Tuesday, 19 March 2013

Lessons from history #6: The Vioxx saga


The Vioxx saga contains everything: conflicts of interest, big pharma influence, dodgy government regulators, data fabrication, and a body count. But there is more to the story: it is an example of a common logical fallacy whereby, when faced with a study that shows treatment A to be better than treatment B, we assume that treatment A is providing a benefit, and not that treatment B is harmful. Both assumptions may be equally valid, but we tend to choose the former. Had we not done so in this case, Vioxx might not have harmed so many people.

The saga
Vioxx (rofecoxib) is (was) an anti-inflammatory drug (NSAID: non-steroidal anti-inflammatory drug) for the treatment of conditions such as pain from arthritis. As a newer type of NSAID, it was naturally thought to be better than the time-tested NSAIDs. It wasn’t better (at least according to this Cochrane review), and even the purported advantage in gasto-intestinal side effects were questioned, but that didn’t stop it from being advertised as superior.

The marketing worked. Released in 1999, 5 years later is was earning $2.5 billion per year in sales, making it one of the biggest selling drugs of its time.

The results of some large trials (particularly this one) comparing it to an “old-fashioned” (read: reliable and safe) NSAID (naproxen) caused concern because the rate of heart attacks was significantly higher in the Vioxx group compared to the naproxen group.

The logical fallacy
The difference in heart attacks between Vioxx and naproxen was not thought to be due to Vioxx causing heart attacks, but due to “cardio-protective effects” of the naproxen.

The reality
Vioxx was causing the heart attacks. A later study (here) was stopped early because of increased adverse events in the Vioxx group. An FDA report estimated that over 27,000 heart attacks and deaths occurred in the US between 1999 and 2004 due to the use of Vioxx. Internationally, this has been estimated to be much higher.

The regulator and the conflict
The FDA advisory committee held an extraordinary meeting to discuss the Vioxx problem. They decided in a vote of 17 to 13 (2 abstentions) to keep Vioxx on the market (yes, the same FDA that estimated all those deaths and heart attacks). Of the 32 members on that panel, 10 were receiving funding from the manufacturer, Merck. Of those 10, all but one voted to keep it on the shelf. Surprised? I thought not.

What happened
Fortunately, the decision by the FDA didn’t matter. The company withdrew the drug on it's own. They saw the writing on the wall, and on the lawsuits, and they switched to damage control mode. Vioxx was the biggest drug recall in history, costing billions in lost profits and lawsuits, and thousands of lives.

The Lancet published an editorial and review (cumulative meta-analysis) that was highly critical of the FDA and Merck, concluding that the drug should have been withdrawn in 2000 based on data available at the time.

The lesson
There are many examples of the logical fallacy whereby we assume a benefit from medicine when one does not exist. It arises from our preconceived notions of medicine and the prevailing wisdom that stuff we do works. It is similar to the fallacy whereby, when two treatments are shown to be equal, it is assumed that they are both equally effective. The assumption that they are both equally ineffective (or harmful) may be just as valid – we just don’t consider it.

Interestingly, despite the Vioxx saga being reported widely, very few people (including doctors) know about it.

6 comments:

  1. Hi doc,
    Good read. thanks.

    And in the mean time, history seems to repeat itself WAY too close to the Vioxx saga: Voltaren/ diclofenac is said to be just as bad as vioxx for people at risk, we should all have known this for years, but do not act upon it... says:

    http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001388

    what's your view?


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    1. Thanks Karel,

      Interesting article - thanks for the link. There has always been discussion around the cardiovascular risk profile of Celebrex (the sister drug of Vioxx), but I was not aware of a risk from diclofenac - one of the most commonly prescribed drugs, period. Now I feel better about recommending plain old paracetamol (acetaminophen) to my osteoarthritis patients. It is very effective and safe, although until now I was mainly worried about gastrointestinal side effects, as they are much more common.

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  2. You might want to check out the recently published "COX-2 inhibition: What We Learned - A Controversial Update on Safety Data", which explains in greater detail what happened behind the scenes. Your oversimplification that "Vioxx caused them" fails to take into account that common NSAIDs like diclofenac are just as bad, but still on the market. You also forgot the article which showed naprosyn caused more heart attacks that Celebrex in elderly patients with dementia. An oversight?

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    1. Thanks for the info - I have provided the PubMed link here: http://www.ncbi.nlm.nih.gov/pubmed/24373107.
      Yes, I agree that it looks like Vioxx has been singled out as the bad guy, and that the other NSAIDs got off lightly. I tried to concentrate on Vioxx as a cautionary tale and probably neglected the dangers of similar drugs.
      I am not aware of the naproxen-Celebrex study but will look it up. Thanks again.

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  3. Viox was never banned for the FDA, MSD did it. In these days, I dont have the exact day, one of the person who vote for Vioxx ( it was a General of Veteranes Affaires ) said something like this drug was important because the fight with terrorism in Irak.

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    1. Thanks. Yes, I pointed out in the blog that the FDA had an extraordinary meeting and chose to keep Vioxx on the market.

      Regarding the War on Terror, you may be confusing this with the common statement that more people died from taking Vioxx than died in the 9/11 attacks or died in Iraq (Americans that is, many more civilians have died in Iraq).

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