How Biogen’s Aduhelm Approval Marks a Precipitous Turning Point for the FDA

In the weeks following the FDA’s approval of Biogen’s aducanumab (Aduhelm) on June 7, 2021, the decision has been met with intense scrutiny and debate directed at nearly every level of the process.

And all the furor underscores one key question: Was the decision ethical? Regardless of the answer, the consequences of the process may ultimately jeopardize the American public's trust in the FDA, experts said.

The monoclonal antibody’s accelerated approval marks the first new therapy for Alzheimer disease brought to market in nearly 2 decades, although progress in the field has been growing in recent years. The treatment functions by targeting the buildup of amyloid beta plaques in the brain, which are thought to be a pathophysiological driver of the neurodegenerative disease.

But little evidence exists proving reduction of amyloid actually helps patients by improving their memory and cognitive problems. Indeed, previous trials of drugs targeting this potential root cause have yielded numerous failures. For this reason, Aduhelm was granted accelerated approval, which is based on its “effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients.”

In other words, the drug was approved to treat amyloid plaque buildup and not the actual disease, which constitutes an important distinction, said Aaron S. Kesselheim, MD, JD, MPH, a professor of medicine at Harvard Medical School and a faculty member in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, during a panel presented by The Hastings Center, a nonprofit bioethics research organization.

“There is a lot of uncertainty in the field about whether changing amyloid plaques, even in patients with early Alzheimer disease, is meaningful in altering the course of the disease,” Kesselheim said.

Biogen’s 2 clinical trials on the drug were halted in 2019 as data revealed it provided no benefit to patients’ cognitive function. The company later conducted another analysis of 1 trial, which found that at high doses, Aduhelm resulted in slightly slower cognitive declines, and it subsequently applied to the FDA for approval.

Under accelerated approval, the company has until 2030 to conduct and report evidence from a new clinical trial demonstrating the treatment’s efficacy. Should this clinical trial reveal the drug is not effective, the FDA has authority to withdraw the treatment from market.

However, FDA follow-up of these trials has historically been lax. In addition, encouraging patients with Alzheimer disease to participate in a clinical trial where they run the risk of receiving a placebo may be difficult, “when they could just go next door and get [Aduhelm] in usual clinical practice,” said Kesselheim.

In the 2 initial trials, approximately 40% of patients experienced brain swelling and hemorrhaging. Because of this, patients who take Aduhelm must undergo regular brain scans for monitoring purposes, potentially driving up the cost of treatment.

These controversial starting points represent just a fraction of the problems raised by the drug’s approval, which ultimately led to 3 resignations from an FDA advisory committee, including Kesselheim.

Aduhelm’s approval came after the independent committee voted nearly unanimously against the approval of Aduhelm, saying evidence did not show it improved patients’ cognitive function. But the option of approving the drug through an accelerated approval was not considered during this meeting, and the FDA ultimately granted approval on a different basis than that which it asked the committee to consider.

During the advisory committee meeting, the FDA “explicitly excluded discussion of amyloid plaque as a surrogate for clinical effect,” according to Kesselheim.

The fact the FDA “switched the premise on which they were evaluating the drug and then approved the drug on a totally different premise than they presented to the advisory committee made me concerned that they weren’t using the advisory committees as they should—as truly independent expert views on an important issue,” Kesselheim said. This conflict contributed to his decision to resign from the position.

Aduhelm, administered via infusion, is projected to cost $56,000 for a 1-year supply, putting it out of financial reach for many patients and families suffering from Alzheimer’s effects. Although a portion of the treatment may be covered by insurers—if administration is deemed medically necessary—costs will vary depending on insurance plan.

Several Blue Cross Blue Shield plans have already announced they will not cover Aduhelm, as they consider it an investigational treatment. Meanwhile, CMS announced it will begin a National Coverage Determination analysis to determine if Medicare will have a national policy for the drug. As part of the process, a 30-day public comment period began on July 12, and the Center will host 2 public listening sessions throughout the month.

Medicare administrative contractors representing 12 jurisdictions across the country are currently making coverage determinations at the local level.

Adding to the price tag debate, a recent report update from The Institute for Clinical and Economic Review (ICER) found the health-benefit price benchmark for the drug should be set at $3000 to $8400 annually—a stark contrast to Biogen’s steep estimation.

More than 1 in 9 individuals aged 65 and older have Alzheimer dementia in the United States, and that number will only increase as populations age. These patients also represent one of the key cohorts covered by Medicare, which is funded in part by taxpayers.

Estimates indicate Medicare could end up spending tens of billions of dollars on the drug—money that could, according to some experts, be more effectively spent elsewhere to better improve older Americans’ quality of life. Fear of the program’s financial future, along with other issues associated with the decision, prompted 2 congressional committees to launch reviews into the approval.

In addition to questionable efficacy data and cost concerns, a series of blunders at the FDA—currently led by a temporary commissioner— further compounded backlash to this approval.

Initially, Aduhelm was indicated for all 6 million patients with Alzheimer disease in the United States, despite the fact Biogen’s clinical trials only included those with early stages of the disease.

Following confusion over the broad indication, the FDA walked back on its decision and issued an update to the drug’s label. “Treatment with Aduhelm should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied,” the FDA said.

A wholly separate issue concerning the independent nature of the FDA was brought to light when STAT News reported on a potentially compromising relationship between drug reviewers at the Administration and Biogen. These revelations prompted House Democrats to demand documents from Biogen regarding the relationship, while acting FDA Commissioner Janet Woodcock, MD, called for an independent inspector general investigation of her own administration’s actions.

Specifically, Woodcock requested “an independent review and assessment of interactions between representatives of Biogen and the FDA during the process leading to the decision to approve the biologics license application to determine whether any of those interactions were inconsistent with FDA policies and procedures.”

The Big Question

Given all the cost, safety, efficacy, and regulatory concerns associated with the drug, the question posed to providers proves incredibly challenging: Should I prescribe this treatment to patients?

Alzheimer disease is one of the more devastating neurological conditions as it ultimately renders patients devoid of any memories and eventually reliant on continual bedside care.

Not only does this disease take a toll on patients, but caregivers must cope with the months-long deterioration of a loved one’s memory while providing support for everyday tasks that become increasingly difficult.

“This is a disease that relentlessly chips away at a person’s self-determination and autonomy,” said Jason Karlawish, MD, during the Hastings panel. Karlawish is a Hastings Fellow and a professor of medicine, medical ethics, health policy and neurology at the University of Pennsylvania’s Perelman School of Medicine and co-director of Penn’s Memory Center.

“I have a real commitment to doing everything I can to preserve, protect and defend [patients’] autonomy… If someone chooses to take [Aduhelm], I will write a prescription. But I am a reluctant prescriber,” he said, adding patients and their families must be educated about the drug’s uncertainty of benefit, risks, the process by which it came to be approved, and other considerations.

“I would be very enthusiastic about having someone in a clinical trial to study it. But I’m unenthusiastic about writing a prescription to give it to someone in what amounts to an n of 1 clinical trial,” Karlawish said.

Despite the largely negative reception of the approval in the Alzheimer field, several institutions and individuals have come out more strongly in favor of the decision, purporting that the hope offered by the drug’s potential outweighs its many shortcomings.

“Today’s accelerated approval of Aducanumab by the FDA, the first new Alzheimer’s drug on the market in nearly 2 decades, provides hope as another important step in the fight against Alzheimer’s disease. We are hopeful that it will improve the quality of life for individuals living with Alzheimer’s disease and their caregivers. Patient access and affordability to all of those in need is of significant importance,” the Alzheimer’s Foundation of American said in a statement.

Writing in STAT News, Emil D. Kakkis, MD, PhD, the CEO, president, and founder of Ultragenyx Pharmaceutical, applauds the FDA's decision, stating “When it comes to making new therapies for complex, difficult-to-treat diseases, history has shown that progress can’t be made without taking a first — often controversial — step.”

Kakkis drew comparison between the decision and that to create the accelerated approval program, which led to advances in the oncology field and HIV treatments.

“Opening the door to the use of a biomarker for accelerated approval led to significant investment in new and better drug targets and alternative mechanisms of action,” Kakkis argued. “The same could be true for Alzheimer’s disease, for which the prevention of neurocognitive decline is the goal, and it may take many years before clinical symptoms can be observed and measured, which is required to demonstrate efficacy in a conventional development pathway reliant upon clinical outcomes.”

Taking the opposite view, Kesselheim and Karlawish pointed out how the decision could set a precedent for approval of other understudied and unproved therapies, both for Alzheimer disease and additional conditions.

“Does this reflect the new way things are happening at FDA? There are other drugs in the pipeline that could get this kind of approval now,” Karlawish said. Eli Lilly recently announced it would apply for accelerated approval of its Alzheimer drug donanemab following the decision.

“I can’t fault a company for doing what companies do. If the regulators are changing the standards for what it takes to get a drug to market” then companies will take advantage of these loosened requirements, Karlawish said. But other Alzheimer drugs in the works with similar targets “could now be popped out into clinical practice without the studies that are needed to show ‘Is this the drug I should prescribe for my patients?’”

If that does happen, the FDA needs to be held accountable for demanding the additional studies mandated by accelerated approval, the experts said. The FDA could make sure these trials are already underway or are set up prior to the drug’s approval, ensure trials are carried out at a high level or rigor with reasonable endpoints, and, if trial results are negative, the regulator could automatically remove the drug or indication from the market.

“None of those things currently happen,” Kesselheim said.

Given all of these factors, instead of just investigating the relationship between Biogen and the FDA, the pair argue Woodcock’s investigation should be broader in scope. “All aspects of this approval process should be investigated,” Kesselheim stressed.

Maintaining the public’s trust in the FDA is paramount to the agency's continued success, experts noted. But because its budget it largely dependent on fees from industry, and it is regularly evaluated based on the number and speed of new approvals, the Aduhelm saga highlights the overall fragility of the FDA's integrity.

“If I was at FDA, if I was Janet Woodcock, I would say, ‘Does the American people trust the FDA?’” Karlawish said. “And if there's even a doubt about the answer to that question, then she needs to repair that trust, because trust is like porcelain. It's easily cracked but once it's cracked it's hard to repair.”

When it comes to use of the drug, for Kesselheim the “almost imperceptible” cognitive improvements shown in the single positive arm of the Aduhelm trial prevent him from feeling comfortable prescribing it.

“I would not recommend this drug and I wouldn’t administer it because I don’t think that the drug has sufficient evidence that it works,” he said.

In the end, some providers may leave the informed decision up to patients, as even access to a drug that holds a chance of improving the debilitating diseases’ course could provide them not only with a renewed sense of agency, but a sense of hope that was absent prior to the approval.

“I am not going to let my patients be the crucible upon which this fight is fought,” Karlawish said. “They have to live with this disease. All disease is bad. This disease is uniquely bad.”

More studies ultimately need to be carried out to firmly establish a surrogate approach to treating Alzheimer disease, Karlawish and Kesselheim stressed.

“I can tolerate a risky drug if I know it’s got some benefit,” Karlawish said. But with Aduhelm, that benefit has not been established."

“Indeed, the FDA knows it’s not been established because they want a confirmatory trial conducted as part of their approval, and Biogen has 9 years with which to get those data…These data, this trial, this drug was not the set of data to enter into that new biomarker-based world.”