FDA’s surprise decision this week to approve Biogen’s treatment for Alzheimer’s Disease has raised serious questions about the validity and value of the agency’s accelerated approval process. The agency approved Aduhelm (aducanumab) based on data from one clinical trial that shows some effect on reducing amyloid beta plaques in patients with mild cognitive impairment.1 Unlike most surrogate markers supporting early approval, that effect has not been linked to clinical benefit, challenging its validity for anticipating patient gains.
The broad labeling approved for the new drug, moreover, has generated heated debate among scientists, researchers, patients and payers as to the long-term impact of the approval decision on the credibility and independence of FDA decisions. Coming in the wake of an assessment of several cancer therapies that gained accelerated approval but failed to document long-term benefit, the decision has raised questions about approving new drugs and biologics based on preliminary evidence of possible benefit that awaits later confirmation. FDA emergency use authorizations (EUAs) for some questionable and harmful anti-COVID-19 treatments already have eroded public confidence in the scientific and medical validity of some agency actions, and many research leaders fear this recent decision will heighten those concerns.
The very high price tag set by Biogen also is heightening the debate over pharmaceutical costs, reimbursement and prescribing. In setting a price of $56,000 a year, way above the cost-effective threshold of $2500 to $8000 calculated by the Institute for Clinical and Economic Review (ICER), Biogen stands to earn some $17 billion a year from the drug, according to Wall Street analysts, particularly with a label that opens prescribing to both early and severely debilitated Alzheimer’s patients. All eyes are on how Medicare and health and drug plans will set coverage parameters and how doctors and medical authorities will identify those individuals most suitable for treatment. ICER will further examine the drug’s appropriate use and insurance coverage at a meeting on July 15, 2021.2,3 Biogen says it has begun to negotiate value-based contracts with major payers such as Cigna and CVS Health to support access to the drug. But just how the parties will link payment to treatment outcomes remains to be seen.
FDA’s accelerated approval process was launched in the 1980s to provide early access to treatment for dying AIDS patients with no available treatment. Since then, it has been utilized to speed approvals of new therapies, primarily for AIDS and cancer where validated surrogate markers have provided evidence that a drug has potential for curbing disease.4 Many accelerated approval products have been able document continued benefit from post-approval studies, building support among industry sponsors and patient advocates for the process. Some consumer groups and health care providers, though, complain of long delays in confirming benefit and have questioned the often high cost of paying for unproven treatments.
Last April (2021), FDA held an unusual three-day meeting of its Oncologic Drugs Advisory Committee to evaluate supplemental indications for several leading cancer therapies where confirmatory trials provided only limited evidence of ongoing clinical benefit.5 Although FDA revoked the added indication for only one product, it continues to examine these therapies and to struggle with the difficulties in conducting post-approval trials. Biogen is not expected to provide confirmatory data from a post-approval study for years, if not decades, further undermining the accelerated approval paradigm.
It remains to be seen whether the flexibility applied by FDA reviewers to the new Alzheimer’s drug reflects a broader, less rigorous approach to approving treatments for devastating conditions with urgent need of treatment. The significance of FDA’s action is apparent in a personal message from Patrizia Cavazzoni, director of the Center for Drug Evaluation and Research (CDER). She notes that CDER reviewers carefully vetted highly complex data to reach its conclusion that the surrogate endpoint is “reasonably likely” to predict clinical benefit.6 Cavazzoni acknowledges “residual uncertainties” about the drug and its potential for reducing clinical decline from Alzheimer’s disease, but critics maintain that this and earlier studies show no link between reducing amyloids in the brain and improved health. In basing its approval on “potential benefit,” as opposed to clear clinical benefit, FDA has angered and confused both its critics and advocates.
Some industry analysts predict that this more flexible approval standard will drive a surge in R&D for additional Alzheimer’s drugs as well as other experimental treatments for rare and lethal diseases. Several leading pharma companies are testing new Alzheimer’s treatments that also aim to reduce amyloid in the brain or to clear other invasive substances. But many scientists fear that approvals based on limited evidence of clinical benefit may generate confusion and uncertainty that only deters investment in R&D.
One outcome, though, is that FDA analysts and pundits no longer will assume that agency reviewers will follow the recommendations of its advisory committees, as usually is the case. The advisory committee that assessed the Biogen drug last November voted almost unanimously against approval based on the limited evidence of effectiveness, but FDA reached its own conclusion.