Harvard Doctor Urges FDA Reforms After Biogen Alzheimer Nod

A prominent Harvard doctor who was one of three experts to quit a U.S. advisory panel after Biogen Inc.’s Alzheimer’s drug Aduhelm was approved said regulators should have tougher standards for granting clearances to unproven medications.

The accelerated approval program used to approve the Biogen drug has been around for almost three decades. It’s been hailed for quickly addressing unmet medical needs with novel treatments. But it’s faced criticism after Aduhelm was cleared because it reduces amyloid, a physical biomarker or surrogate linked to Alzheimer’s, without proving it can slow or treat the disease.

In a viewpoint published Tuesday in the Journal of the American Medical Association, Aaron Kesselheim and two co-authors urged regulators to promptly take treatments off the market once they’re proven ineffective and to cut back on the use of surrogates as a basis for approval.

Confirmatory trials that “use clinical endpoints, not biomarkers that have not undergone validation” should be a mandate, the writers concluded.

The U.S. Food and Drug Administration’s decision to approve Aduhelm showed the importance of needing better consensus and transparency around the use of biomarkers in drug approvals. Kesselheim was joined in his comments by Bishal Gyawali, a cancer doctor and associate professor at Queen’s University in Canada, and Yale professor Joseph S. Ross.

Aduhelm’s approval has proven to be highly controversial. The FDA faced criticism for approving the drug over the objections of its outside expert advisory committee, leading to the three panelists -- including Kesselheim-- resigning.

Last week, U.S. lawmakers probing the Aduhelm approval asked the company to turn over years of internal documents about the drug’s development and the company’s dealings with regulators.

Critics of the program have also raised concerns around drugmakers missing deadlines on the mandated follow-up trials. And in some cases, the FDA has failed to take back the approval of a drug for years after a negative study finding.

Confirmatory Trials

To avoid situations like this, the viewpoint’s authors recommend that confirmatory trials are finalized and agreed on before drugs receive accelerated approval so that trial enrollment can occur as soon as the treatment has been given the green light.

Updates on the confirmatory trials should be published at least once a year, the authors said, and on completion of the trial, findings should be promptly released to the public.

During the early months of 2021, several pharma giants -- including AstraZeneca Plc and Merck & Co. -- voluntarily withdrew cancer drug indications after failing to meet their post-marketing requirements.

Automatic Withdrawal

However, the authors said that if a trial is negative, regulators should automatically withdraw accelerated approval. It shouldn’t be left for the manufacturers to voluntarily withdraw, they said.

Although drug pricing isn’t regulated by the FDA, the authors recommend organizations such as the Centers for Medicare & Medicaid Services and the Department of Veterans Affairs should consider approaches to minimize the cost of accelerated-approval indications, for example by capping the price of drugs or excluding them from coverage mandates for Medicare and Medicaid.

“For the public and physicians to trust the pathway and the clinical value of drugs with accelerated approval, reforms as well as the timely completion of post-approval trials are needed,” the authors wrote.

©2021 Bloomberg L.P.

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