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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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December 20, 2002

Trials of Trials

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Posted by Derek

As I mentioned yesterday, I think the kind of study that compared diuretics with other hypertension medicines was a very good thing. So why don't we see more of these?

There are several reasons. It's worth thinking about the different levels of testing, and what questions they're designed to answer. At the first level, you have questions about specific drugs - is Drug A safe to take, compared with taking nothing? Does Drug A work, compared with taking a placebo? These are the usual subjects of Phase I and II clinical trials.

There's a third question, namely, how good is drug A versus other drugs that work the same way? That one doesn't get answered as often as it should, because the FDA generally only requires testing against placebo. A debate has been going on about when it's appropriate to run head-to-head trials rather than placebo-controlled, and it happens more often than it used to. Drug companies aren't always eager to try this, because they sometimes fear that the advantages of their new compound may turn out to be more subtle than they'd like. But if they think they've got a clear edge, then a trial like this is just the thing. I think we're going to be seeing more and more FDA requests for these sorts of trials, which will definitely make life harder for drug development, but in a good cause.

Beyond specific drug questions, you get to mechanism issues: Does therapy A work better than therapy B? That's what the diuretic study was designed to answer, and it's the rarest kind of all. It's a situation, though, like the old proverb that says when you strike at a king, you have to kill him. If you run one of these trials and your advantage isn't there, you're probably sunk - and if a safety liability shows up versus the existing therapy, you're completely sunk. This is what happened to Bristol-Meyers Squibb when they run Vanlev (omepatrilat) against Vasotec (enalapril) for hypertension. Vanlev's never going to see the light of day, and neither is any other ACE/neutral endopeptidase inhibitor combination.

As one of the interviewees in Wall Street Journal noted:

Duke's Dr. Catliff says it isn't reasonable to expect the pharmaceutical industry to onduct head to head studies needed to answer questions of both science and money. "It's sort of an all or nothing game," he says. There is a potential gain for the winner, but a huge risk for a loswer. Some results could essentialy kill the market for a drug. "The industry can't afford to take that kind of risk."

Well, whether it's reasonable or not, he's right that companies aren't going to line up to do this sort of study. The business is risky enough already, thanks. No one company is going to try it unless they're forced to (like BMS.) That goes double when you're comparing existing therapies, things that are already on the market. But that doesn't mean that I don't think this kind of study should be done - on the contrary. I think that the NIH's model for the ALLHAT hypertension study could be the way to go - let people run the study who won't be cutting their own throats by running it. It'll be interesting to see if they get a general mandate (and funding) to do just that.

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