FDA’s controversial approval of Alzheimer’s drug draws calls for reform

WHEN MASS GENERAL BRIGHAM announced two weeks ago that it would not offer a controversial new drug treatment for Alzheimer’s disease to patients, it was an important statement from the state’s leading provider network. On Thursday, Blue Cross Blue Shield of Massachusetts, the state’s largest private insurer, said it won’t cover the drug developed by Cambridge-based Biogen, which critics say was approved despite no evidence of clear benefit to patients. 

Several Boston area health care experts, including a doctor who served on a US Food and Drug Administration advisory committee that recommended against the approval of the drug, being marketed under the name Aduhelm, applauded the announcements. But they said the announcements may carry more symbolic value than clear impact, and that comprehensive reform of the FDA and the Medicare system are the real answer to the problems raised by the controversy. 

Last November, an FDA advisory committee voted nearly unanimously to recommend against approving aducanumab, the generic name for the new Biogen drug. Two clinical trials of aducanumab had been halted in 2019 when there was no clear evidence of any benefit. Biogen subsequently reported, however, that further analysis of one of the trials showed a very modest slowing of cognitive decline. No such benefit was seen in the other trial. The drug also carries a significant risk of brain swelling and possibly bleeding for which patients must be carefully monitored. 

The FDA approved the drug in June over the recommendations of the drug advisory committee.

The drug was given the green light under the agency’s accelerated approval process, not based on evidence that it slowed cognitive decline or extended life for Alzheimer’s patients but because of evidence that it can reduce a sticky substance in the brain known as amyloid, which has been hypothesized to be a cause of Alzheimer’s. The FDA said the drug’s effect on this “surrogate endpoint,” met the standard of being “reasonably likely” to predict an actual benefit of Aduhelm on survival or progression of the disease. A surrogate endpoint is a lab measurement, brain scan, or other finding that is sometimes used as stand-in for what doctors really want to know — whether a treatment improves survival or lessens symptoms of a disease.  

Three members of the advisory committee, including Harvard Medical School professor Aaron Kesselheim, resigned in protest following the FDA action.

“There’s no clear evidence that it does anything,” Kessleheim said of the drug in an interview. In his resignation letter to acting FDA commissioner Janet Woodcock, Kesselheim called the Aduhelm case “probably the worst drug approval decision in recent US history.”

Kesselheim said the advisory committee was specifically told the drug was not being considered for accelerated approval and that the FDA was not considering the surrogate outcome of an effect on amyloid plaque as the basis to consider its efficacy. “So this was very anomalous,” he said.

The FDA defended its decision in a statement pointed to the drug’s effect on “a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients.”

“The FDA’s decision to approve Aduhelm is based on the scientific evaluation of the data in the application, an extensive review of relevant scientific literature and the Advisory Committee discussion,” said a statement from an FDA spokesperson. “We also considered multiple statements submitted by the public, including the Alzheimer’s scientific community.” The statement said the agency often works closely with industry to “foster drug development” and understand emerging data, “especially in areas where there is a significant need for treatments for devastating diseases.”

The FDA requires that drugs given accelerated approval with surrogate endpoints be tested in “confirmatory trials” to determine if there is a clear clinical benefit to patients. But Kesselheim says that process has been less than rigorous and is in need of major reform. 

If those follow-up studies don’t confirm a drug’s benefit, the treatment is supposed to be withdrawn by the manufacturer or have approval revoked by the FDA. In a paper Kesslheim co-authored in the journal JAMA Internal Medicine following the aducanumab approval, he and two colleagues argued that withdrawal of FDA approval should be automatic when those trials don’t pan out. They were also critical of the long time given to companies to carry out those trials, saying Biogen was “inexplicably” given nine years to complete studies confirming a clinical benefit of aducanumab. They also questioned the large share of such trials in which the FDA allows surrogate outcomes to continue to serve as the study endpoints.  

“The inherent quid pro quo is you get on the market sooner, but you need to complete these confirmatory trials quickly, and if they’re negative the drug has to be dropped,” Kesselheim said of the idea behind the FDA’s accelerated approval process. 

Biogen in a statement defended Aduhelm’s accelerated approval based on its effect on amyloid plaque, “a surrogate biomarker that is reasonably likely to predict clinical benefit, in this case a reduction in the rate of clinical decline. We believe that this will be further established as we collect more data from the ongoing EMBARK study and the post-marketing confirmatory trial.” In a separate statement shortly after the FDA approval in June, Biogen said it was “working with urgency” toward the goal of completing a confirmatory trial ahead of the nine-year timetable. 

The drug was initially approved for all Alzheimer’s patients, but that approval was amended about a month later to restrict use to those with mild or early stages of the disease. Aduhelm, which must be administered in monthly intravenous infusions, is priced at $56,000 per year. 

Aduhelm is the first drug approved for Alzheimer’s disease since 2003, and there has been tremendous pressure to develop treatments for a devastating and fatal illness that affects an estimated 6 million Americans and millions more people worldwide. But critics say that led to embrace by government regulators of a drug that could bring billions of dollars in sales to Biogen, despite no clear-cut benefit to patients. 

Some physicians, as well as the leading advocacy group for Alzheimer’s patients, say the drug represents a worthwhile step, despite the questions about its effectiveness. 

“While not a cure, this new drug is the first FDA-approved treatment shown to reduce one of the defining brain changes of Alzheimer’s disease — the clumping of amyloid plaques in the brain — that disrupts brain function,” said Kristen Clifford, chief program officer at the Alzheimer’s Association, in a statement. “There is a dire and drastic need to offer relief and support to the millions of Americans impacted each day by the crushing realities of Alzheimer’s. This reality, combined with the scientific data, is what led to our support for approval with a confirmatory trial.”

Questions have been raised, however, about inappropriately close interactions between the FDA and Biogen during the drug review and approval process. In July, the FDA acting commissioner asked the inspector general of the Department of Health and Human Services to investigate those and other issues related to Aduhelm. Meanwhile, two congressional committee chairs wrote to the FDA last month seeking more information on its internal handling of the issue. 

Kesselheim, who is also a faculty member in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital, said he has no insight, beyond news reports, into what took place behind the scenes at the FDA. “I don’t know what to make of it,” he said of the FDA approval. “All I know is the outcome was a bad outcome and the process was a concerning process.”

Kesselheim said reforms that bolster the FDA’s independence should be considered. Those should include measures that “give the FDA more authority and make it less subject to the vagaries of presidential administrations and congressional budget realities,” he said. User fees from pharmaceutical companies and other regulated companies currently account for 45 percent of the FDA’s budget. Kessleheim said he would favor complete government funding of the agency. 

Amitabh Chandra, a Harvard economist who is director of health policy research at the Harvard Kennedy School and a professor in the business school, said the case “highlights the importance of having an independent and well-resourced FDA.” 

In the meantime, Chandra said, the decisions by prominent provider networks like Mass General Brigham not to offer the drug or the Blue Cross announcement that it won’t cover it are much less significant than the looming coverage decision by Medicare. The vast majority of Alzheimer’s patients are 65 or older and therefore insured through the federal program. (Some low-income older Americans are also insured through Medicaid.) 

Medicare has said it will determine in the coming months whether to cover Aduhelm, but Chandra thinks it’s unlikely the government insurer will deny coverage for a drug that’s received FDA approval, regardless of questions about its efficacy. “So it will be paid for by taxpayers,” said Chandra. 

He said the combination of aducanumab’s unproven benefit, high cost, and the enormous prevalence of the condition it was developed to treat underscores the importance of passing health care reform that allows Medicare to decline to cover a drug or to piggyback on prices negotiated by private insurers for drugs like this. Congressional Democrats, meanwhile, have called for reform that allows Medicare to negotiate prices directly, a move President Biden recently signaled support for, but those efforts have yet to advance. 

“This is a problem where you’ve got the FDA approving the drug and Medicare essentially being forced to cover it,” said Chandra. “People should not blame the pharmaceutical company for that.” The FDA made a mistake in approving the drug, “and the mistake is amplified because Medicare has no teeth” in pricing, said Chandra, who called the Aduhelm story a “design failure” of Medicare and “regulatory failure” of the FDA. “You should fault Congress for that.”

Kesselheim said the government should be reaching agreements with pharmaceutical companies on pricing that is based on the demonstrated effectiveness of their products. “I think we should be negotiating prices so they are more in line with the clinical benefit the drugs provide,” said Kesselheim. “In the case of aducanumab, this is now on the market without any evidence of clinical benefit, but only the promise of clinical benefit.” 

John McDonough, a professor at the Harvard TH Chan School of Public Health, pointed to the Institute for Clinical and Economic Review, a Boston nonprofit that carries out pricing analyses of drugs that weigh the strength of their benefits and risks, as a model for the kind of system the US should adopt. 

“Every other advanced nation has some structure to do drug evaluations for pricing purposes,” said McDonough. 

Chandra said the Aduhlem controversy highlights other shortcomings of the US health care system and the choices that have been made about what sort of care is paid for by insurance. Alzheimer’s patients who spend down their assets can become eligible for Medicaid, which will cover some types of long-term care. But Medicare does not cover such care, which can include services to help patients remain at home rather than move to an institutional setting. 

“It is weird that we would pay $56,000 [a year] on a drug that doesn’t benefit patients, but we would never contemplate giving every Alzheimer’s patient $56,000 to buy long-term care,” he said.