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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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September 6, 2012

Accelerated Approval And Its Discontents

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Posted by Derek

This may sound a little odd coming from someone in the drug industry, but I have a lot of sympathy for the FDA. I'm not saying that I always agree with them, or that I think that they're doing exactly what we need them to do all the time. But I would hate to be the person that would have to decide how they should do things differently. And I think that no matter what, the agency is going to have a lot of people with reasons to complain.

These thoughts are prompted by this article in JAMA on whether or not drug safety is being compromised by the growing number of "Priority Review" drug approvals. There are three examples set out in detail: Caprelsa (vandetanib) for thyroid cancer, Gilenya (fingolimod) for multiple sclerosis, and the anticoagulant Pradaxa (dabigatran). In each of these accelerated cases, safety has turned out to be more of a concern than some people expected, and the authors of this paper are asking if the benefits have been worth the risks.

Pharmalot has a good summary of the paper, along with a reply from the FDA. Their position is that various forms of accelerated approval have been around for quite a few years now, and that the agency is committed to post-approval monitoring in these cases. What they don't say - but it is, I think, true - is that there is no way to have accelerated approvals without occasional compromises in drug safety. Can't be done. You have to try to balance these things on a drug-by-drug basis: how much the new medication might benefit people without other good options, versus how many people it might hurt instead. And those are very hard calls, which are made with less data than you would have under non-accelerated conditions. If these three examples are indeed problematic drugs that made it through the system, no one should be surprised at all. Given the number of accelerated reviews over the years, there have to be some like this. In fact, this goes to show you that the accelerated review process is not, in fact, a sham. If everything that passed through it turned out to be just as clean as things that went through the normal approval process, that would be convincing evidence that the whole thing was just window dressing.

If that's true - and as I said, I certainly believe it is - then the question is "Should there be such a thing as accelerated approval at all?" If you decide that the answer to that is "Yes", then the follow-up is "Is the risk-reward slider set to the right place, or are we letting a few too many things through?" This is the point the authors are making, I'd say, that the answer to that question is "Yes", and we need to move the settings back a bit. But here comes an even trickier question: if you do that, how far back do you go before the whole accelerated approval process is not worth the effort any more? (If you try to make it so that nothing problematic makes it through at all, you've certainly crossed into that territory, to my way of thinking). So if three recent examples like these represent an unacceptable number (and it may be), what is acceptable? Two? One? Those numbers, but over a longer period of time?

And if so, how are you going to do that without tugging on the other end of the process, helping patients who are waiting for new medications? No, these are very, very hard questions, and no matter how you answer them, someone will be angry with you. I have, as I say, a lot of sympathy for the FDA.

Comments (7) + TrackBacks (0) | Category: Drug Development | Regulatory Affairs | Toxicology


1. anon the II on September 6, 2012 9:08 AM writes...

My cheesy barometer for determining whether any regulatory agency is doing a good job is that everybody complains about them. As soon as somebody seems happy with a regulatory agency, I get suspicious.

A tough job for people with tough skin.

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2. John Schilling on September 6, 2012 9:15 AM writes...

"Three examples involving drugs for treatment of cancer, multiple sclerosis, and stroke highlight the complex safety issues..."

Three examples out of sixteen in 2011 alone. To me, that raises the obvious suspicion of cherrypicking. Can someone with JAMA access check and see if they at least summarized the outcomes of the other thirteen cases, or gave their rationale for chosing those three?

Because if these are the worst of the lot, three out of sixteen doesn't seem terribly surprising, or even terribly terrible. And at least one of the three seems to have been a neutral rather than negative outcome.

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3. Bob P. in Fort Walton Beach, FL on September 6, 2012 12:29 PM writes...

I think the slider setting should depend on the ailment being treated. For rabies, for example, where there is little in the way of effective treatment once symptoms become apparent, it is, to my thinking, worth taking great risk - worst case is the patient is every bit as dead as with the current best available treatment. At the other end of the "OMG I'm going to die" spectrum, as a perhaps ridiculous case, insufficient eyelashes, why bother with any acceleration?

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4. CMCguy on September 6, 2012 1:45 PM writes...

You say "I think, true - is that there is no way to have accelerated approvals without occasional compromises in drug safety" and not sure is definitively that true unless dealing with side affects and population responses. From what I have observed and been involved in the accelerated aspects have little to do with the Safety side of the drug development equation as typically might be more "liberal" with Efficacy requirements. Tox Studies and other preclinical aspects in submissions are the same level and definitely seen no short cuts in the CMC portions. What is most impacted are the Clinical Trials, particularly use of surrogate markers, that reduce the size and time of the Phase II/III efforts. Means probably are not getting as strong a read on the side affects and variability in populations that may show up post-approval and is more magnified than the risk that is always there but would not really go as far as saying that is a true compromise as more a reflection of a more minimalistic approach applied in desperate situations.

The FDA is indeed in a hard place and in the main I suggest do a good job but in the end they are up against the uncertainty always dealt with in complex human biology and treatment options.

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5. luysii on September 6, 2012 7:43 PM writes...

There will always be rare and serious side effects of new drugs which won't be picked up by even large premarket studies. The reason is the extremely large genetic variation between people, which large scale genome sequencing is in the early stages of showing us.

Intriguing that Pradaxa is one of the drugs mentioned, as it was recommended for a close family member on Coumadin when it first came out.
I became quite gun-shy of using drugs until a year or so after release, due to my clinical experience with Felbamate. So I passed on Pradaxa.

For why we'll always have side effects and the Felbamate story see

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6. interested on September 6, 2012 8:10 PM writes...

Derek and commenters,

Interested to hear your take on the recent BMS/Inhibitex's HCV nuc inhibitor being stopped at Phase II.

(link to press release in the name... i think)

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7. silverpie on September 7, 2012 7:32 AM writes...

6: Your link goes to the main list of press releases. The one dated 23 August is the one in question. (I've attempted the direct link in my name.)

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