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

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A US Food and Drug Administration advisory committee meeting on Biogen, Inc.’s Alzheimer’s drug aducanumab will offer some insight into the amount of flexibility the agency and its external experts are willing to exercise for neurodegenerative diseases with high unmet need, particularly in the wake of a December 2019 guidance document on the quantum and type of data capable of satisfying the “substantial evidence” standard.

On 6 November, the Peripheral and Central Nervous System Drugs Advisory Committee will consider the benefit/risk profile of aducanumab, an anti-amyloid-beta antibody infusion intended for treatment of Alzheimer’s, according to a notice due to publish in the Federal Register on 29 September. The meeting will be held virtually due to the COVID-19 pandemic. (Also see “Virtual Advisory Committees: US FDA Clears A Big Test With OxyContin Meeting” -Pink Sheet, 17 Sep, 2020.)

Biogen submitted the biologics license application in July. (Also see “Keeping Track: Biogen’s Aducanumab Headlines Midsummer Submission Round-Up” – Pink Sheet, 8 Jul, 2020.) The application is undergoing a priority review with a 7 March 2021 goal date, but Biogen said the FDA intends to act even earlier on the application. (Also see “Adu-CAN-umab? Reading The Tea Leaves For Biogen’s US Filing For Alzheimer’s Drug” – Pink Sheet, 10 Aug, 2020.)

The FDA’s decision to accept the BLA for filing, rather than issuing a refuse-to-file letter, surprised some agency observers given questions about the adequacy and robustness of the data package and whether it can satisfy the efficacy standard.

The aducanumab review could have implications for many other development programs and disease categories, as it could signal how far the agency is willing to bend when it comes to demonstrating substantial evidence of efficacy under a December 2019 draft guidance.

“Maybe this action on Biogen’s Alzheimer’s drug is a signal that the FDA is going to start treating neurological disorders with that same degree of flexibility that FDA shows to oncology.” – Hyman, Phelps and McNamara’s Frank Sasinowski
For example, Alzheimer’s is far from a rare disease, with more than 5 million Americans ages 65 and older living with Alzheimer’s dementia in 2020, according to the Alzheimer’s Association, but the aducanumab review could lay the groundwork for changes to development of treatments of rare neurodegenerative diseases.

“Maybe this action on Biogen’s Alzheimer’s drug is a signal that the FDA is going to start treating neurological disorders with that same degree of flexibility that FDA shows to oncology,” said Frank Sasinowski, director at Hyman, Phelps and McNamara, who works with sponsors and patient advocates on rare disease drug development.


If approved, aducanumab would become the first disease-modifying treatment aimed at slowing or stopping the progression of Alzheimer’s.

Whether the drug is actually approvable, however, has been the burning question since October 2019, when Biogen announced plans to submit a BLA based on data from trials the company previously had said were not successful.

In March 2019, Biogen and partner Eisai Co., Ltd. said they would discontinue the Phase III EMERGE and ENGAGE trials in patients with mild cognitive impairment due to Alzheimer’s disease and in patients with mild Alzheimer’s disease dementia. The decision to stop the trials was based on a futility analysis conducted by an independent data monitoring committee, which found the studies were unlikely to meet their primary endpoint. (Also see “Why Biogen/Eisai’s Aducanumab Failure Is Not The End Of Amyloid Hypothesis” – Scrip, 21 Mar, 2019.)

However, in a surprise announcement just seven months later, the development partners said they planned to pursue regulatory approval based on a new analysis, conducted by Biogen in consultation with the FDA, of a larger dataset from the Phase III studies, including additional data that became available after the prespecified futility analysis. (Also see “An About Face As Biogen Says It Will File Aducanumab In Alzheimer’s” – Scrip, 22 Oct, 2019.)

In this new analysis, EMERGE met its primary endpoint showing a significant reduction in clinical decline with high-dose aducanumab. Furthermore, results from a subset of patients in ENGAGE who received sufficient exposure to high-dose aducanumab support the findings from EMERGE, even though ENGAGE did not meet its primary endpoint, Biogen said.

In EMERGE, high-dose aducanumab was associated with a 22% improvement in CDR-SB (Clinical Dementia Rating-Sum of Boxes) scores relative to placebo, with a p-value of 0.01, according to data presented at the Clinical Trials on Alzheimer’s Disease annual meeting in December. Key secondary endpoints also were statistically significantly positive in EMERGE in the high-dose group.

In contrast, in ENGAGE low-dose aducanumab was numerically, but not statistically significantly, better relative to placebo on the primary endpoint; high-dose aducanumab was numerically worse than placebo. However, in a post hoc analysis, data from a subset of patients exposed to high-dose aducanumab showed favorable trends that supported the EMERGE findings, Biogen said.

Inconsistent or mixed efficacy data are not unusual in neurologic diseases, where endpoints are often composites or scales that attempt to quantify patient-reported and functional parameters. In cases of unmet medical need, the agency has a record of 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.

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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