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Pink Sheet – Accelerated Approval: Mid-Review Decisions ‘Not The Norm’ But Will Continue, FDA’s Cavazzoni says

Pink Sheet – Accelerated Approval: Mid-Review Decisions ‘Not The Norm’ But Will Continue, FDA’s Cavazzoni says

Without directly referencing Biogen, Inc.’s Alzheimer’s drug Aduhelm (aducanumab-avwa), the leader of the US Food and Drug Administration’s drugs center defended the agency’s ability to make “rare” decisions about the use of accelerated approval during the course of an application review.

Speaking at a 20 July Friends of Cancer Research meeting on use of circulating tumor DNA in the development of cancer therapies, Center for Drug Evaluation and Research director Patrizia Cavazzoni emphasized the importance of early planning and coordination between sponsors and the FDA to develop the evidence needed to support an application for accelerated approval and to ensure that confirmatory trials are feasible and conducted in a timely fashion.

To further enhance the use of accelerated approval in oncology and other therapeutic areas, there needs to be “consistent upfront planning and direct interactions with FDA regarding validation of new endpoints and confirmatory trials as early as possible in the development program, the earlier the better,” she said.

“While this upfront planning is very important and very feasible in most circumstances, we also have to take into consideration the fact that there will always be those more rare instances where FDA may determine that accelerated approval is the appropriate pathway only as we review the application, and we observe that the data and the evidence that were generated in the development program are suitable and are supportive of utilizing accelerated approval,” Cavazzoni said.

“I don’t necessarily see those instances as the norm. However, there will continue to be situations such as that one.”

Evolving Views On A Surrogate

Cavazzoni’s comments are notable given the agency’s controversial regulatory action on aducanumab.

Biogen’s biologics license application for the amyloid beta-directed antibody included two similarly designed Phase III studies that were terminated prematurely for futility. One study ultimately was deemed successful, while the second study failed its primary clinical efficacy endpoint.

At a November 2020 advisory committee meeting on aducanumab, Office of Neuroscience director Billy Dunn said the agency was not using brain amyloid plaque reduction as a surrogate for efficacy. (Also see “Biogen’s Aducanumab: Why Accelerated Approval Might, And Might Not, Be An Option For US FDA” – Pink Sheet, 13 Nov, 2020.)

There was no discussion about accelerated approval at the meeting, at which 10 of 11 committee members voted it was not reasonable to consider the one successful Phase III study as primary evidence of aducanumab’s effectiveness for treating Alzheimer’s disease. (Also see “Biogen’s Aducanumab Falls Hard At Panel Review, Leaving US FDA In A Tight Spot” – Pink Sheet, 7 Nov, 2020.)

Yet, in June 2021 the agency granted accelerated approval, concluding there is substantial evidence that aducanumab reduces amyloid beta plaque in the brain and this surrogate endpoint is reasonably likely to predict clinical benefit. (Also see “Aducanumab Accelerated Approval Reflects US FDA Flexibility But Raises Doubts About Confirmatory Trial” – Pink Sheet, 7 Jun, 2021.)

Review memos indicate that as the review progressed after the negative advisory committee meeting, internal support grew for use of accelerated approval.  (Also see “As Aducanumab’s US FDA Review Progressed, Support Grew For Accelerated Approval” – Pink Sheet, 22 Jun, 2021.) Cavazzoni was among the senior CDER officials who supported accelerated approval, and she authored her own concurring review memo. (Also see “Aduhelm’s ‘Complex’ Circumstances Drove Extensive In-House Advice Process Before Accelerated Approval, Cavazzoni Says” – Pink Sheet, 22 Jun, 2021.)

The agency’s failure to convene a second advisory committee to vet a potential accelerated approval of aducanumab may have factored into its recent decision to hold a second panel review to consider additional information on Amylyx Pharmaceuticals, Inc.’s amyotrophic lateral sclerosis treatment AMX0035. (Also see “Will Amylyx’s ALS Drug Benefit From US FDA’s Aduhelm Experience?” – Pink Sheet, 5 Jul, 2022.)

Timely Confirmatory Trials

At the FOCR event, Cavazzoni repeatedly cited the importance of timely initiation of confirmatory trials for accelerated approval drugs and the need to ensure that such trials are feasible and more generalizable than the trial or trials that led to the original approval.

“I cannot emphasize enough the pivotal role of confirmatory studies in accelerated approval, because when we use accelerated approval we inherently acknowledge that there is still some residual uncertainty around the extent of the benefit, the existence of clinical benefit,” she said. “It’s very important that we have these confirmatory studies and that they are conducted in a timely fashion.”

A push for timely initiation and completion of confirmatory trials is not so much an enhancement to the expedited regulatory pathway but “a practice that needs to really be routine in our thinking about development programs and how we interact with developers,” Cavazzoni said.

Cavazzoni’s comments about the need for early planning of confirmatory trials are notable also when viewed in the aducanumab context.

Since accelerated approval was not on the drawing board until late in the review cycle, Biogen had not designed a confirmatory trial at the time of approval. The FDA gave Biogen nearly nine years in which to design and conduct the study.

The length of that runway drew howls of protest from patient groups and agency critics alike. A Pink Sheet analysis showed it to be long among late-stage Alzheimer’s studies and confirmatory trials for other accelerated approval drugs. (Also see “3,189 Days: Aduhelm Phase IV Timeline Is Long Among Alzheimer’s Drugs And Other Accelerated Approvals” – Pink Sheet, 12 Jul, 2021.)

Biogen initiated the confirmatory trial in June 2022 and expects to have data by 2026, well ahead of the nine-year mark.

Center for Biologics Evaluation and Research director Peter Marks also has said more attention needs to be paid by sponsors and the agency to working out issues on surrogate endpoints and confirmatory trials for accelerated approval earlier in the development process. However, Marks has acknowledged that the expedited pathway has sometimes been used as “an off-ramp” for troubled applications. (Also see “Accelerated Approvals Need Earlier Planning On Surrogate Endpoints, Postmarketing Trials – FDA’s Marks” – Pink Sheet, 19 May, 2022.)

Under the negotiated PDUVA VII agreement, the FDA has committed to beginning postmarketing requirement discussions earlier in the review cycle. Under House and Senate user fee legislation, the FDA could require that confirmatory trials be underway prior to approval, and agency officials would be required to specify postapproval study conditions, including enrollment targets, study protocol and milestones, no later than the time of accelerated approval.

However, the state of the user fee legislation is in flux due to the recent introduction by Sen. Richard Burr, R-NC, ranking member of the Health, Education, Labor and Pensions Committee, of a “clean” bill without policy riders, including changes to the accelerated approval program. (Also see “US FDA User Fee Legislation: Is Sen. Burr’s ‘Clean’ Bill A Lifeline – Or A Wrench In The Works?” – Pink Sheet, 15 Jul, 2022.)

Looking Beyond Oncology

FOCR founder and chairperson Ellen Sigal asked how accelerated approval could be leveraged in areas beyond oncology, where the pathway has seen the most use. In response, Cavazzoni cited the need to advance the biological underpinnings of disease, including in the neurodegenerative space.

“We need to learn from the road that we have traveled in cancer to expand the utilization of accelerated approval in other disease areas,” Cavazzoni said. “An example of tremendous unmet medical need are for instance, neurodegenerative diseases, where we really have to … double down on getting to a better understanding of the biology of the diseases and to identify biological markers that could be amenable to be used for accelerated approval.”

In what seems like another not-so-subtle reference to aducanumab, Cavazzoni acknowledged the public debate about the high price of some accelerated approval drugs for which evidence of clinical benefit is still lacking.

“I want to mention this this point, even if it goes beyond FDA’s scope, and what we are seeing is that society and the public are increasingly demanding a solution to the drug cost versus value question, and we have to acknowledge this as we continue to advance and foster the use of this incredibly important regulatory tool,” she said.