Aducanumab May Indicate Erosion of Drug Approval Standards

Health-System Edition, September 2021, Volume 10, Issue 5

The FDA's green light for the Alzheimer medication is worrisome, as clinical trials proved inconclusive.

In my last commentary, I implied that the government, particularly the FDA, has failed to adequately regulate the pharmaceutical industry, which contributes to irresponsible and runaway cost structures.

Shortly after drafting that commentary, the FDA granted approval for aducanumab (Aduhelm) for the treatment of Alzheimer disease (AD),1 suggesting a further erosion of the minimum standards for drug approval related to evidence of efficacy and safety.

To quote a few others:

  • “[T]he aducanumab decision by FDA administrators was probably the worst drug approval decision in recent US history.”—resignation letter written by Aaron Kesselheim, MD, JD, MPH, to FDA Acting Commissioner Janet Woodcock on June 10, 2021, abdicating his position as 1 of 3 scientific members of the FDA Central and Peripheral Nervous System Advisory Committee2
  • “The FDA’s decision to approve aducanumab for anyone with Alzheimer’s disease, regardless of severity, showed a stunning disregard for science, eviscerated the agency’s standards for approving new drugs, and ranks as one of the most irresponsible and egregious decisions in the history of the agency.”—Michael Carome, MD, of Public Citizen’s Health Research Group, in a letter to US Department of Health & Human Services Secretary Xavier Becerra calling for the removal of 3 senior administrators at the FDA3
  • “Given the certainty that harms can occur in patients treated with aducanumab and uncertainty about benefits, we rate the evidence to be insufficient to determine the net health benefit of aducanumab…in patients with [mild cognitive impairment] and mild AD.”—Institute for Clinical and Economic Review (ICER) final evidence report for aducanumab for the treatment of AD4

For those who have not closely followed this story, aducanumab was studied in 2 similar phase 3 clinical trials, EMERGE and ENGAGE, that enrolled patients with mild cognitive impairment due to AD or mild AD dementia who had confirmed brain amyloid by positron emission tomography scan.5 Both trials were stopped early in 2019 because they reached a predefined futility end point relative to the effect on cognitive decline, despite consistent evidence of reduction in amyloid-β plaques in the brain.5

A reanalysis of these data suggests improvement in cognitive decline in the high-dose group in the EMERGE study (NCT02482457), although the clinical relevance is uncertain, but the ENGAGE study (NCT02477800) lacked a similar finding. Several theories have been proposed to explain the differences, but it is safe to say that the evidence of clinical benefit is inconsistent and unreliable.

This uncertainty about clinical benefit must be juxtaposed with the fact that both EMERGE and ENGAGE demonstrated certainty of adverse effects (AEs).5 Approximately one-third of patients developed imaging evidence of localized brain edema and/or hemorrhage.5 Although most patients were asymptomatic, many developed symptoms requiring discontinuing or holding the drug.5 The long-term impact of these changes is unknown.

The FDA advisory committee recommended to not approve the drug for the treatment of AD with a vote of 10 to 1, with the 1 dissenting vote being “uncertain.”6

The FDA moved forward based on a last-minute decision to use the accelerated-approval pathway based on the surrogate end point of the drug’s ability to clear amyloid from the brain.6

The FDA initially approved the drug for patients with AD with no limitations,6 which was mind boggling, given the limitations of the available data regarding those with early stages of the disease. Under a firestorm of criticism, the manufacturer did amend the labeling to limit the indication to those with mild stages of disease, which was approved by the FDA in early July.7

This initially reckless approach to approval by the FDA further brings into question the credibility of this review and approval process. After all, the data did not change between June and July 2021.

Patrizia Cavazzoni, MD, director of the FDA Center for Drug Evaluation and Research, defended this decision on the basis that “the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy,”8 despite the certainty of significant AEs and uncertainty of benefits.

Furthermore, this decision would imply there is broad consensus that reduction of amyloid-β is beneficial in the treatment of AD; however, more than 20 clinical trials of anti–amyloid-β drugs have failed to support that hypothesis.4

The manufacturer (Biogen and Eisai Inc) has announced a drug acquisition cost of $56,000 per year. However, this does not include the cost of administration (an infusion every 4 weeks), diagnostic testing to confirm the presence of amyloid-β plaques, follow-up imaging studies during treatment, and the need for close monitoring for serious AEs.9

To put this in perspective, a JAMA Network paper estimated that if 1 million of the more than 6 million Americans with AD were to receive treatment, the cost to Medicare would be $57 billion per year.10 This is more than the total expenditure on Part B drugs in 2018 and would represent the single highest expense for Medicare.10

ICER estimates that 1.4 million patients meet the definition of early-stage disease.4 The analysis conducted by ICER, assuming a blended outcome analysis of the EMERGE and ENGAGE studies, determined a basecase cost-effectiveness threshold of $2950 to $8360 per year depending on the financial perspective—and this is an optimistic scenario.4 Because most commercial payers are not covering the cost, the Centers for Medicare & Medicaid Services is conducting a national coverage determination analysis expected to take 9 months, and the US Department of Veterans Affairs has decided not to include the drug on its national formulary.11,12 So it appears the payers are more critical of the data than the FDA.

Word limits do not allow me to get into the overall history of the FDA on holding companies accountable for follow-up data for accelerated approval pathway drugs,13,14 but Biogen and Eisai have a 9-year window.

I agree with the opinion of Kesselheim and Jerry Avorn, MD, both professors at Harvard Medical School in Boston, Massaschusetts. In an Op-Ed in the New York Times, they wrote, “The aducanumab decision is the worst example yet of the FDA’s movement away from its high standards.

“As physicians, we know well that Alzheimer’s disease is a terrible condition. But approving a drug that has such poor evidence that it works and causes such worrisome [adverse] effects is not the solution.”15

Hopefully, most major centers will follow the lead of Cleveland Clinic and Mount Sinai Health System and not offer this treatment for their patients until additional evidence of benefits is available.16

Curtis E. Haas, PharmD, FCCP, is the chief pharmacy officer for the University of Rochester health care system in New York.


1. FDA grants accelerated approval for Alzheimer’s drug. FDA. News release. FDA. June 7, 2021. Accessed August 25, 2021.

2. @AKesselheim. Thank you for the support. I’m attaching my resignation letter to help change how FDA solicits and integrates AdComm input. It's gratifying how many of you like me care deeply about the FDA and its intended role in promoting high quality science and therapeutics. More to come... June 10, 2021. Accessed August 25, 2021.

3. Carome MA. RE: the FDA’s reckless decision to approve aducanumab for treating Alzheimer’s disease. Public Citizen. June 16, 2021. Accessed August 25, 2021.

4. Lin GA, Whittington MD, Synnott PG, et al. Aducanumab for Alzheimer’s disease: Effectiveness and Value. Institute for Clinical and Economic Review; August 5, 2021. Accessed August 25, 2021.

5. Aduhelm. Alzforum. Updated August 18, 2021. Accessed August 25, 2021.

6. Belluck P, Robbins. Three F.D.A. advisers resign over agency’s approval of Alzheimer’s drug. New York Times. June 10, 2021. Accessed August 25, 2021.

7. McGinley L. FDA, facing intense criticism, narrows use of Alzheimer’s drug to patients with early-stage disease. Washington Post. July 8, 2021. Accessed August 25, 2021.

8. Cavazzoni P. FDA’s decision to approve new treatment for Alzheimer’s disease. FDA. Updated June 7, 2021. Accessed August 25, 2021.

9. Lovelace B Jr. Biogen faces tough questions over $56-K-a-year price of newly approved Alzheimer’s drug. CNBC. June 8, 2021. Accessed August 25, 2021.

10. Crosson FJ, Covinsky K, Redberg RF. Medicare and the shocking US Food and Drug Administration approval of aducanumab. crisis or opportunity? JAMA Intern Med. Published online July 13, 2021. doi:10.1001/jamainternmed.2021.4610

11. CMS opens national coverage determination analysis on treatment for Alzheimer’s disease. News release. Centers for Medicare & Medicaid Services. July 12, 2021. Accessed August 25, 2021.

12. Kansteiner F. Biogen’s controversial Alzheimer’s med Aduhelm turned away by VA on efficacy and safety worries. Fierce Pharma. August 11, 2021. Accessed August 25, 2021.

13. Mahase E. FDA allows drugs without proven clinical benefit to languish for years on accelerated pathway. BMJ. 2021;374:n1898. doi:10.1136/bmj.n1898

14. Kaltenboeck A, Mehlman A, Pearson SD. Strengthening the Accelerated Approval Pathway: an Analysis of Potential Policy Reforms and Their Impact on Uncertainty, Access, Innovation, and Costs. Institute for Clinical and Economic Review; April 26, 2021. Accessed August 25, 2021.

15. Kesselheim AS, Avorn J. The FDA has reached a new low. New York Times. June 15, 2021. Accessed August 25, 2021.

16. . Belluck P. Cleveland Clinic and Mount Sinai won’t administer Aduhelm to patients. New York Times. July 14, 2021. Accessed August 25, 2021.