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FDA Slams Brakes On Avastin's Accelerated Approval

By Jim Chen et al.

Sunday New York Times editorials are often the venue for weighty issues of broad interest, such as war, peace, growth, recession, and politics.  Seldom do they tackle the technical considerations of the drug approval process administered by the U.S. Food and Drug Administration ("FDA").  However, on December 26, 2010, a full third of the Times' influential editorial space was devoted to the paper's views on a drug used to treat metastatic breast cancers.

Bevacizumab is a recombinant humanized mouse monoclonal antibody that binds to vascular endothelial growth factor ("VEGF"), a protein that promotes angiogenesis, the growth of new blood vessels.  By binding to VEGF, bevacizumab blocks binding at the VEGF receptor.  Under some circumstances and for some specific cancers, AvastinÒ (the brand name under which Genentech - recently aquired by Roche - markets bevacizumab) has been observed to inhibit angiogenesis in cancerous tumors, thereby slowing tumor growth.

What prompted the Times' editorial was a recent decision by the FDA to reverse its previous accelerated approval for the use of AvastinÒ to treat metastatic breast cancers.  In 1992, the FDA introduced "accelerated approval" as a means to speed up the regulatory approval of some drugs and biologics.  As provided for in 21 CFR 314.510, accelerated approval is a pathway through which a drug applicant carrying out clinical trials can temporarily substitute a "surrogate endpoint" - a marker indicating a clinically meaningful outcome - for an actual "clinical benefit" to gain preliminary approval.  A similar pathway for the accelerated approval of biologics is set out in 21 CFR 601.41.  This approval pathway is especially valuable in the case of drugs whose clinical benefits may not fully manifest themselves for years.  Upon accelerated approval, the drug may be marketed with a label listing the specific disease indication evidenced by the surrogate endpoint.  However, the applicant must then conduct post-marketing (or "phase 4") confirmatory clinical trials.  If these phase 4 clinical trials support an actual clinical benefit, then the FDA grants the drug regular, full, approval.  In the case of AvastinÒ, the FDA judged phase 4 trials non-confirmatory, and has announced its intention to withdraw its preliminary approval in the case of metastatic breast cancers.

Without FDA approval, by law Genentech will have to remove the metastatic breast cancers indication from the drug's label.  Unless the FDA is forced to reverses its decision as a result of the scheduled hearing, or after Genentech's further legal appeals in federal court, insurance companies will soon drop their coverage for AvastinÒ treatment, which can cost more than $100,000 per patient per year, and has generated blockbuster earnings for Genentech.  The FDA has suffered much passionate criticism of this decision, including from patient advocates and Roche.  Nevertheless, the Times supports the FDA's reversal, and believes the agency "has shown courage in following the scientific evidence on this highly emotional issue."

In recent years, the FDA has been criticized - even demonized - for limiting access to experiment drugs, even to those for whom such drugs might be their only hope of survival.  An especially contentious, and tragic, example of this ongoing controversy culminated in  the Abigail Alliance v. Eschenbach (D.C. Circuit 2007;  en banc) decision, in which the court held that there was "no fundamental right...of access to experimental drugs for the terminally ill."  Though the facts surrounding the preliminary approval differ markedly, the current regulatory dispute over AvastinÒ may generate similar emotional echoes.

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Full post as published by Biolaw Blog on December 27, 2010 (boomark / email).