FDA Highlights Flexibility in Approving Rare Disease Therapies

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FDA leaders insist that the decision to approve Sarepta’s Exondys (eteplirsen) should not be considered a model for future development of orphan drugs.

In the wake of FDA’s controversial approval of Sarepta’s Exondys (eteplirsen) for Duchenne muscular dystrophy (DMD) in September 2016, agency leaders insist that the decision should not be considered a model for future development of orphan drugs. At the same time, FDA officials point to a strong record of supporting innovative strategies and accelerated approaches for the development and approval of new therapies to treat rare critical conditions. They urge patient advocates to further these efforts by contributing to the development of registries and natural history studies and innovative research methods, but not try to influence regulatory decisions, especially by leveling personal attacks on FDA staffers.

FDA Commissioner Robert Califf commented at an October 2016 summit sponsored by the National Organization for Rare Disorders (NORD) that FDA staffers want to collaborate with sponsors and with patient groups during drug development, but that it is crucial to preserve FDA’s independence in approval decisions from “the vicissitudes of political influence.” Efforts by outside parties to shape approval decisions risk undermining public confidence in the agency, Califf noted.

John Jenkins, director of the Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER), emphasized that the decision to approve Exondys despite little evidence of efficacy should not be regarded as a “good model for other development programs.” Patient advocates strongly criticized FDA reviewers for opposing approval of the drug, and CDER Director Janet Woodcock in the end overrode her staff and made the call for approval. She based that decision on limited risk to severely ill DMD patients, emphasizing at the NORD summit that postapproval confirmatory studies will be critical in determining whether the drug has benefit to patients and should remain on the market.

Califf said he deferred to Woodcock’s decision on the DMD treatment to avoid setting a precedent of political appointees intervening in the agency’s scientific process. While FDA decision-making often is difficult and imperfect, Califf said that “political meddling” would undermine the agency’s strong culture of professionalism.

And personal attacks on FDA reviewers, commented Jenkins, can create an atmosphere of “distrust and isolation,” rather than collaboration. And that will make it even harder to recruit and retain qualified review staff at FDA, he said.

Accelerated and novel approaches


Jenkins noted that Woodcock’s decision reflects a maximum amount of regulatory flexibility, as clinical benefit was not adequately demonstrated in the drug’s development program. FDA’s record for using a range of accelerated development and review approaches is evident in the high number of rare-disease therapies approved this past year based on less than the usual two randomized clinical trials. He noted that more than 80% of orphan drugs are tested using novel endpoints, innovative clinical trial designs, and expedited development and approval programs, evidence of FDA’s support for innovative approaches for developing and testing these crucial medicines.

At the same time, sponsors should include randomized controlled clinical trials in protocols to provide FDA with “good scientific information to make good regulatory decisions,” said CDER Deputy Director for Science, Richard Moscicki. Jenkins added that a randomized controlled clinical trial often provides the fastest way to show drug effectiveness, while starting with open label studies can lead to misleading findings and a “cascade” of errors.

Moscicki noted that efficient development of rare-disease therapies involves rigorous collection of natural history data to help researchers understand the disease, plus qualification of important assays and biomarkers prior to their use in clinical trials. Well-validated assays are important before starting clinical trials, advised Jenkins, or the sponsor risks wasting clinical specimens-something he considers particularly serious when conducting tests on children. A poorly planned development program, especially for a rare-disease therapy, he said, “misuses valuable patient resources.”

Collaboration with all parties is crucial in generating evidence, and Califf urged patient advocacy groups to be involved in patient recruitment to clinical trials and in the development and design of studies to support new drugs. Natural history studies are particularly critical in designing more effective and informative clinical trials, particularly for rare diseases with small patient populations. Patients can help improve the development of rare-disease therapies by providing input on which outcomes matter the most and by helping to draft guidance on developing drugs for a specific condition.

The good news, said Woodcock, is the emergence of more “robust pipelines” for therapies for rare diseases, more international collaboration in this area, and good results from regulatory flexibility in evaluating orphan drugs. FDA approved Exondys under its accelerated approval program based on some evidence of protein production; now the challenge is to see if confirmatory trials show more benefit, or lack of efficacy.