U.S. lawmakers are asking questions about the process that led the U.S. Food and Drug Administration to approve a controversial drug for Alzheimer’s disease. The latest is House Representative Katie Porter (D-CA), who released an open letter late Tuesday calling for the inspector general of Health and Human Services to investigate the relationship between the FDA and the drug’s makers, Biogen.
In early June, the FDA approved Biogen’s antibody-based treatment aducanumab for Alzheimer’s. Now marketed as Aduhelm, the drug is given through infusion once a month and is the first ever treatment intended to slow the progression of the incurable, ultimately fatal neurological condition, rather than simply treat its surface symptoms. While hailed by some Alzheimer’s patient groups and organisations, many scientists expressed concerns about the actual effectiveness of Aduhelm long before its approval — concerns that have only gotten louder since.
“Patients should have confidence that their treatment plans are based on science, not cosy relationships between Big Pharma and FDA officials,” Porter said in a tweet announcing her letter.
In November 2020, the FDA assembled an expert panel to review the clinical trial evidence of Adhulem, a step often taken before they weigh in themselves. The experts were unanimous in not recommending the drug for approval (one expert voted uncertain, while the other 10 voted no). At the time, it seemed to doom the drug’s chances, since the FDA seldom disagrees with an advisory committee’s verdict.
However, in justifying their decision, the agency used a loophole of sorts. They gave Aduhelm an accelerated approval, a designation intended for treatments of a serious or life-threatening illness that are expected to be better than existing options. Importantly, the accelerated approval allowed the FDA to use a “surrogate endpoint” as evidence for the drug actually working as claimed — in this case, the reduction of amyloid plaque, the deposits of beta amyloid that build up in the brain and are thought by many scientists to play a pivotal role in causing Alzheimer’s disease.
In clinical trials, Aduhelm did seem to reduce amyloid in patients. But both of Biogen’s Phase III trials were terminated early in 2019 on the instruction of an independent monitoring board, which determined the drug would not noticeably improve patients’ cognitive function. Outside experts have since disagreed with Biogen’s later interpretations of the data that suggested Aduhelm could work at higher doses. The company is now mandated to conduct a new clinical trial to confirm the drug’s benefits, but it’s a process that could take up to nine years, all the while selling the drug at an estimated $US56,000 ($71,826) a year.
Soon after the FDA’s approval, three of the advisory members recruited by the FDA to review potential new neurological drugs resigned from their positions, including two involved in reviewing Aduhelm. One of these members, Joel Perlmutter, warned at the November meeting that approving an Alzheimer’s drug without strong evidence could set back efforts to approve a truly promising drug “for more than a couple of years, for many years.” In his resignation letter, another member, Aaron Kesselhelm, called the Aduhelm approval “probably the worst drug approval decision in recent U.S. history.”
Porter’s letter brings up these points, as well as more recent reporting from STAT News on the lengthy collaboration between members of the FDA and Biogen prior to Aduhelm’s approval. According to STAT News, the company embarked on a dedicated mission (dubbed Project Onyx) to woo Billy Dunn, head of the FDA’s office of neuroscience, following its decision to apply for approval. In mid-2019, Dunn’s office reportedly met with Biogen to advise they go for an accelerated approval, and both sides continued to work together on collecting and analysing the data used for the formal application. Perhaps damningly, the FDA has publicly asserted that it only considered an accelerated approval for Aduhelm this year, and it did not tell its advisory members of the possible switch to this pathway.
“It appears very clear that Biogen had an inside route to FDA officials and had undue influence over their decision making and the evidence presented in various settings,” Porter stated in her letter.
Porter has joined others, including former health secretary Donna Shalala and consumer advocate groups like Public Citizen, in calling for the HHS’ Office of Inspector General to look into the approval. The letter also follows an announcement in late June by House representatives Frank Pallone, Jr. (D-NJ), chairman of the Committee on Energy and Commerce, and Carolyn B. Maloney (D-NY), chairwoman of the Committee on Oversight and Reform, that their respective committees would hold their own joint investigation on Aduhelm’s approval and its pricing.
There remain many questions surrounding Aduhelm, including whether its high costs will overwhelm the coffers of the federal Medicare program, which covers the majority of Alzheimer’s patients, and whether drugs designed to tackle amyloid remain viable treatments for Alzheimer’s in the first place. Far from bringing relief to patients and families, it’s now looking more likely to cause major problems for everyone else.