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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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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April 16, 2008

Fun With Bacteria

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Posted by Derek

A recent interview in Nature Reviews Drug Discovery with John Powers, formerly of the FDA, points out some problems in designing antibacterial drug trials. Some of these are unique to this area, although others we're stuck with wherever we go.

For one thing, it’s surprisingly hard to make sure, when you’re selecting patients, that the people you’re letting into the trial have the disease that you’re trying to treat. The example used is that some 5% of the patients who present with cough actually have pneumonia. Pneumonia is a very good disease to treat with antibacterial drugs, but you’d better make sure that your patients actually have it. There are some tests available to make sure that a given pathogen is present, although they aren’t available in every case you’d want them to be. If you don’t have such a screen, you risk having a very heterogeneous patient population, which will likely as not obscure the effectiveness of the drug you’re testing.

Then there’s the related difficulty in treating some conditions that you’d think would be clear cases for antibacterials: ear infections, for example. The problem is, it’s surprisingly hard to show benefit for some of these things with existing drugs. The underlying infection may be hard to get to (poor circulation in the infected area), or it may be an intrinsically heterogeneous condition like sinusitis. (That can be the result of umpteen different sorts of bacteria, or it could well be something viral, or several varieties of fungal infection, or allergies, what have you). There’s no point in running a head-to-head with an existing medication in these cases; you should run against placebo. That'll be enough of a challenge.

Another problem is that some of the bacterial diseases progress rather quickly – ahead, in some cases, of our ability to usefully diagnose them. That presents a real challenge for a clinical design, one that is dealt with, in many cases, by not attempting to gather rigorous clinical data under these conditions at all. In this field, diagnostic tools have to be fast if they’re going to be of much use.

There are two sides to all these problems: not only do you want to get the drug to the people who need it (and who will respond to it) the most, you want avoid giving it to people who won’t respond at all. That’s not just for the reasons given above (it’ll mess up your data), although that’s enough all by itself. No, the other problem is that spreading your drug around to inappropriate patient populations will just bring on resistance even faster. That’s going to happen no matter what, of course – the key is to have it happen as slowly as possible.

Comments (5) + TrackBacks (0) | Category: Clinical Trials | Infectious Diseases


COMMENTS

1. milkshake on April 16, 2008 7:54 AM writes...

Another problem is that even if you manage to find an amazing new antibiotic that is 1) effective 2) can be dosed conveniently 3) has a mild side-effect profile 4) has no cross-resistnace with other antibiotics, it is likely to end up as a third, fourth alternative or even a last line of defense, to keep the resistance from developing to it - it will go off patent before it becomes the mainstay prescription.

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2. Gaudisso on April 16, 2008 5:54 PM writes...

That's just not true. If a new drug works it'll be prescribed as a first line or second line drug by physicians regardless of formulary status, co-pays or risk of resistance. A good example of this is the use of Levaquin which I prescribe empirically for a wide variety of conditions. I'll certainly consider the use of generics like azithromycin first (I don't even consider using amoxicillin any more), but if a patient's situation and condition warrants more aggressive treatment I have no qualms about using more expensive drugs like Levaquin. It simply works.

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3. hibob on April 16, 2008 6:00 PM writes...

milkshake-
The (asinine) way around that is to test and market the antibiotic against one strain of bacteria, even if it has broad spectrum efficacy. That way it becomes the first line of defense for one bug, rather than the last line of defense for all of them.

Next up: formulate your drug as an injectable rather than as a pill, so that it qualifies for reimbursement as physician-administered under Medicare!

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4. Rita on April 16, 2008 11:14 PM writes...

Hey, where's the story on how Merck fabricated its studies and had shill scientists sign their names to the drivel?

Or does that not count as part of the pipeline?

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5. sroy on April 17, 2008 4:00 AM writes...

So I hear Vioxx caused a three fold increase in the risk of death in Alzheimer's (AD) patients.

Now that is actually something useful- think of the savings in long term care because of premature death (especially given the legal issues surrounding open euthanasia).

AD increases the patient's risk of dying substantially by itself, therefore increasing it a further threefold shows that the drug had a pharmacological effect, though it clearly did not translate into the desired therapeutic effect- nothing a little marketing can gloss over.

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