FDA on Tuesday released documents detailing the process behind its controversial approval of aducanumab, which will be sold under the brand name Aduhelm—the first Alzheimer's drug to receive FDA approval in nearly two decades.

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How Aduhelm was approved

In order to seek FDA approval of Aduhelm, Biogen launched two Phase 3 randomized controlled clinical trials of the drug—but the trials were halted in March 2019, after independent monitors determined the drug was unlikely to benefit patients.

However, in October 2019, Biogen announced that it had conducted a new analysis of data from the trials. According to the updated analysis, a high dose of Aduhelm in one trial showed a small benefit in slowing cognitive decline, and in both trials Aduhelm was effective at removing beta-amyloid proteins.

Biogen submitted its analysis of the Phase 3 trials to seek FDA approval for the drug. Late last year, a panel of independent experts convened by FDA looked at Biogen's data. They determined there was not enough evidence to suggest the treatment had a significant benefit for patients, and they argued the drug should not be approved.

However, FDA is not obliged to follow the panel's recommendations, and on June 7, it announced the decision to approve Aduhelm on a conditional basis—saying Biogen must still conduct a large clinical trial to confirm that removing beta-amyloid proteins actually leads to cognitive benefits for patients.

If that future trial fails, FDA could rescind the drug's approval. The trial could, however, take years to complete.

Critics of FDA's decision have raised several concerns with the process, including the unusual decision to disregard the recommendation of the independent expert panel; the relative weakness of Biogen's clinical trial data; that other drugs that have reduced beta-amyloid proteins have failed to demonstrate a cognitive benefit; and that FDA approved the drug for all Alzheimer's patients, even though clinical trials examined only those with relatively mild impairment.

Further, they have noted that Aduhelm's list price of $56,000 could present a significant financial burden to Medicare and insurers, as well as to patients.

What new documents show about FDA's process

Following controversy of the conditional approval, FDA on Tuesday released new documents providing insight on the process that led to the agency's decision.

According to the documents, FDA officials over the course of two meetings presented the application from Biogen to the Medical Policy and Program Review Council, a group within FDA that helps set the agency's policies. Based on those meetings, they determined that—while it was unclear whether Aduhelm actually slows the progression of Alzheimer's—there was "convincing evidence" it had a "robust" effect on beta-amyloid proteins.

As a result, the review council concluded that based on current understanding of Alzheimer's, it was "reasonably likely" that the drug's effect on beta-amyloid proteins provides a cognitive benefit, which they said "supports the accelerated approval of" the drug.

According to the documents, seven high-ranking FDA officials then met on April 26 to discuss those conclusions. The officials included Patrizia Cavazzoni, director of FDA's Center for Drug Evaluation; Peter Marks, head of FDA's biologics division; Rick Pazdur, an expert in accelerated approvals at FDA; and Sylvia Collins, director of FDA's Office of Biostatistics.

At the time of that meeting, most participating officials supported approving the drug, with one abstaining and another—Collins—being the only dissenting voice. According to the documents, Collins believed the drug should not be approved, arguing that "there is insufficient evidence to support accelerated approval or any other type of approval."

According to the documents, there were no further meetings on the issue. The agency then released its conditional approval of the drug about six weeks later, on June 7, STAT News reports.

Officials address concerns about new precedent

According to STAT News, other memos indicate that FDA statisticians were concerned about the potential approval and advised against it, with one document from FDA's office of neuroscience raising concerns about whether an approval would enable potentially ineffective drugs to garner similar support.

Specifically, according to STAT News, accelerated approval is typically reserved for therapies that haven't yet been demonstrated effective in large trials—but in this case, the drug had been through two Phase 3 trials, which produced " conflicting evidence." However, the council said FDA had the authority to issue accelerated approval for any drug "upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit."

As Peter Stein, director of FDA's Office of New Drugs, explained in one of the documents, "[T]he evidence is not sufficiently compelling or persuasive to meet the substantial evidence standard for standard approval." However, he added that "the results … strongly suggest that treatment with aducanumab may result in clinical benefit."

As a result, he said the drug merited accelerated approval, because in that process, "there is a recognition that there remains residual uncertainty of clinical benefit, typically because the studies assessing clinical benefit are ongoing, but here because the results of the studies assessing clinical benefit strongly suggested but did not establish benefit."

Moreover, he pointed out that if the agency were to delay approval so the company could finish another trial, patients during that multi-year wait period "could suffer irreversible loss of brain neurons and cognitive function and memory."

"This is not the typical run-of-the-mill situation," Stein said. "But just because it's not the typical situation doesn't mean that the fit was not quite, quite, quite good for what accelerated approval is built for and how it's to be done."

Woodcock voices support

Acting FDA Commissioner Janet Woodcock said she "fully support[s]" FDA's approval of Aduhelm, but acknowledged "that there are different opinions about this decision, including within FDA, and there likely will continue to be questions around our process for review and the data we considered to support the approval."

Ultimately, Woodcock said, "an experienced group of medical reviewers at FDA concluded that there was sufficient evidence to approve the Alzheimer’s therapy via the accelerated approval pathway" (Herper et. al., STAT News, 6/22; McGinley, Washington Post, 6/22; Edney/Langreth, Bloomberg, 6/22; Walker/Burton, Wall Street Journal, 6/22).