Darrow, Avorn, and Kesselheim on the new FDA category of "Breakthrough" Drugs.

This weeks New England Journal of Medicine includes a terrific article by Darrow, Avorn, and Kesselheim: New FDA Breakthrough-Drug Category- Implications for Patients, 370 New Eng. J. of Med. 1252-1258 (March 27, 2014).  (the full text is available free online at http://www.nejm.org/doi/full/10.1056/NEJMhle1311493).  The authors point to the relatively high rate of post-market safety issues as well as non-efficacy issues that have surfaced in recent years with respect to drugs approved on the basis of accelerated approval using surrogate endpoints.  There is an important balance to be maintained between expediting access to life-saving new drugs and the hasty approval of new drugs that pose serious risks that outweigh their benefits.  The authors make a strong case that this balance has been lost, and that we may well be doing more harm than good for some of the most vulnerable members of our society-- patients affected with life-threatening diseases for which there are few if any therapeutic options. As the article points out, in the case of accelerated approval with commitments for post-market studies (referred to as Phase IV studies), NDA sponsors have generally been very slow in conducting those studies and gathering data. In one of the worst such examples cited in the article: "Gemtuzumab ozogamicin was approved in 2000 for the treatment of pediatric leukemia on the basis of limited data, but it was withdrawn from the market in 2010 after confirmatory trials initiated in 2004 showed increased mortality and no efficacy [citation omitted]." In other words, children with leukemia were treated for 10 years with a drug that in fact increased their risk of dying. In another example cited in the article, bevacizumab (Avastin) was approved for metastatic breast cancer on the basis of accelerated approval using surrogate endpoints. The post-approval data showed no increase in survival, and, given the serious adverse effects of the drug, the FDA withdrew approval for the indication. This subsequent FDA action was nevertheless met by significant opposition from patient groups, which evidences the understandable desperation of terminally ill patients and their loved ones.

So, given the "delicate balance"¹ between accelerating access and "first do no harm", is there a pharmaceutical policy proposal that can improve what is now a system that may be tipping too far towards acceleration? I have a thought- just a brand new idea that I would like to put out there for others to comment on and add to the mix of the discussion. Hold the NDA sponsors feet to the fire by adding to the expanded access provisions under which the FDA already allows companies to charge for investigational drugs- 21 CFR 312.8(b)(1). What is needed is a form of accelerated approval that is not, in fact, full approval, but is instead an approval to distribute the drug in the market, as though it were approved, but at a price that would be allowed for an investigational drug, until such time as the sponsor completes the agreed-upon collection of further data and it has been reviewed by the FDA. This would essentially build on the HIV-only "Parallel Track" created by the FDA that was used only once, for stavudine.² The concept of parallel track, coupled with a cost-basis reimbursement mechanism, just might bring access and evidence back into balance. It would certainly motivate drug companies to gather the evidence as expeditiously as possible. I look forward to the discussion.

1One of my favorite plays bears that title, Edward Albee's "A Delicate Balance." If you ever have the opportunity to see it, do.

2FDA, Expanded Access and Expedited Approval of New Therapies Related to HIV/AIDS, online at http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/hivandaidsactivities/ucm134331.htm (visited March 26, 2014).