My father died of Alzheimer’s disease in 2010. Since April, my mother has lived in the memory-care unit of a nursing home in Connecticut. She is lucid at times, but more often she has trouble remembering whether I am her son, her husband, or her father. I have covered wars and riots and a long string of epidemics. None of them frightened me the way that Alzheimer’s does. I am far from alone. More than six million Americans are living with Alzheimer’s, a number that is certain to grow as more people survive into their eighties and nineties. But tens of millions of their family members, colleagues, and friends also struggle every day with the reality of this wholly disabling disease.
Last week, in what should have been truly exciting news, the Food and Drug Administration approved aducanumab, the first new drug in nearly twenty years that is designed to treat Alzheimer’s patients. But, in doing so, the agency ignored the overwhelmingly negative recommendation of the Peripheral and Central Nervous System Drugs Advisory Committee, none of whose members found sufficient evidence that the drug could slow the cognitive decline that is a hallmark of dementia. Ten members voted against approval; one voted “uncertain.” Another member abstained because he had been an investigator on one of the drug’s two major trials.
By the end of the week, three of the committee members had resigned, and many experts suggested that the new drug, which Biogen will market as Aduhelm, could cause more problems than it will solve, both for people with Alzheimer’s and for the nation’s health-care system. “This might be the worst approval decision that the F.D.A. has made that I can remember,” Aaron Kesselheim, a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, told the Times. He resigned from the committee on Thursday, after having served on it for six years.
Another member who resigned, David S. Knopman, a neurologist at the Mayo Clinic, wrote to the F.D.A. that “the whole saga of the approval of aducanumab . . . made a mockery of the committee’s consultative process.” (The F.D.A. is not bound by any committee recommendation. Usually, when the agency disagrees with its advisory boards, it does so to reject a drug that has been endorsed. It is very rare for the agency to ignore such an overwhelmingly negative recommendation.)
The decision will have implications that reach far beyond the introduction of a single drug designed to treat one disease. In the past, the F.D.A. approved several therapies aimed at relieving symptoms of Alzheimer’s; these medications attempt to regulate chemicals that ferry messages between nerve cells. But none of those drugs stop the damage to the brain. At best, they have proved moderately successful for a few months.
Until now, there have been no drugs that treat an underlying cause of the disease. Aducanumab, which has been in clinical trials for years, attacks the amyloid-protein plaques that many researchers believe impair the cognitive function of the brain. Scientists regard those plaques as clear biological markers of Alzheimer’s, and they have tried for decades to demonstrate that reducing those amyloid levels could help patients to regain their cognitive abilities, or at least to halt their decline. None of the drugs in those past studies had any impact on the progress of the disease.
The two clinical trials that led the F.D.A. to approve aducanumab achieved the same indirect goal: showing the drug’s ability to reduce plaques that accumulate in the brain. But the initial data on slowing patients’ cognitive decline was so poor that, in 2019, the company halted the studies. It was only after researchers from Biogen, in consultation with the F.D.A., reëxamined the data later in the year, and included more than three hundred additional participants who completed the studies after the initial data was evaluated, that they noticed something they regarded as promising. In one of the two studies, the drug seemed to slow cognitive decline in a number of early-stage patients who were treated with a high dose of the drug. The difference between the effect of aducanumab and the placebo was a fraction of a point, on an eighteen-point scale. The second study found that the drug offered no benefit.
Nonetheless, instead of evaluating this medicine solely on whether it affects cognition, the F.D.A. granted conditional approval based on aducanumab’s ability to reduce those amyloid plaques. It’s not unusual for the F.D.A. to grant early access to drugs that seem to work on surrogate markers, like the plaques or blood levels, rather than on the direct improvement of a patient. The agency has granted what is generally known as accelerated approval to more than two hundred drugs since 1992. Most are for rare diseases, which affect few patients, or, as is the case with Alzheimer’s, those for which there is no other available treatment. The agency requires that pharmaceutical companies conduct additional clinical trials to prove that the treatment works. For a drug like aducanumab, such a study will take years—and it will remain on the market throughout that study. Since previous clinical trials that linked reducing plaques to improved brain function have uniformly failed, experts were seeking a more promising result. They did not find it.
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Aducanumab will not be a simple medicine to take, and it will demand many resources. The drug needs to be administered intravenously for an hour; that will almost certainly require a visit to a clinic or doctor’s office. Patients will need regular M.R.I.s, in part to insure that they are not suffering adverse effects from the treatment. About forty per cent of participants in the two studies experienced (mostly mild) brain swelling or bleeding after taking the drug. And the company has said that a prescription will cost fifty-six thousand dollars a year. That figure has already caused outrage. The Institute for Clinical and Economic Review carried out an analysis of the trial results and concluded, as have so many other experts, that “current evidence is insufficient to demonstrate that aducanumab benefits patients.” The organization denounced the pricing structure of what it said “now seems likely to become one of the top selling drugs in the history of the United States.” It is not yet clear which private insurers will pay for it. The vast majority of Alzheimer’s patients are elderly, and many are insured by Medicare. Even if the federal government could negotiate significantly lower prices, Medicare does not have the money to spend billions of dollars a year on one questionable therapy.
Last Monday, Patrizia Cavazzoni, the director of the F.D.A.’s Center for Drug Evaluation and Research, issued a statement attempting to explain the agency’s decision. “We ultimately decided to use the Accelerated Approval pathway—a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit,” she said. “In determining that the application met the requirements for Accelerated Approval, the Agency concluded that the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy.”
Experts have struggled to find a scientific rationale. “I’m quite surprised,” Caleb Alexander, a Johns Hopkins epidemiologist who served on the F.D.A.’s advisory panel and voted against the approval of aducanumab, told Stat News. “The most compelling argument for approval was the unmet need but that cannot, or should not, trump regulatory standards,” he said. “It’s hard to find any scientist who thinks the data are persuasive. Unmet need is an important contextual factor but it’s not an evidentiary threshold.”
Moreover, the studies focussed on people in the early stages of the disease, but the F.D.A. has approved the drug for use by anyone with Alzheimer’s—even though it was not tested on people with more advanced cases. That almost assures that thousands of seriously ill Americans will take the drug without any scientific justification for doing so. Jason Karlawish, a co-director of the University of Pennsylvania’s Penn Memory Center, in Philadelphia, who ran one of the trial sites, told Reuters, “This decision has shaken the foundations of the scientific process and methods.” He added, “It’s a disturbing set of events, scientifically, clinically, politically.”
AIDS activists began to campaign for earlier access to experimental medicine in the late nineteen-eighties. They argued that people who were almost certain to die and had no alternatives should have the opportunity to take those drugs before trials had proved they were effective. That practice was considered acceptable at the height of the AIDS epidemic, when so many people resorted to dangerous remedies that caused real harm, even death. It was not until 1987, six years into the epidemic, that AZT, the first drug to treat AIDS directly, was approved.
The approach soon became routine for many diseases. It has been a largely successful attempt to balance compassion with the need for useful data. Fast-tracking the release of experimental medicines makes sense when the alternative is death. And it makes sense for diseases that affect a small population. Recently, though, an increasing number of drugs have been approved by that process. Critics argue that those approvals are too often based on tangential indicators that do not lead to better health outcomes.
It has only been a year since Donald Trump extolled from the White House podium the virtues of hydroxychloroquine as a preventative against COVID-19. There was no acceptable data to suggest that it worked. For some people, the drug was actually dangerous. But the F.D.A., under pressure from the White House, issued an emergency-use authorization. Less than three months later, once the drug’s failure became too clear to ignore, the agency was forced to withdraw the authorization.
This is not how the F.D.A. is supposed to work. Millions of Americans rely on the agency to sift through data and present scientifically valid results. It is there to protect us, not to tell us what we want to hear. Often, this means that agency officials are required to convey bad news rather than hope. Understandably, we all prefer hope, but erasing the distinction between a medicine that works and one that does not will never provide it. And if the F.D.A. doesn’t understand that, who will?