Health Letter, July 2021
By Michael Carome, M.D.
If you’re not outraged,
you’re not paying attention!
Read what Public Citizen has to say about the biggest blunders and outrageous offenses in the world of public health, published monthly in Health Letter.
In one of the worst decisions in its history, the Food and Drug Administration (FDA) on June 7 approved drugmaker Biogen’s monoclonal-antibody drug aducanumab (ADUHELM) for the treatment of Alzheimer’s disease. The FDA took this action despite the nearly unanimous conclusion of an independent panel of experts convened by the agency in November 2020 — and of many other scientists, neurologists and geriatric specialists — that there was inadequate evidence that the drug is effective for slowing cognitive decline in patients with Alzheimer’s disease.
After aducanumab’s two identical phase 3 trials were stopped early because a preliminary analysis found that they were unlikely to show the drug benefitted Alzheimer’s disease patients, the FDA and Biogen worked collaboratively to salvage the drug. They jointly relied on dubious analyses that overemphasized the results of one phase 3 trial suggesting the drug at a high dose may provide minimal benefit on one measure of cognitive function but disregarded data from the other phase 3 trial showing no benefit of the drug at any dose. For the meeting of the FDA’s independent panel of experts, the agency and Biogen co-authored an unprecedented joint briefing document on aducanumab that was heavily biased in favor of the drug.
In December 2020, Public Citizen called for an investigation into the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analysis of data from the key clinical trials of the drug. This close collaboration before and after the submission of the company’s marketing application for aducanumab dangerously compromised the integrity of the FDA’s review.
Using its accelerated approval pathway, the FDA ultimately based its approval on findings that aducanumab reduced amyloid plaques (deposits) in the brains of Alzheimer’s disease patients — a so-called surrogate endpoint. The agency claimed that “it is expected that the reduction in amyloid plaque will result in a reduction in clinical decline.” However, other experimental drugs for Alzheimer’s disease that reduced amyloid plaques in the brain of Alzheimer’s disease patients failed to provide clinical benefits. And even in the two phase 3 trials of aducanumab, there was little correlation between the reduction in amyloid plaques in the brain and the decline in cognitive function.
Moreover, FDA officials had told the panel of independent experts convened in November 2020 to assess whether the drug works that the agency was not considering approving the drug based on the surrogate endpoint of reduced amyloid plaques in the brain. But seven month later, the agency did exactly that without reconvening these experts to seek their advice on such action.
Finally, the safety and effectiveness of aducanumab were evaluated only in subjects with mild Alzheimer’s disease, yet the FDA inexcusably approved the drug “for the treatment of Alzheimer’s disease,” meaning Biogen can market the drug for use in any patient with Alzheimer’s disease regardless of disease severity, despite the complete absence of any evidence that the drug is safe and effective for patients with moderate or severe Alzheimer’s disease. Such an action by the agency was not evidence-based and defied reason given that patients with moderate or severe Alzheimer’s disease plausibly could be more susceptible to the adverse brain effects caused by the drug than patients with mild Alzheimer’s disease.
The FDA’s decision showed a stunning disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
Furthermore, approving aducanumab despite the lack of evidence of effectiveness has raised false hope for millions of Alzheimer’s disease patients and their families and will potentially bankrupt the Medicare program because of the drug’s exorbitant price — $56,000 per year — and impede for years the development of other experimental treatments for the disease.
Under the leadership of Dr. Janet Woodcock over the past three decades, the relationship between the FDA’s Center for Drug Evaluation and Research and the pharmaceutical industry has grown ever cozier — resulting in regulatory capture of the agency by the industry — and the agency’s standards for approving new drugs have gradually eroded. The approval of aducanumab sets the bar for ensuring the safety and effectiveness of new drugs at a dangerous new low, not just for future Alzheimer’s disease drugs but also for future drugs for a wide array of other diseases. The FDA no longer is the world’s gold standard for drug approval and safety.
New leadership of the FDA and CDER is a prerequisite for restoring the agency’s credibility and reversing the slide in the agency’s standards for ensuring the safety and effectiveness of new drugs. Therefore, Acting FDA Commissioner Woodcock and other senior agency leaders responsible for the approval of aducanumab must go.