The US Food and Drug Administration’s controversial recent approval of Alzheimer’s drug Aduhelm has been subject to vociferous criticism from many in the scientific community. Amidst concerns surrounding the drug’s efficacy and price, several expert advisors to the FDA have resigned in protest and calls for top officials to step down are growing.
Early in June the FDA granted Aduhelm (also known as aducanumab) Accelerated Approval, a conditional approval offered to experimental drugs serving serious unmet needs to patients with no alternative treatment options. Accelerated Approval allows a treatment to be administered to patients while further trials are conducted to confirm efficacy.
The FDA approval came despite an expert advisory panel almost unanimously concluding there was no convincing evidence the drug worked. This was based on two large Phase 3 clinical trials which were initially discontinued due to insufficient efficacy before a subsequent data analysis months later claimed the drug may have worked in some patients receiving higher doses for longer periods of time.
Since the authorization three members of the 11 person advisory panel that recommended against the FDA’s approval have resigned in protest. While the FDA is not compelled to follow the advice of its independent advisory committees, it generally does. A recent study found the FDA goes against its expert recommendations 22 percent of the time, and in those instances it generally is associated with committee votes that are much closer than what was seen in the Aduhelm scenario.
In a frank resignation letter advisory committee member Aaron Kesselheim called the Aduhelm approval, “probably the worst drug approval decision in recent US history.” Kesselheim says the FDA approval hinged on a “last minute” switch to a different endpoint that was not discussed by the advisory panel.
The key factor cited by Kesselheim is the FDA’s statements on Aduhelm’s efficacy in reducing amyloid plaques in the brains of Alzheimer’s patients. The Phase 3 clinical trials did offer evidence the drug reduces amyloid burden, a pathological characteristic some consider as key to the cognitive decline seen in the disease. However, the trials did not find these amyloid reductions correlated with any cognitive benefits. And Kesselheim notes in his resignation letter that the FDA told the the panel “we’re not using amyloid as a surrogate for efficacy” at the time of the meeting.
A recent letter to the chair of the advisory panel from Billy Dunn, the FDA’s chief of neuroscience, attempted to explain this unexpected pivot from the regulatory organization. Dunn says, “further discussion within the FDA” following the advisory panel meeting raised consideration of Accelerated Approval as a pathway for authorization.
“To be approved under this pathway, there must be substantial evidence of the drug’s effectiveness on a surrogate endpoint—usually an endpoint that reflects the underlying disease pathology,” writes Dunn. “An effect on this surrogate endpoint must be shown to be reasonably likely to predict clinical benefit. We concluded that these requirements were met for aducanumab, with substantial evidence that the drug reduces amyloid beta plaque, and that this reduction is reasonably likely to predict clinical benefit.”
A statement from Patrizia Cavazzoni, director of the FDA’s Center for Drug Evaluation and Research, reiterated Dunn’s argument affirming the drug’s effect on reducing amyloid plaques as sufficient for Accelerated Approval.
“After the Advisory Committee provided its feedback, our review and deliberations continued, and we decided that the evidence presented in the Aduhelm application met the standard for Accelerated Approval,” stated Cavazzoni. “We thank the Advisory Committee for its independent review of the data and valuable advice.”
Both Dunn and Cavazzoni’s public statements heavily stress the unmet need for Alzheimer’s treatments. Cavazzoni makes it clear the “need for treatments is urgent” and notes alongside the expert advisory committee’s recommendation the FDA also “listened to the perspectives of the patient community”.
The federal government will bear the brunt of the new spending
Dunn was even more direct in his statement, saying “the decision on whether aducanumab will be used for treatment will be made by patients, their families and caregivers, and health care professionals.” He concluded his letter by suggesting the evidence of efficacy for Aduhelm was balanced with the need for a treatment by patients in the community.
“The public can be confident that the Agency used a rigorous, science-based approach to assess this therapy, considering all of the evidence in the application, and also the tremendous unmet medical need for the many patients living with this disease,” writes Dunn.
An editorial penned by two neuroscientists from the University of Pittsburgh argues “unmet need” should not be a factor influencing whether the FDA approves a new drug. While the lack of any disease-altering Alzheimer’s therapy is certainly a problem, the authors stress this is not something the FDA should consider.
“…that is not a problem the FDA can solve,” the editorial states. “Its decision should have been based solely on the drug’s safety and efficacy. But it wasn’t. Public comments from a broad spectrum of scientists and physicians over the past few weeks and months, including the FDA’s own panel of experts, have made it clear that the data needed to back up approval were simply not there.”
Despite the FDA’s seeming "something is better than nothing" argument for Aduhelm’s conditional approval the exorbitant cost of the drug looks set to weigh heavily on US public health care for years to come. Law professors Nicholas Bagley and Rachel Sachs warn the US$56,000 per patient annual cost of Aduhelm could cost US taxpayers tens of billions each year.
“The federal government will bear the brunt of the new spending,” the pair explain in an editorial for The Atlantic. “The overwhelming majority of people with Alzheimer’s disease are eligible for Medicare, the federally run insurance program for elderly and disabled Americans. If even one-third of the estimated 6 million people with Alzheimer’s in the United States receives the new treatment, health-care spending could swell by $112 billion annually.”
Non-profit consumer advocacy organization Public Citizen has called for the resignation, or removal, of acting FDA commissioner Janet Woodcock, along with both Dunn and Cavazzoni. Directly addressing Xavier Becerra, Department of Health and Human Services secretary, the director of Public Citizen’s Health Research Group Michael Carome argues the approval gives “false hope” to patients and damages the agency’s credibility.
“The FDA’s decision to approve aducanumab for anyone with Alzheimer’s disease, regardless of severity, showed a stunning disregard for science, eviscerated the agency’s standards for approving new drugs, and ranks as one of the most irresponsible and egregious decisions in the history of the agency,” says Carome. “The sheer recklessness of the FDA’s approval of aducanumab cannot be overstated.”
For years now the FDA was the single most obstinate barrier to new pharmaceuticals; research was done and shelved, because of burgeoning red-tape requirements. Now in this Adulhelm debacle we finally have the chance to see the rats come out of the woodwork---it appears it was mostly these "expert advisors" that were holding back drug development, and are now outraged that their nitpicking objections are no longer heeded. How terrible, patient needs outweighing formal requirements! It also seems that many of these offended advisors have been triggered into resigning---well, good riddance to them.
Hope that the FDA has found its cojones for good, and the same Accelerated Approval will be used for the many new cancer, arthritis, antibiotic, anti-senescence, and other much needed treatments that have been waiting in the wings for years.
Agree about accelerated approval when there are no alternatives - But the argument here is about the efficacy rather than safety and a sudden (and dubious) change of end point. This is about the approval of a very expensive (profitable) drug without proven efficacy of an end point that shows patient benefit and with cost that could cripple health budgets with minimum patient benefit..
Perhaps the FDA need to put a new qualification which is the cost of the drug. If it was $1 per year treatment, no argument its worth the risk but at $56,000 per annum with its poor efficacy it isn't!
Maybe this is just another example of the way we reward research companies (by high selling costs) for the development of new drugs and treatments, there must be a better way?
The key phrase is "almost unanimously". Seems like an audit of FDA leadership relationships to the Pharma companies might be called for here.
The FDA has a well-established reputation for being too slow and bureaucratic , but that does not seem to be the issue here.
Donald Trump's "Right To Try" proposal was the right thing to do for folks who have no other options.