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Editor’s Commentary

Why FDA, Biogen should be unusually transparent with aducanumab data: an Editor’s Commentary

The best way to convince the public that FDA made the right decision — whatever decision it makes — is for FDA and Biogen to lay all their cards on the table.

The best way to convince the public that FDA made the right decision — whatever decision it makes — is for FDA and Biogen to lay all their cards on the table.

Jun 2, 2021 | 11:51 PM GMT

FDA’s decision about Biogen’s aducanumab will be of profound importance to Alzheimer’s patients and their families, determining if they have access to the treatment and shaping the future of Alzheimer’s drug development. The fate of aducanumab will not, however, create a precedent that can be extrapolated beyond the products regulated by the Office of Neuroscience at FDA’s Center for Drug Evaluation and Research.

Whatever decision FDA makes will create a great deal of controversy and disappointment. That’s out of FDA’s control and shouldn’t be a concern to the agency. What should be of concern is whether the decision is made in a way that strengthens or weakens trust in FDA. 

It is possible for FDA to influence the extent to which the decision enhances or degrades confidence among the public, patients and drug developers that medical product reviews are based on science and conducted in a fair, objective manner.

The broad public interest in Alzheimer’s, coupled with controversy over the convoluted path aducanumab has traveled, put the onus on FDA and Biogen to be proactive in disclosing information which they are legally permitted to keep secret. 

There’s no approval lite

The aducanumab review has gained international prominence because of the devastating toll Alzheimer’s takes on millions of patients globally, and because rather than maintain an arm’s length distance from the drug’s sponsor, the Office of Neuroscience has appeared to embrace and advocate on behalf of Biogen Inc. (NASDAQ:BIIB). An advisory committee hand-picked by FDA rebuked the agency, voting unanimously to recommend rejecting the application despite a glowing review, and accused Billy Dunn, director of the Office of Neuroscience, of acting as a cheerleader for the company.

In the months following the November 2020 meeting of the Peripheral and Central Nervous System Drugs Advisory Committee, some of its members have publicly called on FDA to heed their advice.

The opposite view is equally loud. Politically potent patient groups are pressuring FDA to approve aducanumab, asserting that they can’t wait for the outcome of additional trials.

Pundits are predicting that FDA will split the difference by granting aducanumab “conditional approval.” It won’t, for a simple reason: there is no such thing as conditional approval, at least not in the U.S.

The only reasonable basis for FDA to grant accelerated — not conditional — approval would be a determination that Biogen has demonstrated efficacy as measured by a surrogate or interim endpoint that predicts clinical benefit. That’s not something the company or FDA has claimed, and it isn’t possible to conjure up a validated surrogate endpoint from thin air.

FDA has spent decades assuring patients and physicians that accelerated approval is not “approval lite,” that the strength of evidence required is the same as for regular approval. Accelerated approval is meant to allow products to get onto the market based on endpoints that are “reasonably likely to predict the intended clinical benefit.” It doesn’t allow regulators to take a chance on data that don’t make the grade and allow the sponsor to fill in the blanks after a product is on the market.

If FDA approves aducanumab, some critics will point to the decision as evidence that the agency has been captured by industry, and will repeat calls for firewalls to be erected between staff who oversee drug development and those who make approval decisions. They’ll be wrong. No one benefits from a review conducted by officials who aren’t intimately familiar with the regulatory and scientific decisions made in the years prior to submission of a marketing application.

Other critics will say that the approval will usher in an era in which companies, pressured in some cases by investors, will routinely dredge data from failed Phase III studies for plausible explanations of benefit in a subpopulation, rally allies in patient groups and gain approval for ineffective or unacceptably dangerous drugs. They’ll also be wrong.

The aducanumab decision will say a lot about how the Office of Neuroscience works, some about how FDA handles disputes between medical reviewers and biostatisticians, and very little about how other parts of the agency will respond in similar circumstances.

FDA works in silos. For better or worse, its offices and divisions operate with a great deal of autonomy.

No one who has watched FDA carefully over the last decade believes that a decision about approval requirements for an Alzheimer’s drug is going to influence the way cancer drugs are reviewed. The principle holds for other offices and divisions. 

A possible turning point

Even if the aducanumab decision doesn’t set broad precedents, it could be a turning point for FDA as a whole.

Public perception that FDA has lost its objectivity, that pressure from patient groups or coziness with industry has colored its decisions in ways that harm the health of American patients, would further erode confidence. FDA still has a lot of ground to recover after a series of erratic, politically influenced decisions on COVID-19 emergency use authorizations called its independence and competency into question.

A decision to reject aducanumab could also have negative consequences if patients feel that their needs have been sacrificed on the alter of statistical purity.

That’s why clear, convincing explanations for FDA’s action on aducanumab, whatever it is, are critically important.

FDA can’t make a decision that satisfies everyone, but it should do its best to demonstrate that it has behaved honorably.

In addition to releasing the usual package of medical and scientific data, FDA and Biogen should seek to clear the air by agreeing to release all of the data that can be made public without exposing information that could lead to identifying patients or exposing commercially sensitive information.

The data trove should include emails, phone logs and other communications between Dunn and other FDA officials and Biogen, especially during the period between the company’s announcement that it was abandoning aducanumab and its subsequent decision to revive the application. The story of how this happened, and the role FDA officials played, will come out sooner or later. Sooner would be better. 

Interactions with patient groups should also be made public.

If FDA approves aducanumab, it should explicitly address issues raised by its advisory committee, explaining in detail why it rejected its recommendations or what dispositive data has emerged since November. 

If FDA determines that aducanumab can’t be approved now, it should indicate what data, if any, could lead to an approval in the future, and whether there is enough to support access on a compassionate use basis while more data are being collected. 

Editor’s commentaries do not necessarily reflect the views of BioCentury.

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