The Food and Drug Administration’s process for approving the Alzheimer’s drug Aduhelm, despite great uncertainty about whether it worked, was “rife with irregularities,” according to a congressional investigation released on Thursday. The agency’s actions “raise serious concerns about F.D.A.’s lapses in protocol,” the report concluded.
The 18-month investigation, initiated by two congressional committees after the F.D.A. approved the drug, also strongly criticized Biogen, Aduhelm’s manufacturer. Internal documents showed the company set “an unjustifiably high price” of $56,000 a year for Aduhelm because it wanted a history-making “blockbuster” to “establish Aduhelm as one of the top pharmaceutical launches of all time,” even though it knew the high price would burden Medicare and patients, the report found.
The investigation said Biogen was prepared to spend up to several billion dollars — more than two-and-a-half times what it spent developing the drug — on aggressive marketing to counter expected “pushback” over whether Aduhelm was worth its price. The report said the campaign planned to target doctors, patients, advocacy groups, insurers, policymakers and communities of color, who were drastically underrepresented in its clinical trials of the drug.
The F.D.A. is now evaluating two other Alzheimer’s drugs for possible approval early next year, including one that Biogen helped develop. The congressional report said the agency “must take swift action to ensure that its processes for reviewing future Alzheimer’s disease treatments do not lead to the same doubts about the integrity of F.D.A.’s review.”
Representative Frank Pallone, a Democrat and chair of the House Energy and Commerce Committee, said in a statement that the report “documents the atypical F.D.A. review process and corporate greed that preceded F.D.A.’s controversial decision to grant accelerated approval to Aduhelm.”
His committee conducted the investigation with the House Committee on Oversight and Reform, chaired by Representative Carolyn Maloney, also a Democrat. In a statement, she said she hoped the report would be “a wake-up call for F.D.A. to reform its practices and a call to action to my congressional colleagues to continue oversight of the pharmaceutical industry to ensure they don’t put profits over patients.”
In a statement, the F.D.A. said: “We fully cooperated with the committees’ evaluation and we continue to review their findings and recommendations.”
It also said it was the agency’s job to frequently interact with companies to collect accurate information. “We will continue to do so, as it is in the best interest of patients,” the statement said. “That said, the agency has already started implementing changes consistent with the committee’s recommendations.”
“Biogen stands by the integrity of the actions we have taken,” the company said in a statement. It added, “Alzheimer’s is a highly complex disease and we have learned from the development and launch of Aduhelm.”
Aduhelm’s approval in June 2021 caused an outcry from many Alzheimer’s experts. Major health systems, including the Cleveland Clinic and the Department of Veterans Affairs, decided not to offer Aduhelm, an intravenous infusion, citing its uncertain benefits and risks of brain swelling and bleeding. After Medicare sharply limited its coverage of Aduhelm, the drug — still expensive even after Biogen halved its annual price to $28,800 — was essentially sidelined from the marketplace.
The report included the F.D.A.’s own internal inquiry into its Aduhelm review process, an inquiry first reported by The New York Times in 2021. The agency’s self-examination, conducted shortly before Aduhelm was approved, was less negative than the congressional findings, but identified similar issues and said its collaboration with Biogen “exceeded the norm in some respects.”
That internal inquiry, which the F.D.A. had not previously disclosed, found that agency officials leading the Aduhelm evaluation did not pay enough attention to dissenting views from the agency’s own statistical team, which said there was inadequate evidence that Aduhelm worked. After expressing those reservations, team members were excluded from some deliberations and given little notice about the preparation of a key document.
That document was a presentation which, in a highly unusual move, the F.D.A. jointly produced with Biogen for a November 2020 meeting of the agency’s independent advisory committee. The congressional investigation said the F.D.A. had done joint presentations only nine times before, all involving cancer drugs, and that in the bullish joint Aduhelm presentation, at least one point attributed to Biogen was actually written by the F.D.A. The advisory committee overwhelmingly voted against approval.
The F.D.A.’s inquiry concluded that “given the internal disagreement” within the agency “and the lack of a unified F.D.A. perspective on the data, the use of the joint briefing document was not an appropriate approach in this instance.”
The F.D.A.’s inquiry and the congressional investigation both found that the agency did not properly document many interactions with Biogen. Beginning in July 2019, in an unusual arrangement called a “collaborative workstream,” it met repeatedly with Biogen to analyze data from one clinical trial that had failed and another trial that seemed slightly successful, helping advise whether the company should seek approval.
Over 12 months, there were at least 52 meetings, and not all of them were documented fully under F.D.A. standards, the congressional report said. In addition, “there was no official memorialization of at least 66 calls or substantive email exchanges,” the report said. Even the F.D.A.’s internal inquiry said its review “did not reveal a clear record of the number and nature of interactions” between the agency and Biogen.
The F.D.A.’s own internal inquiry said there was “no evidence” its interactions with Biogen were “anything but appropriate,” given the data’s complexity and the importance of Alzheimer’s, but it issued four recommendations to prevent future problems. The congressional report said that more than a year later, the F.D.A. still had not fully implemented them.
The congressional report also questioned the F.D.A.’s decision to give the drug a special designation, known as “accelerated approval.” The agency had “abruptly changed course,” the report noted, after months of saying Aduhelm would only be considered for traditional approval.
The report, confirming previous reporting by the Times, said the change came after a council of senior agency officials met to review Aduhelm, also called aducanumab, and resoundingly agreed there wasn’t enough evidence that it worked. According to minutes of the meeting obtained by The Times, the council said another clinical trial should be conducted first, and one member warned that otherwise, approval could “result in millions of patients taking aducanumab without any indication of receiving any benefit, or worse, cause harm.”
But just three weeks after that meeting, in April 2021, the F.D.A. told Biogen it was now considering Aduhelm for “accelerated approval,” which allows authorization of drugs with uncertain benefit if they can treat serious diseases with few other options and if their biological mechanism is considered reasonably likely to help patients. Accelerated approval requires companies to conduct another trial, but the report noted that the F.D.A. gave Biogen more than eight years to complete it, allowing Aduhelm to be given to patients during that time.
The agency’s justification for accelerated approval was that Aduhelm targets a protein, amyloid, that forms plaques in the brains of Alzheimer’s patients. But many Alzheimer’s experts said years of data had not shown that reducing amyloid slowed cognitive decline.
The congressional report said it was a “notable lapse” that the agency did not reconvene an independent advisory committee or an internal group of experts to consider accelerated approval. It also said the agency contradicted its own guidance for Alzheimer’s drugs, which said “the standard for accelerated approval” had not yet been met for the disease. In its statement on Thursday, the F.D.A. said it “plans to update” the guidance, issued in 2018, “with the goal of continuing to further our drug review processes.”
The report also delved into the F.D.A.’s initial decision to approve Aduhelm for all Alzheimer’s patients even though it had only been tested on people in mild early stages of the disease. F.D.A. officials, justifying the decision, told the committees the broad label would have benefits, including allowing patients to continue on Aduhelm after their early disease worsened.
But Biogen’s own advisers had warned that allowing Aduhelm for all Alzheimer’s patients could lead to safety risks and other issues, including access problems for appropriate patients, the report found.
“Biogen’s Alzheimer’s disease team leaders expressed concern that the company could lose credibility by advocating for a broad label that exceeded the clinical trial population,” the report said. An outside consultant who interviewed doctors, patient advocates and insurers warned it would “likely be giving false hope to patients desperate for anything that might slow the progression of the disease.”
Still, Biogen accepted the F.D.A.’s suggestion. One company document said Biogen had “NO plan to push back on broad label indication internally or with the regulators.” Only after public confusion and criticism did Biogen ask to have the label narrowed, which the F.D.A. quickly did.
The report said Biogen set a high price for Aduhelm because, according to a company presentation, “our ambition is to make history.” Anticipating criticism, “Biogen developed an external narrative about the drug’s value to sell to patients and the public,” the report said.
Biogen planned “an extensive media campaign directed at patients” that would involve connecting more than 50 journalists with medical experts supportive of the drug to “‘shape the narrative’ around Aduhelm,” the report said.
The congressional report issued three recommendations the F.D.A. should adopt immediately, including proper documentation of its interactions with drug companies and clear protocols for when it can create joint presentations with them. The report also recommended that Biogen and other companies clearly communicate safety and efficacy concerns to the F.D.A. and consider the actual value of a drug when setting prices.
“The American people rely on F.D.A. for assurance on the safety and efficacy of the medications they take, and it is incumbent upon drug companies such as Biogen to ensure that the well-being and safety of patients are prioritized,” the report concluded.
