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FDA should weigh the benefits, not just risks, of non-toxic Duchenne Treatment

The Hill, May 31, 2016

FDA should weigh the benefits, not just risks, of non-toxic Duchenne Treatment

By Dr. Carrie Miceli and Dr. Stanley Nelson

On April 25, we joined with hundreds of families from 38 states and over a dozen scientists and physicians from leading institutions to add our scientific voices at a vital FDA advisory committee hearing on eteplirsen, which has been in clinical trial for over five years to help treat Duchenne muscular dystrophy. Duchenne muscular dystrophy is the most common lethal genetic disease of childhood world-wide, affecting primarily boys and resulting in progressive loss of all muscle function. There are no FDA approved drugs for Duchenne, and the prospect of approval made this advisory committee the largest gathering of Duchenne patient families, clinicians and scientists ever.  We were united to push eteplirsen toward accelerated approval based on sound scientific assessment of an unconventional small non-placebo controlled study trial and patient experience. 

The FDA review team questioned the trial data because the study was small, only 12 boys treated, and was not using a double-blind placebo controlled design. However, 13 world-renowned Duchenne clinicians and scientists, including ourselves, testified during the Open Public Hearing in an unprecedented show of support for accelerated approval based on strong evidence of dystrophin production and substantive evidence of clinical efficacy. Prior to the AdCom, 36 Duchenne experts, including many who attended the AdCom, voiced their strong support of accelerated approval of eteplirsen based upon their scientific evaluations of the data package and briefing documents in the form of a letter to the FDA.

At the Open Public Hearing, the trial data was further bolstered by compelling testimonials from boys receiving eteplirsen in the ongoing 5 year trial and on the already initiated confirmatory trials, as well as their parents and supporters. While these testimonies of small but meaningful gains in muscle skills like climbing into a car, unscrewing the cap of a water bottle, feeding oneself more easily do not fit neatly into consideration by the FDA, as parents of a teen, Dylan, living with Duchenne, we know first hand how meaningful and life-changing these subtle gains are. The universal desire of patients to remain on study drug due to increased quality of life, coupled with strong safety record, and supported by concrete science provides ample evidence warranting accelerated approval. 

The 2012 FDA Safety and Innovation Act enables the FDA to use the accelerated approval pathway for rare diseases, like Duchenne.  To highlight the intent of FDASIA, Congressman Mike Fitzpatrick (R-PA) testified at the AdCom on behalf of 109 bipartisan Congressional representatives who signed a letter addressed to the FDA urging strong consideration of expert and patient perspectives based on smaller trials in weighing accelerated approval for drugs treating serious rare disease with unmet need.

The FDA drug evaluation process is set most often to avoid approval of a drug, which ultimately proves to be ineffective.  However, it is of grave importance to consider that a greater harm may exist from a 'Type 2 error' in which an effective drug is erroneously rejected. The FDA must balance the risks of approval versus rejection, and acknowledge that both decisions carry risks for the patients and families affected. This is especially important for Duchenne, where waiting for approval carries a guarantee of disease progression.

Not approving eteplirsen carries a risk that a drug targeting the precise genetic mutation, which required over 15 years of research, many tens of millions of dollars to develop and test, and countless patient hours in clinic to demonstrate efficacy will pass the window of opportunity for commercialization without ever being available for most patients with Duchenne.  While the vote by the advisory committee was 6 to 7 against accelerated approval, the final decision rests with the FDA, which just announced that it won’t complete its review of eteplirsen, by the scheduled May 26 deadline.

We are encouraged that multiple senior FDA officials attended the AdCom and had the opportunity to directly see and hear expert commentary and are hopeful that the FDA will recommend accelerated approval based on the strong scientific rationale. The time to take steps in the right direction to alleviate some of the suffering felt by patients of the disease is now.

Miceli is Professor of Microbiology Immunology and Molecular Genetics, UCLA and co-director of the Center for Duchenne Muscular Dystrophy.  Nelson, is Professor of Human Genetics, David Geffen School of Medicine at UCLA and a co-director of the Center for Duchenne Muscular Dystrophy. For video footage from key scientific testimony presented at the April 25 Advisory Committee Meeting, click here.