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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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November 21, 2004

Safe, And Other Four-Letter Words

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Posted by Derek

According to the FDA's safety maverick, David Graham, there are at least five approved drugs out there that are unsafe and should probably be pulled from the market. Roche's Accutane, AstraZeneca's Crestor, GSK's Serevent, Pfizer's Bextra and Abbott's Meridia are all on his chopping block.

Well, Graham may not feel that he has enough power at the FDA, but he sure swings some weight in the stock market. All these companies lost several per cent of their market value on Friday, taking the whole drug sector with them. What everyone wants to know is: are these drugs safe?

What a useless question. I mean it - we're never going to get anywhere with that line of thinking. "Safe" is a word that means different things to different people at different times, which is something you'd think any adult would be able to understand. The only definition that everyone would recognize, at least in part, is "presenting no risk of any kind to anyone." That'll stand as a good trial-lawyer definition, at any rate.

And by that one, not one single drug sold today is safe. Of course they aren't. These compounds do things to your body - that's why you take them - and that's inherently risky. I don't think that I'm alone in the drug industry as someone who never takes even OTC medication unless I feel that the benefits outweigh the risks, and the risks are never zero. I know too much biochemistry to mess around with mine lightly.

The drug industry, the FDA, physicians and most patients recognize that safety standards vary depending on the severity of the disease. Toxic drug profiles are tolerated in oncology, for example, that would have stopped development of compounds in almost other area. And the standards go up as additional drugs enter a market - yes, I'm talking about those evil profit-spinning me-toos. One of the best ways to differentiate a new drug in a category is through a better safety profile.

So when someone asks, "Is drug X safe?", they're really asking a whole list of questions. What are the risks of taking the compound? That is, how severe are the side effects, and how often do they occur? How do those stack up against the benefits of the drug? Then you ask the same set of questions in each patient population for which you have distinguishable answers.

To pick an example from Graham's list, Accutane has big, dark, unmissable warnings all over it about not taking the drug while pregnant or while it's possible to become pregnant. Has that stopped people? Not enough of them, unfortunately. And this is a drug for acne, which can be disfiguring and disabling, but is not life-threatening. If it were a drug for pancreatic cancer, we wouldn't be having this discussion.

The COX-2 inhibitors look much better (in a risk-reward calculation) in the patients who cannot tolerate other anti-inflammatory drugs because of gastrointestinal problems. Vioxx itself also looks a lot more reasonable in patients who are not in the higher-risk cardiovascular categories. But it (and the others in its class) have been marketed and prescribed to all kinds of people, and the fallout is just starting. How about Pfizer's Bextra? As an article in the New York Times aptly puts it:

"Another disaster in the making? No one knows. The parallels between Vioxx and Bextra are eerie. There are mounting worries about Bextra's safety, just as there were with Vioxx. Drug-safety advocates are calling Bextra a danger, just as they did with Vioxx. Pfizer, Bextra's maker, defends its drug just as Merck did. And studies of Bextra provide ammunition to both sides, just as studies of Vioxx did.

What should the F.D.A. do? The answer is as clear as mud, just as it was with Vioxx. The twin controversies demonstrate the problems that the F.D.A. routinely faces in trying to strike the right balance between the risks and benefits of prescription drugs. There is almost never a perfect answer. . ."

Strike that "almost", guys.

Comments (3) + TrackBacks (0) | Category: Toxicology


1. jeet on November 22, 2004 3:32 PM writes...

I would suggest that the market is reacting to two outcomes;

one, the possibility that one or more of these drugs will be pulled from the market

two, the possibility that use of these products will decline since doctors will be more careful and that maybe the FDA will tighten the marketing restrictions already in place for these products

As you point out part of the vioxx problem is that the safety/ efficiacy profile of the drug wasn't in line with clinical use. I know that a fair number of people believe that the relaxing of direct to patient marketing rules may be a factor. Is it? I don't know. I see this as a part of the give-and-take cycle between the FDA and pharma that has led to our current system; which (on whole) does a very good job in finding the right efficacy and safety balance.

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2. jsinger on November 22, 2004 4:18 PM writes...

Another irony here is how the pendulum swings between the denunciation of "me-too" drugs and the discovery of "unsafe" bogeyman drugs. Is Crestor indistinguishable from every other statin or is it the worst thing since thalidomide?

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3. Harry on November 22, 2004 7:08 PM writes...

I would submit that a good part of the reason for market sell-off is that traders (if not investors) see the beginning of another silicone breast implant scenario: 1) "consumer advocates" start talking up "safety issues" 2) after enough hubbub has been created the FDA announces an investigation, or even better - a suspension of sales 3) trial lawyers begin trolling for plantiffs in order to file huge class-action suits 4) seeing bankruptcy looming, the defendants propose a settlement and the creation of a huge trust for the "victims" (and huge fees for the attorneys) 5) a portion of the fees are reinvested in "consumer advocate" organizations
6) the cycle begins again with a search for new "dangers".

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