no melanomas are detected during that time, and that the risk doesn't begin until the melanomas are first discovered. The risk is present from the beginning but only evident at 18 months.
Finally, Merck is asking us to believe that it didn't suspect from the outset that Vioxx might increase the risk of heart attacks and strokes. It's telling us that its studies were adequately designed to detect both the incidence and possible underlying mechanisms of cardiovascular risks. It wants us to accept that a nine-month study, abruptly concluded, was insufficient evidence for the withdrawal of Vioxx because it was reasonable to presume that naproxen had a cardio-protective effect.
For me, the sad but inescapable conclusion is that Merck made an informed decision to avoid knowing the full extent of Vioxx's potential risks for heart attacks and strokes.
There's lots more good stuff in the story, but I've probably excerpted too much already, so go check it out. At the end of the article, Burton calls for transparency of the data so independent doctors and scientists can review it for themselves. Finally, Burton acknowledges that decisions to take drugs must involve a personal risk-benefit analysis between us and our physicians. But we can't have drug companies playing a shell game with us and revealing only those results it wants us to see.
Posted by rigd0003 at March 31, 2005 03:38 PM | News
Comments
I am so glad that I am a test engineer in the Semiconductor Industry rather than the pharmeceutical (did I spell that right?) industry.
If something I am respoinsible for testing fails in the field, it gets sent back with an angry letter from the customer, and we replace it and do failure analysis that usually indicates that someone forgot to deal with ElectroStatic Discharge (ESD) properly. (The best way to explain ESD is to rub your feet, in socks only, across the shag carpet and touch your brother when he least expects it. Everyone with a brother will understand, if you don't have a brother, sorry. Try touching anything metal and grounded, instead That is ESD).
In the drug industry, fails in the field means someone got sicker or died. In my industry, the only way someone could die is if the chip was used in a weapons system (in which death is the goal, and luckily none of my stuff is), or in stuff like medical systems or nuclear reactors or something. Since the stuff I work on goes into cell phones, computers, and other consumer electronics, if I screw up my test, it just means someone can't download their porn at Starbucks or they can't get the latest P. Diddy ringtone on the cell phone.
If someone has trouble connecting to the World of Warcraft server, and it is due to my negligence as a test engineer, I won't loose sleep at night. If a pilot crashes his plane because if it, I will. Luckily, I haven't been in that boat.
Recently, my boss told me that the GPS chips I am working on will probably go into a new system used by search & rescue teams. I suppose if we supply bad chips due to errors I made, and people in danger can't be rescued because of the bad chips, I will feel really, extremely crappy. But I will know that I did my best, and it wasn't like Merck, who appears to be just deciding to ingnore responsibility in these matters.
Posted by: Allan at April 23, 2005 09:09 AM