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Derek Lowe The 2002 Model

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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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« Vaccines and Human Folly | Main | Happy Fourth of July »

June 30, 2005

Where's the Combo?

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Posted by Derek

Gruntdoc wonders about why a particular combination therapy isn't available yet. Skin infections with methacillin-resistant staphylococcus aureus (MRSA), which I hope I never come any closer to experiencing, are treated with one of several antibiotic combinations, but they're all administered as separate drugs.

The answer is what you might suspect: the FDA would want clinical trials of the single-dose combination, just to make sure that things work the way that they're supposed to. Any company developing the combo would have to recoup those costs, not to mention the costs of then beating the drum for the idea that the new combination is a better idea. But the antibiotics in question are generics, which means that there could be some real cost-containment issues over the use of a more expensive combination.

But we have a rather close example at hand: the recently approve BiDil. (Here's the package insert, in PDF format.) That's a combination of two generics, too, which (famously) shows far better effects in the black population than it did in general clinical trials. Nitromed, the developer of the therapy, had to run some pretty reasonable-sized ones, and they spent a lot of money in the process.

They started by establishing that the blood levels of the two drugs were reasonable when given in combination, and went on to a group of 186 male patients. That trial (with 273 in the placebo group) didn't show a benefit, but hinted at one in the black subjects. The company also ran an 804-patient trial against enalapril, and saw the same trend, which led to the definitive 18-month trial in 518 black patients (with a roughly equal number in the placebo arm.) Keep in mind, this is all for two drugs whose individual efficacy was well-studied.

Note added after original post: Nitromed was after something more than the individual efficacy of each drug. Their hypothesis was that the combination would make the blood-pressure-lowering effect much more pronounced, and that this would translate into clinical benefit as seen in eventual mortality. Why this only seems to be the case in the black population is a head-scratcher. The situation for combination antibiotics would be simpler. So. . .

A combination antibiotic trial wouldn't be as long, or as expensive. But it wouldn't be negligible, either, and it's likely that some companies have run the numbers and decided that the investment would be unlikely to pay off.

Comments (3) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Infectious Diseases


1. GruntDoc on June 30, 2005 10:29 PM writes...

Thanks! That was what I was wondering. So, I'll just keep writing two prescriptions.

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2. Elias on July 1, 2005 11:37 AM writes...

Since BiDil seems to address the lower amounts of nitric oxide (or perhaps NOS enzymes) in blacks when compared to other races, would this suggest that blacks also suffer from higher rates of impotence or lower rates of idiopathic Parkinsonism (assuming NO is involved in PD, as some believe)?

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3. jeet on July 6, 2005 11:33 AM writes...

plus there is always the question of reimbursement. insurance payers and/ or medicare/ medicaid/ government payers do not consider new formulations (unless tied to specific clinical data indicating how the new formulation is more effective than previous ones/ current formulation) as sufficient enough technical advances to justify new pricing. so if you would like to develop a combination drug of two generics, you could charge whatever you would like, but the payers will only give the doc/ hospital the sum of the two generics as reimbursement

like all things in our convoluted system, there are examples where this may not be the most optimal way of encouraging innovation, however I think this is a good way to keep the line drawn between reformulations with significant advantages (i.e., Abraxane) vs. those with ease of use advantages (BilDil). It will be interesting to see what all the hospital P&T committees & payer review groups think of BilDil

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