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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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June 13, 2006

Disapproval of Approvability

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Posted by Derek

I've written before about how seemingly obvioius combination therapies can be hard to develop. Last Friday we had some more evidence of that.

Pozen, partnering with GlaxoSmithKline, has been trying to put together two well-established drugs for migraine: GSK's Imitrex (sumitriptan) and the OTC pain reliever naproxyn. But the FDA sent them the dreaded "approvable" letter, requesting more information (which, who knows, might require more studies) and Pozen's stock took the plunge. (Another small company, Neurocrine, went through a similar wringer a couple of weeks ago - I'm backed up on writing about that, but I hope to soon).

Analysts seem to be optimistic about the drug's eventual chances, but that doesn't do you as much good if you were holding the stock before the FDA letter. These "approvable" letters seem to have been increasing in frequency the last couple of years, and it's turning into a real problem. Such a letter either turns out to be not too big a deal, in which case a company's stock has been slaughtered for nothing, or it turns out to be such a big deal that you wonder why the company (and the agency) didn't come to some understanding about it before.

Is the FDA too risk-averse, or are companies trying to get too-thin NDAs through? My money's on the first explanation, in most cases. I think that the whole COX-2 debacle has helped to put the agency into a better-safe-than-sorry mode. I understand the need for caution, but (here comes a general principle of life): just because you can mess things up in one direction doesn't mean that you can't mess them up in the opposite one. Saying that the agency is too cautious doesn't mean that I think that they should let everything through - but letting some things through would be nice.

(See this Business Week piece for more on the approvable problem).

Comments (12) + TrackBacks (0) | Category: Drug Development


1. Mark Senak on June 13, 2006 8:35 AM writes...

I would consider a third proposition, which I actually referred to today in my posting on Eye on FDA. That is that a lot of the compounds coming to FDA consideration today had their clinical trials formulated pre-COX-2 and are having them considered post-COX-2. At the Advisory Committee meetings on the COX-2s, more than once AC members made the statement that the safety paradigm was dramatically shifting. Given that, what will happen to those compounds that already had their clinical trials designed and executed prior - that I think is the flood of approvable letters.

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2. Derek Lowe on June 13, 2006 8:52 AM writes...

That's a good point - we're seeing a time-lag disconnect. If that's the problem, it sure is a hard deal for the people who have things in front of the FDA now, isn't it?

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3. Still Scared of Dinosaurs on June 13, 2006 10:30 AM writes...

The only thing the existence of an approvable letter means is that the agency wants more time to issue a decision. Everything else is in the details, which are often strongly suspected prior to issuance of the letter itself.
As to the time lag, that's always there and it's mixed blessing for the sponsor. Otherwise the argument you often see in biopharma stock chats* that "the FDA can't approve this s**t knowing that a much superior drug (developed by our favorite company) if following right behind" would have some merit.
It can't be otherwise, though. An example is the original approval trials for ifn-a in "non-A, non-B" hepatitis. After the trials the characterization, and subsequently practical testability, of HCV came about. What do you do? Give the sponsors a pass? Send them back to square one? Or interpret the data as best you can given what is now known?
The first time big trials are run to pharma standards in an indication they almost always make large changes to the understanding of the disease in question, just not ones the sponsor wanted.
* If you have time to waste reading them, they have been something of a guilty pleasure in the past.

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4. Jeremiah on June 13, 2006 10:56 AM writes...

At Lilly, we were getting approvable letters frequently (the pipeline was rich and delicious at that point) and they would trumpet it on the corporate news channel that broadcast in every cafeteria as a wonderful achievement. We all knew better, of course. An approvable letter was honestly akin to a rejection; it was another year or two of studies as the patent burned up. At the time, Lilly was having serious problems getting their GMP practices up to date. Years of patents were destroyed there too. It’s become a problem, but I would prefer the FDA be cautious then risk public safety.

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5. Robert R. Fenichel on June 13, 2006 3:11 PM writes...

I was at FDA 1988-2000, latterly as Deputy Division Director for Cardiovascular Drug Products. Before PDUFA, Approvable letters were issued to indicate that only a few details (usually the wording of labels) remained. The time between Approvable and Approved rarely exceeded 6 weeks.

After PDUFA pressed FDA to play by the clock, it was recognized that an Approvable letter counts as an action for PDUFA purposes. That changed the whole nature of the game. Under the new regimen, there may not be more Approvable letters, but the time a typical application spends in the useless limbo of Approvable is greatly increased.

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6. dave s on June 13, 2006 3:25 PM writes...

COX-2 Pfui! When I was at FDA we all knew that Frances Kelsey got the Medal of Honor for dragging out the approval of thalidomide.
Memories are long over there! Sometimes, doing nothing is good...

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7. secret milkshake on June 13, 2006 5:41 PM writes...

The Posen/SMK product is evergreening plain and simple. I wonder if the "approvable" letter is just a counter-ploy to defeat such evergreening.

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8. Tom Womack on June 13, 2006 5:52 PM writes...

Out of curiosity, what prevents a doctor today from writing a scrip for imitrex and suggesting that the patient also take naproxyn? I had the impression that doctors had fairly wide latitude in prescriptions of that kind.

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9. Still Scared of Dinosaurs on June 13, 2006 9:43 PM writes...

Nothing prevents it, but who profits when it happens? Not Pozen, I'm betting.
Compliance is more of an issue with two meds, the costs may be more (one copay plus the otc cost of naproxen) and the naproxen dose in the combo may not be offered otc. But if this was a rescue med type situation where both drugs served to kick down a migraine quickly and other factors aren't at play your suggestion would definitely be viable.

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10. Kay on June 14, 2006 7:04 AM writes...

Why would FDA go out of its way to shepherd a non-advance? It would seem that a Laugh-Test Consultant could make good money by saving these silly combo companies from embarrassment.

Little has changed for those who are working on drugs for serious unmet needs.

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11. tom bartlett on June 14, 2006 12:01 PM writes...

Posen's "non-advance" is unimpressive, but I'd agree the FDA is way too conservative. And, as a nation, we are litigious--witness all the frivolous COX-2 cases. I expect the future will hole MORE, rather than less "CYA" action.....

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12. Daniel Newby on June 14, 2006 3:25 PM writes...

Is the FDA really being overcautious in this case? Pozen's Trexima is, after all, a COX inhibitor combined with a vasoconstrictor, formulated for maximum peak blood levels. It's an ideal combo drug for bringing a cardiac surprise to statistical significance.

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