August 5, 2021 2:23 PM EDT

In theory, the approval of the first drug to treat Alzheimer’s disease would be cause for universal celebration. But from the moment the U.S. Food and Drug Administration (FDA) approved aducanumab on June 7, the drug has been beset by controversy about whether the drug is actually effective—and if the agency bent to pressure from maker Biogen. The conflict came to a head Wednesday when the agency watchdog, the U.S. Department of Health and Human Services Inspector General, announced that it would look into the drug’s accelerated approval, including allegations that the FDA had an “inappropriately close relationship” with the pharmaceutical industry. However, the agency will not reexamine the science behind the approval.

The turmoil has had major repercussions for aducanumab’s rollout. Already, some major medical institutions have said they will not provide it, doctors don’t feel comfortable prescribing it, and members of the FDA advisory committee resigned in protest over the approval. The Alzheimer’s Association, a patient advocacy and research group, on the other hand, stands by the approval and says that patients should have the option of deciding whether or not they want to try it.

Doctors take issue with the quality of the data on which the FDA’s decision was based, and they are also criticizing how the agency reviewed the drug, which will be marketed under the brand name “aduhelm.” After reports that members of Biogen allegedly met with members of the FDA outside of their formal regulatory capacity, the agency announced on July 9 that it would investigate how the drug was approved. Following that announcement, the Cleveland Clinic, the Mount Sinai Health System in New York and Providence, a health care system based in Renton, Wash., all decided that they would not carry the drug, at least until the results of the investigation are complete. A handful of Blue Cross Blue Shield plans have also said that for the time being they would not reimburse the drug, which is expected to cost $56,000 a year.

It’s a blow to the more than 6 million Americans currently living with Alzheimer’s, a neurodegenerative disorder that primarily affects memory and cognitive function. For decades, their hopes have been raised and dashed as new drug candidate after new drug candidate failed to show much benefit. Given the lack of available options, aduhelm’s approval was, unsurprisingly, a new source of optimism.

“Does the phrase ‘phones ringing off the hook’ mean anything to you?” says Dr. David Reuben, director of the Alzheimer’s and Dementia Care Program at University of California, Los Angeles about the initial response from patients in the days after the approval. “We spent several days when all we were doing was answering questions about aducanumab.”

Those answers, however, are probably not what those patients want to hear. Aducanumab was approved by the FDA despite the fact that 10 of the 11 members of an advisory committee of independent experts the agency convened for guidance voted that there was not enough evidence to justify approval.

Alzheimer’s experts agree that aducanumab helps reduce the buildup of amyloid protein plaques in the brain, which are the hallmark of Alzheimer’s and which many believe represent the first step in the decades-long unfolding of the disease. The question is whether this reduction translates into meaningful and quantifiable benefits for patients, as measured by cognitive tests as well as changes in their ability to be independent and conduct daily activities like dressing themselves, driving and navigating trips outside the home.

The data there are murky, mainly because the trial results submitted by Biogen and Eisai were complicated. The companies conducted two similar studies, started several months apart, focusing on patients with mild cognitive impairment and evidence of amyloid in the brain, as confirmed by brain imaging. Early results from one study showed no benefit of aducanumab in improving cognitive test scores, while the other trial did. Because of the negative results, the companies decided in March 2019 to stop both studies after statisticians determined that the drug likely would not help patients.

Several months later, however, after a more thorough analysis, the companies reported that in fact there were hints of benefit even in the trial that had been deemed a failure. When the FDA advisory committee reviewed the two studies and the additional re-analysis, the group said more data confirming the positive study’s result would be needed, given the complexity of the conflicting outcomes of the two existing studies.

When the FDA went to make its decision, it took that concern into consideration as well as another pressing one: the fact that there are no disease-modifying treatments for Alzheimer’s. Current drugs only address the symptoms of the condition, while aducanumab, which attacks the amyloid plaques in the brain, targets what is believed to be one of the causes of the disease. In an explanation published in JAMA Internal Medicine, three FDA leaders explained that they agreed with the advisory committee that the existing evidence was complicated to interpret, and therefore looked to an alternative regulatory pathway: accelerated approval. Accelerated approval allows the agency to approve a drug based on a single positive study and other corroborating evidence, in situations where there is an unmet need for treatments, which the FDA felt was the case with Alzheimer’s.

The agency, however, made this decision without consulting the advisory committee, which ostensibly exists to provide expertise on such decisions. And according to an investigation by STAT including review of internal FDA and Biogen documents, the opportunity to pursue accelerated approval had been discussed several months before in a campaign Biogen dubbed “Project Onyx,” even though this option was not mentioned to the advisory committee when it met in November. These discussions occurred, according to the internal documents, outside appropriate regulatory interactions between the FDA and Biogen. “The decision to use the accelerated approval process was made at the 11th hour, and without consultation with the advisory committee,” Dr. Caleb Alexander, professor of epidemiology and medicine at Johns Hopkins Bloomberg School of Public Health and member of that committee told TIME in June after the approval. “It’s unclear why.”

The FDA further confused matters by initially approving the drug for all Alzheimer’s patients, even though it was only studied in those at the earliest stages of disease. A month after the initial approval, the agency revised the label to specify that the drug has not been studied in people with more advanced disease.

Meanwhile, several members of the advisory committee resigned in protest over what they saw as the agency dismissing its advice. “Without additional data presented to me or to others on the advisory committee, the FDA granted accelerated approval of aducanumab for treatment of Alzheimer’s disease,” Dr. Joel Perlmutter, professor of neurology at Washington University St. Louis and one of the members who resigned, wrote to TIME, explaining his resignation. “Approval of a drug that is not effective has serious potential to impair future research into new treatments that may be effective for treating Alzheimer’s disease.”

The patient perspective

Doctors are split between those considering prescribing the drug for the right Alzheimer’s patients, and those who won’t prescribe it and plan to refer their patients who want it to physicians who will. That leaves patients more confused than hopeful over the first drug to treat their disease.

“I don’t plan to prescribe it,” says Reuben. “Because I’m not convinced that it is going to be beneficial to my patients.”

Patient advocacy groups have been more supportive of the drug, recognizing that while it’s not a panacea, it’s a welcome option after decades without any true treatments. “There hasn’t been a drug approved for Alzheimer’s in almost 20 years,” says Russ Paulsen, COO of Us Against Alzheimer’s. “And there hasn’t been this kind of [disease-modifying] drug for Alzheimer’s ever. We know there are some researchers who don’t believe the data are as clear as they would like them to be. But the patients we’ve talked to say, ‘Let me have that choice. Let me have a chance.’”

Dr. Maria Carillo, chief science officer of the Alzheimer’s Association, has seen a similar reaction among her group’s communities. “We believe this is a treatment that should be given to individuals so they have an option—an option now while we look for additional evidence not only for this treatment but for others coming down the pike.” The decision by certain hospitals not to provide the drug, and by physicians not to prescribe, she says, is “unacceptable for these organizations to be creating barriers to access for those who could benefit [from the medication]. Patients need to be given an option, and physicians need to be given an option so that they can provide that option to their patients who can make informed choices about their health.” Critics of aduhelm’s approval say they are driven by patient interests, and are concerned that the approval will give people false hope. “I believe that the FDA and the advisory committee has a responsibility to help protect these patients and families, which at times means facing difficult decisions,” says Perlmutter. He and others believe the existing data simply aren’t strong enough to say that the drug has significant clinical benefit.

Phil Gutis, right, with his husband Tim Weaver at their home in Solebury, Pa., July 2020. “If you present a drug to me that might help to slow the deterioration, hell yes, yeah make it available,” says Gutis. “That’s the voice I feel is completely lost in all this.”
Courtesy Tim Weaver

Many patients themselves, however, disagree. “I understood the perspective of the doctors who are greeting this with skepticism,” says Phil Gutis, 59, who has Alzheimer’s and was part of the aducanumab trial. “But at the same time, I started getting angry because I feel like these doctors and researchers, they’re not putting themselves in our shoes. Why shouldn’t I have the opportunity to have a drug that might help me? I understand all the caveats and the concerns, but this is a fatal disease, and there’s no treatment available.”

“If you present a drug to me that might help to slow the deterioration, hell yes, yeah make it available,” says Gutis. “That’s the voice I feel is completely lost in all this.”

Doctors who aren’t comfortable prescribing the drug are preparing to have detailed discussions with their patients about the pros and cons of the medication—the risks of brain inflammation weighed against the small and, in some scientists’ opinion, uncertain potential benefit in slowing progression of Alzheimer’s. For patients still eager to try the drug, health care providers are directing patients to other providers who are willing and capable of administering it by IV infusion. Reuben says he is also suggesting they consider joining the new trial that the FDA required Biogen to conduct to confirm the positive results. “Some people are not going to want that, however, since they have a 50-50 chance of getting the drug and they probably want a 100% chance of getting the drug,” he says.

The FDA gave the companies nine years to complete the additional study, and enrollment might be slow if patients aren’t willing to get randomly assigned to receive placebo when they could find a doctor who might prescribe it.

Cost is the other challenge for patients looking to get the treatment—most insurers take their reimbursement cues from the Centers for Medicare and Medicaid Services, which has said it will do a national coverage analysis before deciding, and that could take months. Without insurance coverage, it’s unlikely many patients will be able to afford the drug, which many may have to take for years.

For now, some patients are waiting to see how the ongoing debate ends up getting resolved, not to mention the outcome of the FDA investigation. But that could end up costing them valuable time, since the drug is meant for people at the earliest stages of disease. Aduhelm works best when it can target and destroy amyloid before it forms the large, sticky plaques that strangle and damage nerves. Once the nerves are compromised, the drug likely won’t have much effect.

Geri Taylor, right, with her husband Jim in Monument Valley, Az., Oct. 2018.
Courtesy Jim Taylor

In Geri Taylor’s case, joining the aduhelm study earlier in her disease process seemed to make a difference, and her cognitive decline appeared to slow. Because of her participation in the trial, the nurse from New York City and Connecticut is among the few patients currently receiving the drug. “I’m looking forward to having this help,” she says, “so I can go about my daily business.

Contact us at letters@time.com.

Read More From TIME

Related Stories

EDIT POST