One of the most important decisions in the history of the Food and Drug Administration is quickly approaching. By early June, the agency should have a verdict on whether to approve aducanumab, a potentially first-of-its-kind treatment for Alzheimer's disease that became a major source of hope and controversy over the last two years.
Aducanumab is meant to the slow the cognitive decline that Alzheimer's patients experience by combating what many believe to be the root cause of disease. Such a treatment would be in high demand, given Alzheimer's care has been limited to medications that alleviate symptoms rather than change the disease's course. However, the data supporting aducanumab have come under intense scrutiny, leaving many doctors and researchers on the fence about its seeming benefit.
In November, the FDA convened a group of experts who advise the agency about brain drugs, and asked them whether there was enough positive evidence to say aducanumab works. Their answer was resoundingly negative, with all but one member voting against the drug.
While the FDA typically follows the recommendations of its advisers, it isn't required to. The agency is under immense pressure to clear more Alzheimer's treatments. And with certain high-ranking members of the FDA taking a favorable view of aducanumab, it's possible the drug may still be approved.
Perhaps that's why, on Tuesday, three of those FDA advisers rehashed their arguments against aducanumab in an editorial published in JAMA. The authors were Caleb Alexander, a professor of epidemiology and medicine at Johns Hopkins University; Aaron Kesselheim, a professor of medicine at Harvard Medical School; and Scott Emerson, a professor emeritus of biostatistics at the University of Washington.
The three were among the most vocal committee members in criticizing Biogen's case for aducanumab at the November meeting.
In their editorial, Alexander, Emerson and Kesselheim noted how the two large, near-identical clinical trials meant to prove aducanumab's merit showed very different results. One found patients who received a high dose for a long enough period of time did significantly better on a cognitive test than patients who received placebo. The other had the opposite outcome.
The authors called out the after-the-fact analyses that aducanumab's developer, Biogen, used to explain the disparate results. Namely, they took issue with how these "post hoc" analyses essentially presumed the positive study was reliable and the negative study was more a fluke, even though the consistent failure of drugs that work like aducanumab would suggest otherwise.
"In short, while post hoc analyses are useful for generating interesting hypotheses to be tested in future trials, the post hoc analyses regarding aducanumab provided limited information useful in deciding the benefit of this new drug and these post hoc analyses should not be the basis for FDA approval," they wrote.
The authors also detailed the close working relationship between the FDA and Biogen to analyze the clinical trial data. This "unusual degree of collaboration ... has been criticized as having potentially compromised the FDA's objectivity" in reviewing the drug, according to the three advisers.
While the authors acknowledged the dire need for safe and effective Alzheimer's drugs, and commended Biogen for running two large, valuable clinical trials, they ultimately see "no persuasive evidence to support approval of aducanumab at this time." FDA statisticians, ahead of the November advisory committee meeting, drew similar conclusions.
Though the arguments brought up in the JAMA article aren't new, "the decision by these authors to reiterate these points speaks to the degree to which they strongly believe that an aducanumab [rejection] is the correct decision here," wrote Brian Skorney, an analyst at Baird who's been critical of aducanumab and its approval odds.
The advisory committee members "clearly want FDA to remember what they said and not allow the long time frame between the meeting and the new [review deadline] to diminish their conclusions," Skorney added in his March 30 note to clients.