Editor’s Commentary

FDA’s aducanumab decision will erode public trust: an Editor’s Commentary

FDA should disclose the data that led it to put so much confidence in amyloid plaque clearance as a surrogate marker in Alzheimer’s disease

FDA should disclose the data that led it to put so much confidence in amyloid plaque clearance as a surrogate marker for slowing the progression of Alzheimer’s disease.

In granting accelerated approval to aducanumab from Biogen, FDA has weakened the bonds of trust that are its greatest strength. The action doesn’t mean FDA will approve drugs based on post hoc statistical manipulations, that it will be swayed by politically potent patient groups, or that it will treat advisory committee deliberations as decoration for decisions that have already been made — but it makes these notions more plausible.

Patrizia Cavazzoni, director of FDA’s Center for Drug Evaluation and Research, has made it clear that she views the Aduhelm aducanumab decision as setting a precedent for the use of biomarkers to support approval of treatments for neurodegenerative diseases. This raises but does not answer the question of whether it will set the evidence bar higher for conditions other than Alzheimer’s.

The impact of the decision goes far beyond the Alzheimer’s community by eroding confidence in the agency as a whole. It may not be possible to quantify the value of confidence in FDA, but trust in the agency’s integrity is nonetheless important, and is not consistent with the idea that hope or fear should outweigh evidence.

Vaccine hesitancy, which is exacerbated by skepticism about FDA’s integrity, shows the toll exacted by assaults on truth and science and the consequences of people placing their faith in conspiracy theories and their health in the hands of Dr. Internet.

The approval is being celebrated by some patient groups, but everyone stands to lose if FDA can’t be trusted to make impartial decisions. The way the agency unveiled its Aduhelm decision will weaken the confidence of the scientific and medical community in FDA’s ability to make independent science-based decisions. FDA says its decision is based on science, but it has failed to share the science, to demonstrate that it isn’t taking an unacceptable gamble with the lives of millions of Alzheimer’s disease patients.

The agency has stated that it is willing to accept “residual uncertainty” about Aduhelm in a way that fails to dispel the idea that accelerated approval is a form of “approval lite.” 

The difference between science and science fiction is data. Asserting that a decision is based on science is credible only if data supporting the decision are available for interrogation, if theories refuting a hypothesis have been examined and found wanting.

As Christopher Hitchens said, “what can be asserted without evidence can also be dismissed without evidence.”

FDA has put its chips on the hypothesis that clearing β-amyloid plaques slows the progression of Alzheimer’s disease. That would be acceptable if it had presented data demonstrating a causal link between β-amyloid clearing and worsening of the disease. In 2018, the agency stated in draft guidance that this theory had not been proved, and at the Aduhelm advisory committee meeting in November 2020 it said it would not rely on a surrogate marker to approve the drug.

FDA has not explained how it came to have so much confidence in the hypothesis or which experts, if any, it consulted in rendering a judgment about a controversy that has split the scientific community. FDA could go a long way toward shoring up confidence in its Aduhelm decision, and in its adherence to science-based regulatory decisions, if it disclosed the basis for its decision to accept β-amyloid plaque clearance as being likely to predict clinical benefit.

In a public letter to the Peripheral and Central Nervous System Drugs Advisory Committee, Billy Dunn, director of FDA’s Office of Neuroscience, indicated that the idea of granting accelerated approval came up only after the committee rejected FDA’s attempt to justify an approval based on clinical data from two studies.

Dunn noted in the letter that the committee had “voted, with 10 members against and 1 member uncertain, that it was not reasonable to consider the evidence of clinical benefit from Study 302 as primary evidence of effectiveness of aducanumab for the treatment of Alzheimer’s disease, with the vote largely based upon the conflicting results of Study 302 and Study 301.”

He told the committee that after the meeting, FDA “considered the uncertainty introduced by the conflicting results” of the two studies and decided that accelerated approval was the best way to resolve the uncertainty. “Our discussions raised further consideration of the accelerated approval pathway; a topic discussed earlier in the development program but not directly discussed during the advisory committee meeting given the focus at that meeting on the evidence of clinical benefit.”

The use of a surrogate endpoint is not an appropriate way to resolve conflicting results from the two studies, Jesse Goodman, a Georgetown University professor and former director of FDA’s Center for Biologics Research and Evaluation and former FDA chief scientist, told BioCentury.

He expressed concern about FDA choosing to base approval on the results from one trial with “minimal positive effects” and to disregard a negative trial. “If we pick and choose which studies to believe and which not, without a clear rationale, while we may sometimes be right, many or most times we will not be, so we risk allowing bias to enter drug research and development more generally, something FDA has worked hard to protect patients from.”

The details of the approval, especially the failure to define the appropriate population for the drug, force the families of vulnerable patients, along with physicians and payers, to make decisions that they are not qualified or prepared to make.

In his letter to the advisory committee, Dunn downplayed the importance of FDA’s approval, suggesting that it is clearing the way for others to make choices. “Ultimately,” he wrote, “the decision on whether aducanumab will be used for treatment will be made by patients, their families and caregivers, and health care professionals.”

Luciana Borio, SVP at In-Q-Tel and former acting FDA chief scientist, believes that by approving Aduhelm based on an unproven surrogate marker, and by failing to identify which Alzheimer’s patients should receive the drug, “FDA is placing unfair burdens on patients and clinicians.” It will be difficult for physicians to decline to prescribe, and hard for families to avoid paying for Aduhelm, even if there are doubts about its benefits, she said.

The approval “exposes physicians to ethical and legal risk and creates a lot of guilt for family members about withholding something FDA has approved. FDA is washing its hands of difficult decisions instead of protecting patients and the healthcare system.”

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