September 26, 2016

FDA Did The Right Thing, Mostly

Joseph V. Gulfo

Visiting Scholar
Summary

One, no, the FDA did not lower its standards in the approval of eteplirsen – the drug is safe and has biological activity, as well as clinical activity seen in a non-randomized study. Two, the FDA needs to ask its AdComms direct, unambiguous questions that capture their approvability recommendations.

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On September 19, the FDA announced that eteplirsen (Exondys by Sarepta Therapeutics) received accelerated approval for the treatment of patients with Duchenne Muscular Dystrophy (DMD). During its development, the drug garnered Fast Track Designation, Priority Review, and Orphan Drug status from the FDA.

Many have criticized the FDA for the decision, lamenting that this signals a lowering of approval standards, which prompted a “civil war” within the agency. Adding fuel to the fire is that last week, Dr. Ronald Farkas, the team leader of the review of the eteplirsen NDA (and a vocal detractor), left the agency.

The seeds for the furor that has erupted in the wake of FDA’s decision, however, were sown at the eteplirsen Advisory Committee (AdComm) meeting in April 2016. Simply put, the FDA asked the AdComm confusing questions, and their answers to the questions has put the FDA on defense in now explaining its rationale for the approval. Rather than calling for a straightforward vote on approval recommendation, as is required by law (and which is done routinely at Cardiovascular and Renal AdComms), the FDA posed questions that did not solicit panel members’ recommendation on approvability.

The questions to the panel were: “Has the Applicant provided substantial evidence from adequate and well controlled studies that eteplirsen induces production of dystrophin to a level that is reasonably likely to predict clinical benefit?” and “Do the clinical results of the single historically-controlled study (Study 201/202) provide substantial evidence (i.e., evidence from adequate and well-controlled studies or evidence from a single highly persuasive adequate and well-controlled study that is accompanied by independent findings that substantiate efficacy) that eteplirsen is effective for the treatment of DMD?”

Compare this to the question asked at a recent Cardiovascular AdComm – “Should rivaroxaban be approved for use in ACS?” Simple, to the point; no caveats; no (mis)leading the panel. To the first confusing question at the eteplirsen AdComm, the panel voted seven to six against; to the second, it voted seven to three against. Neither question addressed approvability, as mandated in the statute – AdComms are convened “for the purpose of providing…recommendations to the Secretary regarding…approval for marketing of a drug…”

The FDA questions to the AdComm were confusing in another respect, as well – the term of art, “substantial evidence,” was defined quite narrowly. The AdComm was not advised that historical control studies are considered to provide “substantial evidence,” as per the statute – “The results of treatment with the test drug are compared with experience historically derived from the adequately documented natural history of the disease or condition, or from the results of active treatment, in comparable patients or populations. Because historical control populations usually cannot be as well assessed with respect to pertinent variables as can concurrent control populations, historical control designs are usually reserved for special circumstances.”

DMD is certainly a special circumstance as there is no cure. Affected individuals are typically non-ambulatory by the age of twelve. Contractures develop as the disease progresses, and in the absence of optimal care, including corticosteroid treatment, physical therapy and nocturnal assisted ventilation, most patients succumb to the disease by the age of 20 years as the result of respiratory and/or cardiac complications.

Both of the issues with the AdComm questions resulted in a vote that did not reflect the AdComm’s true opinion on the critical question of whether the drug should be approved. As Dr. Bruce I. Ovbiagele, chairman of neurology at the Medical University of South Carolina, who voted negatively, said, “Based on all I heard, the drug definitely works, but the question was framed differently.”

So, had the questions been asked appropriately, the panel would have voted at least seven to six for accelerated approval in April. And, this is exactly what the FDA did yesterday – it granted expedited approval for eteplirsen.

So, what is the lesson? One, no, the FDA did not lower its standards in the approval of eteplirsen – the drug is safe and has biological activity, as well as clinical activity seen in a non-randomized study. Two, the FDA needs to ask its AdComms direct, unambiguous questions that capture their approvability recommendations. Had they done so, there would have been no second-guessing and no Sturm und Drange over their decision to approve eteplirsen.