Biogen’s AdComm Meeting Will Test FDA’s “Substantial Evidence” Flexibility

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looking beyond primary endpoints to find support for efficacy – an approach that could bode well for the aducanumab review. (Also see “Biogen Aducanumab BLA Plan Is In Line With US FDA Neurology Division Precedent” – Pink Sheet, 10 Nov, 2019.)

Some may view the controversial accelerated approval of Sarepta Therapeutics, Inc.’s Duchenne muscular dystrophy Exondys 51(eteplirsen) as the ultimate exercise of regulatory flexibility in the rare neurodegenerative disease space. Center for Drug Evaluation and Research director Janet Woodcock made the approval decision over the objections of the clinical review team and other senior staff. (Also see “Sarepta’s Eteplirsen Approved After Contentious Internal FDA Debate” – Pink Sheet, 19 Sep, 2016.)


Biogen has repeatedly said that the FDA believed the existing data on aducanumab were sufficient to support a BLA submission.

The advisory committee provides an opportunity for a public airing of concerns about the adequacy of the efficacy data. The panel could support approval based on the existing data package, or recommend against licensure pending another trial.

The meeting and BLA review could be a big test of the agency’s December draft guidance on substantial evidence.

The guidance discusses the quantity and quality of evidence needed in a given development program – such as two adequate and well-controlled trials, or one adequate and well-controlled trial plus confirmatory evidence – to satisfy the substantial evidence of efficacy standard.

The guidance cites examples of clinical circumstances where additional flexibility may be warranted, including when the disease is life-threatening or severely debilitating with an unmet medical need, when the disease is rare, and when conducting a human efficacy trial is not ethical or feasible.

Reliance on a single large, multicenter trial to establish effectiveness generally should be limited to certain situations, including where the trial has demonstrated a “clinically meaningful and statistically very persuasive effect” on mortality, severe or irreversible morbidity, the guidance states.

For Sasinowski, the FDA’s acceptance of the aducanumab BLA for a disease with a high unmet need suggests that a single study could be considered “highly persuasive” if it has a p-value of 0.01.

“When I see the FDA reach out with this kind of data that Biogen has that’s publicly available … it suggests that this could be the application of that new articulation of when additional flexibility may be appropriate,” Sasinowski told the Pink Sheet in a recent interview. “I think that was a real dramatic step forward for FDA in the December 2019 guidance document and … we might be seeing the application of that.”


Ronald Bartek, president and cofounder of the Friedreich’s Ataxia Research Alliance, said the aducanumab filing decision is further proof of the FDA’s commitment to flexibility for diseases with a high unmet need, which is particularly true in the rare disease space, where it can be difficult to enroll a sufficient number of patients in studies.

“That commitment is genuine and it’s being borne out every day,” Bartek said.

Friedreich’s ataxia (FA) is a debilitating, life-shortening, degenerative neuromuscular disorder that affects approximately one in 50,000 people in the US. There are no approved treatments.

The agency is working with FDA drug sponsors and the patient community to try to figure out what kind of “additional evidence” – such as crossover extension studies, or measures of activities of daily living and quality of life – could support results from a single study, even when data from that lone trial demonstrate an incremental treatment effect that is not profound but still clinically meaningful, Bartek said.

“They are trying to help by looking harder and harder at what kind of confirmatory evidence might be made available” to support the ability to file on the basis of a single adequate and well-controlled trial, Bartek said.

Image: iStock/selvanegra

This article was first published on Sept. 28, 2020 in the Pink Sheet.

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Sue is a senior editor with Pink Sheet, where she writes primarily about drug, biologic and biosimilar regulation, FDA advisory committees and product approvals. Follow @PinkSheetSutter

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