Alzheimer’s disease affects millions. We need effective therapies.
Over decades, the US Food and Drug Agency (FDA) earned a worldwide reputation as a competent and trusted regulator, establishing standards for drug development and approval that have been mirrored worldwide. Through its efforts, drug safety catastrophes have been averted. It has been criticized, however, for not doing enough to prevent other catastrophes.
Regulatory capture is a term used to describe the behaviour of a regulator, created to work for the public interest, when begins to take positions or make decisions that favour that industry it is regulating – over those of the public. In 2021, the FDA approved a new Alzheimer’s disease drug, Aduhelm, despite negative clinical trial evidence and over the advice of its own advisory committee. This approval prompted questions about the FDA’s decision-making process, and Steven Novella and I both blogged about the approval (and its consequences) at the time. There were also questions about how the manufacturer, Biogen, could justify charging such a high cost for the drug (initial list price was USD$56,000 per year) given its benefits had yet to be proven. That same year, the House Committee on Oversight and Reform launched an investigation. The report was published in December 2022 and is worth a closer look to get some insight into the workings of the FDA and Biogen, and the process that led to this drug’s surprising approval.
The Approval of Aduhelm
I’ll refer the curious reader to past posts about Alzheimer’s disease and this drug, but the background is worth summarizing in brief.
Alzheimer’s disease (AD) is a neurological disease that is the most common cause of dementia. AD is common, and affects an estimated 6 million Americans, with that prevalence expected to increase based on population trends. How AD develops is not known, but it produces changes in the brain that are destructive, progressive, and irreversible. A common feature of AD is the accumulation of protein called “beta amyloid” in the form of plaques that are thought to interfere with signalling and eventually cause cell death. Decades of research and billions of dollars have been invested in developing and testing treatments against beta amyloid after trials in mice showed promising results. No treatments had shown benefit (slowing of disease progression) in phase 3 clinical trials until the lecanemab results were published in late 2022.
Biogen, a pharmaceutical company, has been studying aducanumab, an antibody which targets beta amyloid, for years. Two large Phase 3 clinical trials were established to evaluate the efficacy of the drug in patients with mild AD. These were 18 month trials that measured the effect of aducanumab in early AD. In March 2019 both trials were discontinued after an independent data safety monitoring board concluded that the trials were unlikely to meet their primary endpoint. That is, in the language of clinical trials, they were discontinued “for futility”. Given no drug with a similar mechanism of action had so far been shown to be successful, this was not surprising. Moreover, the drug was not free of harms. It can cause swelling of the brain called amyloid-related imaging abnormalities (ARIA), common to this category of drugs, which can cause symptoms like headache.
In analyses done after the trials were stopped (i.e., a “post-hoc” analysis), the manufacturer claimed the drug was in fact effective, and it filed for approval with the FDA. Aducanumab was reviewed in November 2020 at an FDA advisory committee meeting. (The briefing documents are here.) Among those documents included endorsements from FDA staff members supporting the manufacturer’s contention that the drug is effective. The report also contained comments from other FDA staff members criticizing the efficacy statements and the manufacturer’s reliance on post-hoc analyses, which were (understandably) described as biased. Ultimately the panel votes on the evidence were strongly negative. While the FDA is not required to follow its advisory committee recommendations, these recommendations are typically important. On June 8, 2021 the FDA granted accelerated approval for aducanumab, now branded Aduhelm, while requiring Biogen to do a confirmatory clinical trial over the next nine years. Surprisingly, it did not even limit approval to patients similar to those in the clinical trial, who had mild disease and confirmed amyloid plaques. Instead, it put no restrictions on its use.
Congressional Scrutiny
In June 2021 the House Committee on Oversight and Reform announced it would investigate Aduhelm’s FDA approval and its pricing. They pointed to the broad approval labeling and the decision to approve based on a surrogate endpoint. Following an 18 month investigation, in December 2022, the final report was released. Some of the findings it highlighted included:
FDA interactions with Biogen were “atypical” and failed to follows its own documentation protocol: Beginning in July 2019 there were over 115 meetings/calls/email exchanges between the FDA and Biogen including 40 “working group” meetings, with not all properly documented based on the FDA’s procedures. While this sounds atypical, there is no real way of knowing how different this is from the FDA’s interactions with other companies. Regardless, it failed to follow its own processes, leading to documentation gaps.
The FDA and Biogen collaborated on a joint briefing document for the FDA’s advisory committee that didn’t adequately represent differing views within the FDA: A joint briefing document was used and the FDA and Biogen even shared wording between the two organizations. The FDA’s own internal review (see page 16+ here), previously unpublished, had concluded that a joint briefing document was inappropriate, given the disagreements between the different FDA offices in terms of what the data meant. It should be noted that there were dissenting opinions presented in the briefing documents (e.g., start reading here at page 247), but how this is atypical is less clear. The internal review documents noted that joint briefing documents are not new, and have been positively received by the FDA’s advisory committees.
The FDA pivoted to the Accelerated Approval timeline: The drug was being considered under the “traditional” pathway for approval but the FDA changed it to the “accelerated” pathway which would allow for the use of surrogate data (i.e., the lack of actual patient-relevant endpoints). Why this approval was granted is not fully explained or justified.
The FDA approved a “broad label” despite the lack of clinical data – and Biogen’s own reservations. The FDA approved the drug in a population that was broader than the population studied in its clinical trials. Biogen accepted this label despite their own internal reservations (pg 57+) about the lack of evidence. Biogen subsequently sought a label update, narrowing the recommended patient population, but only after patient/provider confusion and public criticism.
Biogen’s price was intended to “Make History” for the company: Not surprisingly, Biogen viewed this as a significant financial opportunity, and they planned to “Establish Aduhelm as one of the top pharmaceutical launches of all time”. This is not surprising, although it is rare that internal documents are made public – like these one have been.
Biogen anticipated the high cumulative public cost of Aduhelm: With government programs covering an expected 90% of the patient population, Biogen forecast that Aduhelm could cost $12 billion in one year, representing 36% of the Medicare 2018 Part B budget.
Biogen planned a multi-billion marketing campaign, spending more on marketing than the total development cost of the drug: Biogen anticipated spending $3.3 billion on sales and marketing between 2020 and 2024, “more than two and a half times what Biogen spent in total development costs for aducanumab from 2007 until approval in June 2021”. An ongoing criticism of the pharmaceutical industry is that more is spent on marketing than research and development.
Lessons Learned?
The Aduhelm approval was perhaps inadvertently beneficial to drug regulation, in that it was at such odds with the evidence that it led to widespread criticism and public scrutiny of the FDA and its work.
Uptake of Aduhelm, given the controversy and persistent questions about efficacy, has been slow. Many private insurers have refused to cover the drug. The Centers for Medicare & Medicaid Services announced it would only fund the drug when patients take part in a clinical trial.The European Medicines Agency rejected the drug outright. In December 2021, the manufacturer lowered the annual cost of the drug to $28,200. In February 2022, Biogen’s financial statements revealed only $3 million in revenue for all of 2021, a trend that appears to have persisted through 2022. On a positive note, Biogen is doing the clinical trial that the FDA mandated as part of its approval.
Alzheimer’s is a devastating disease and we desperately need good therapies. As I noted back in 2021, a drug that meaningfully affects the course of Alzheimer’s disease justifiably should be a multi-billion dollar drug. Without good evidence that is rigorously assessed in an unbiased manner, we will not be able to determine if aducanumab, or any other potential therapy provides benefit in Alzheimer’s disease. While FDA drug approval has traditionally been seen as a worldwide gold-standard, they did serious damage to their own reputation with the Aduhelm approval. I hope that this investigation and its findings will drive the FDA to ensure its work is consistent with its mission to advance and protect public health.