Intended for healthcare professionals


Should regulatory authorities approve drugs based on surrogate endpoints?

BMJ 2021; 374 doi: (Published 16 September 2021) Cite this as: BMJ 2021;374:n2059

Linked Analysis

Raising the bar for using surrogate endpoints in drug regulation and health technology assessment

  1. Jeanne Lenzer, independent journalist,
  2. Shannon Brownlee, independent journalist
  1. New York, USA
  1. jeanne.lenzer{at}

The aducanumab controversy is the latest example of surrogate endpoints failing to predict clinically important outcomes. Yet, as Jeanne Lenzer and Shannon Brownlee report, they increasingly provide the basis for drug approvals

In November 2020, not one of the US Food and Drug Administration’s 11-member advisory committee voted to approve Biogen’s aducanumab for the treatment of Alzheimer’s disease. When FDA administrators nevertheless went ahead with the approval on 7 June 2021,1 three members of the committee quit in protest, sparking a national outcry.

Several media and medical journals published editorials criticising the decision, the New York Times and STAT published investigative articles about the approval process, two major hospital systems in the US announced they would not administer the drug,2 and a national public interest group called for an independent investigation into the agency’s decision. In response, FDA acting commissioner, Janet Woodcock, has ordered an inquiry, although she has defended the approval.

Beneath the brouhaha lies a deeper concern: has the FDA turned the scientific process on its head by allowing a surrogate endpoint to trump clinical trial evidence?

Accelerated pathway

Biogen had already conducted two randomised controlled trials that were stopped early because they found no patient benefit. Joel S Perlmutter, one of the advisory committee members and professor of neurology at Washington University, told The BMJ that when Biogen and the FDA could not find a patient benefit, they “switched tactics,” focusing instead on a surrogate endpoint, a reduction in brain amyloid plaques found in a post-hoc subset analysis of one of the two trials.3

The FDA approved aducanumab through its “accelerated pathway,” a process created in 1992 to hasten approval of “drugs that treat serious conditions, and that fill an unmet medical need.” Such approvals are based on surrogate endpoints, which the agency defines as “a …

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