Sens. Bill Cassidy (R-La.) and Elizabeth Warren (D-Mass.) don’t agree on much. Yet both are troubled by the U.S. Food and Drug Administration’s approval of the Alzheimer’s disease drug Aduhelm. In a recent letter, they took a slap at the drug, worrying that tens of billions of dollars would be spent on “just one product with limited evidence of clinical efficacy thus far.”
It’s not just politicians who are worried about Aduhelm (the brand name for aducanumab). The drug’s controversial approval has spurred headlines proclaiming that “The FDA Is Broken,” “The FDA Is a Melting Iceberg” and “The F.D.A. Has Reached a New Low.” Aaron Kesselheim, a Harvard Medical School professor who served on the advisory committee that considered Aduhelm and who voted against approving it, called the decision “probably the worst drug approval decision in recent U.S. history” (disclosure: I am a co-author with Kesselheim, including on FDA credibility issues, but I did not consult him in writing this piece). Kesselheim resigned from the advisory committee, along with two other members, to underscore his dissent.
Why are so many people worried about this decision? The answer is that if scientists, health professionals and the public lose faith in FDA approvals, they will lose faith in the quality and safety of the treatments that are approved — and the system that approves them. Credible health treatments depend on credible regulation, and the FDA’s credibility is in serious trouble.
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Aduhelm’s approval was procedurally questionable
Aduhelm’s maker, Biogen, claims that the drug ameliorates conditions associated with Alzheimer’s disease by targeting the buildup of amyloid beta plaques in the brain. Biogen first tested the drug in two randomized, controlled clinical trials but stopped the trials when it became clear that they weren’t detecting a meaningful average treatment effect on the disease. In plain language, the trials didn’t provide good statistical evidence that the drug worked. However, another trial, with about one-eighth as many participants as the other two, showed a modest but statistically significant reduction in amyloid beta. That suggested that whether or not the drug helped Alzheimer’s, it helped prevent the buildup of the plaques, which some scientists believe cause the disease.
Aduhelm appeared to be at a dead end. However, according to biotech publication STAT, Biogen hatched a plan called “Project Onyx,” in which Biogen representatives met secretly with Billy Dunn, an FDA center director friendly to the firm. Dunn and Biogen agreed that a post hoc analysis of the existing trials could focus on the level of amyloid beta as a “surrogate endpoint” (a measure possibly correlated with disease incidence and severity, but not equivalent to measures of severity or incidence itself), STAT reported. This would allow the FDA to approve Aduhelm under easier standards.
None of this persuaded either the FDA’s statistician (who argued that the drug should be rejected) or an advisory committee, in which not a single member voted for its approval. Dunn and his boss, Center for Drug Evaluation and Research (CDER) Director Patricia Cavazzoni, ignored the committee and granted approval to Aduhelm. In short, the drug was approved through a concerted behind-the-scenes effort, sheltered from public view, sidelining high internal dissent and the unanimous skepticism of the scientific advisory committee.
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As the FDA’s reputation withers, so too does Aduhelm’s
Aduhelm has created a different kind of drug regulation controversy. Usually, critics complain either that the FDA has approved drugs that could sicken or kill thousands of people (like the painkiller Vioxx), or that the agency is moving too slowly on lifesaving therapies, as happened during the AIDS crisis. Now, the controversy focuses on whether the drug works, much less justifies its eye-watering expense, estimated at $56,000 per year. Some critics suggest that FDA officials stacked the deck for a decision favorable to Biogen.
The FDA’s reputation for procedural integrity has been damaged. That reputation rests on the FDA’s ability to play both “good cop” and “tough cop” as needed — assessing risk and protecting citizens, while also keeping drug and food companies honest, by getting tough with them when required.
Health professionals seem to be paying close attention to this controversy — a Medscape poll found that 87 percent of physicians disagreed with the approval decision and that 68 percent of neurologists and 79 percent of primary care physicians do not plan to prescribe the new drug. The Institute of Clinical and Economic Review has announced that the drug delivered zero net benefit, while at least a half-dozen insurers have said they wouldn’t cover it.
Nor does the FDA look like a tough cop. Right after the approval was announced, Biogen refused to commit to a timely post-approval clinical trial. Biogen apparently doesn’t fear ex-post regulatory action by the FDA, which cannot seem to “credibly commit” to pull a drug off the market when post-approval trials raise questions.
The weakening of the FDA’s credibility is already hurting public trust in new drugs and treatments. We know that when the Trump administration interfered in the agency’s decision processes last summer, millions were suddenly less willing to get vaccinated against the coronavirus, which causes covid-19.
Medical treatments are credence goods. That is, people can’t easily evaluate their benefits by themselves (as they can apples in a supermarket, or cars they can drive). The public has to rely on the kinds of information obtained from randomized, placebo-controlled clinical trials, as interpreted by the relevant officials and professionals, to know whether drugs actually work or not.
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The FDA officials who helped get Aduhelm approved think it was the right decision. The problem is that few American doctors, scientists or citizens believe them. The people and organizations who will prescribe and pay for the drug are now voting with their dollars and their feet, helping foster suspicion that the deck was stacked in Aduhelm’s favor.
The bigger worry is that if people stop trusting FDA officials, we’re likely to find ourselves back in the kind of world that existed before the FDA, where doctors and patients don’t know whether to trust new drugs and treatments, because there is no independent arbiter to compel rigorous studies and to pronounce a judgment on the merits.
Daniel Carpenter is the Allie S. Freed professor of government at Harvard University and author of “Democracy by Petition: Popular Politics in Transformation, 1790-1870” (Harvard University Press, 2021).