With Supporters Like Those Accelerated Approval Doesn't Need Enemies

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  • 11/21/2011
There has been a lot of coverage about the Food and Drug Administration's decision to revoke approval for the use of Avastin in metastatic breast cancer.  Some commentators – who have at most a third hand understanding of the FDA’s handling of Avastin and how it squares or doesn’t with other cancer drugs granted accelerated approval – have lauded the withdrawal as good for innovation.  Most of it takes at face value FDA Commissioner's Hamburg 69 page decision in which she claims that the 'objective' evidence of benefit did not exist to support approval relative to the serious side effects of the drug. 

In particular, people who should know better let the FDA's spin affect their judgment.  For example, Avik Roy who writes for Forbes and is a fellow at The Manhattan Institute who in turn salutes another MI fellow for his support of the Avastin withdrawal:

"Paul Howard is the guy who gets it right:

        If you think (as I do) that the FDA should be expanding the accelerated approval pathway and allow more drugs to get to market based on promising         early studies. rather than waiting for large Phase III clinical trials that can take years to complete, you can argue that this outcome actually strengthens AA. Critics have charged that AA is sop to industry, and that companies never do the follow up studies to support AA. Avastin proves them wrong.

This is exactly the point. If you want the FDA to approve more innovative, new drugs based on promising but early clinical results, you have to give the FDA a way to revoke those approvals later on, should larger trials prove that those drugs aren't as safe or effective as they first seemed. This is why the FDA should be congratulated for the way it has handled the Avastin breast cancer saga, and why I hope we will see the FDA handle more cases like this one, not less."


Both of them have no clue.  

In fact the decision is less about Avastin and says more about the deep resistance at the Office of Oncology Drug Products to accelerated approval.  And those who support the reversal as some victory for medical innovation and accelerated approval do not understand either the scientific challenges of establishing clinical benefit in first line MBC care and, given how hard it is to demonstrate any clinical benefit in end stage patients, how significant the addition of Avastin to current therapies really is.   I am disappointed that observers treat the decision with the same sort of seat of the pants analysis reserved for Yankee post-game shows.

Dr. Hamburg's sympathy and support clearly lies with patients and the accelerated approval process.  However her explanation of the reason for the withdrawal of the approval reflects a combination of evasiveness and duplicity on the part of FDA staff in the Office of Cancer Drugs that has dogged the accelerated approval of Avastin from the start. 

Dr. Hamburg seeks to refute the claim that the FDA never switched the outcome measure of additional studies Genentech conducted to support ongoing approval of Avastin for MBC.   She claims (and I will guess this was written for her) that progression free survival (how long people lived without tumors growing) was always the standard and that the OODP did not demand to see an increase in overall survival  (how long people with and without Avastin treated before they died of any cause) which is a harder goal to meet.  In fact, her decision memo shows that the FDA never came straight out to say PFS of any given length would be the basis for approval.  Rather, FDA used the words "probably" or "might" and talks about the "potential" of using  PFS for approval as long as the "magnitude" of the benefit was significant given the risks of the drug.  Did FDA ever define what "magnitude" was sufficient?  Never.  Rather, as Dr. Padzur who runs OODP, told Genentech he would determine what the right "magnitude" would be when he saw the results. 

In otherwords FDA said that improvement in PFS is not adequate unless a large enough magnitude that it will decide after the fact and by the way if it doesn’t think it is big enough then a cancer drug must show a statistically significant improvement in OS to support approval.   And Dr. Hamburg calls this objective evidence? 

Additionally, Dr. Hamburg claims that the magnitude of clinical benefit has nothing to do with achieving a statistically significant benefit.  (Those words might and should be used by companies going forward as they design clinical trials.)  All well and good.  Yet the FDA ultimately revoked approval because Avastin did not show a statistically significant increase in overall median survival.   So does statistical significance  matter or not?  Apparently it does when you want to undercut approval for use of a product you opposed at the outset.  Similarly, when Dr. Hamburg claims that Genentech could never identify a subset of patients that might be more likely to benefit from Avastin in MBC she fails to point out that the FDA never asked for such data, nor did it state that it would extend approval based on response in a small group of patients.  In any event, the FDA decided that post-hoc analysis to identify super-response of a statistically significant amount is not evidence of magnitude.  

Her opinion ignores the fact that several other first line treatments for MBC were approved using PFS as an endpoint with half as much clinical benefit.   Let me put in terms that supporters of the decision can understand and let me put it in bold:  Specifically in the first-line treatment of MBC setting, two other drugs have received full approval using progression free survival or time to progression (TTP) effects of a much low magnitude than was used to grant Avastin accelerated approval.  Several second and third line drugs also were given full approval with well below the median gains in PFS of Avastin.  In all but two cases, full approval was granted without a statistical significant improvement in OS.

Dr. Hamburg offers some hints about how to show clinical benefit going forward: patient outcome data will count and designing trials to show which people might gain most from medicines will as well.  Her brief discussion about how groups that support continued use of Avastin in MBC could appear to biased because they receive unrestricted support from Genentech is a very low blow and hypocritical because the FDA is seeking to loosen its own conflict of interest rules to get more qualified experts on it's advisory committees. 

But in general Dr. Hamburg justifies the creation of higher threshold for the use of surrogate endpoints, a threshold that is arbitrary and without any empirical justification, in order to force all drugs to demonstrate OS.  All this suggests that allowing FDA to retain discretion over what is enough benefit will generate more uncertainty and ends accelerated approval as a real alternative.    The Avastin decision says less about the science of the FDA and more about how regulatory uncertainty (as a result of bias or lack of knowledge) can undermine innovation.   How can the so-called supporters of accelerated approval endorse Hamburg’s endorsement of this bait and switch?

Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.

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