Doctors for America commends the Centers for Medicare and Medicaid Services (CMS) for their proposed national coverage decision regarding “Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease” issued on January 11, 2022.1 Doctors for America (DFA) is an independent organization more than 20,000 physicians and trainees from across the country addressing access to affordable care, community health and prevention, and health justice and equity. DFA focuses solely on what is best for our patients, not on the business side of medicine, and does not accept any funding from pharmaceutical or medical device companies, which uniquely positions DFA as the organization that puts patients over politics and patients over profits. CMS’s proposed national coverage decision is in complete alignment with DFA’s mission and efforts in being centered on patients.
Our members were dismayed when in early June of 2021, the Food and Drug Administration (FDA) approved the Alzheimer’s disease drug, aducanumab despite glaring concerns regarding its efficacy and safety.2 Biogen had conducted two pivotal clinical trials of aducanumab, both of which were halted following administration of the treatment for 18 months due to futility in not demonstrating clinical benefit in trial participants.3,4 Unusually, the FDA and Biogen worked closely together to review the clinical trial data again, finding through a post-hoc analysis a statistically significant, but clinically meaningless change from baseline of progression of Alzheimer’s disease in trial participants.5 The FDA convened its own independent expert advisory committee in November 2020, presenting the trial data and new analyses.6 However, the advisory committee voted nearly unanimously against its approval, citing a lack of evidence of the drug’s clinical benefit.
Oddly, the FDA continued to engage with Biogen behind closed doors to find an alternative pathway for approval – namely, the accelerated approval pathway.7 Under this expedited review pathway, FDA allows manufacturers to receive approval based on a surrogate endpoint thought to be predictive of clinical benefit. In the case of aducanumab, the FDA stated that the basis for such approval would be the reduction of the protein, beta-amyloid seen on MRI imaging and hypothesized to be associated with Alzheimer’s disease.8 However, over two dozen studies have failed to show a relationship between levels of beta-amyloid and progression of Alzheimer’s disease.9 In fact, FDA’s own senior officials had reassured advisory committee members at the November 2020 meeting that they would not be using this protein “as a surrogate for efficacy.”6 Nevertheless, the FDA moved forward to grant accelerated approval for this drug based on this unproven biomarker.
Besides lack of efficacy, serious adverse events were also commonly found among trial participants. In a study in JAMA Neurology following FDA approval, Biogen reported that 41% of trial participants administered the higher dose of aducanumab, which was the dosage ultimately approved by the FDA, were found to have brain swelling or bleeding.10 Sixty-four of these participants had to leave the trial due to these side effects. In late November of last year, it was also reported that a 75-year-old woman enrolled into a clinical trial died, likely due to brain swelling from the drug.11 This is currently being investigated by the FDA and Biogen.
Further adding to the uncertainty of whether this drug is beneficial or safe, the manufacturer failed to enroll participants representative of the patient populations most impacted by Alzheimer’s disease. This includes racial and ethnic minorities including Black and Hispanic patients of which Biogen only enrolled one Black participant and 23 Hispanic trial participants into the treatment arm for the dosage approved by the FDA.12,13 Moreover, it is unclear what the efficacy and safety of the drug would be among Medicare beneficiaries overall. Exclusion criteria for the drug’s key clinical trials made over 90% of Medicare beneficiaries with Alzheimer’s Disease and Related Disorders and 85% of those with Mild Cognitive Impairment ineligible to participate in pivotal studies evaluating the efficacy and safety of the drug.14
Given the significant lack of evidence regarding aducanumab’s safety and continued safety concerns, we applaud CMS’s proposed decision to restrict coverage of this drug and others with similar mechanisms of action under Coverage for Evidence Development (CED). Through this program and CMS’s specific requirements of only allowing coverage through a randomized-controlled trial that aims to determine whether such treatments are truly clinically beneficial and have any safety risks, patients will be protected, both medically and financially. Additionally, this will considerably mitigate any uncertainty for clinicians of whether such treatments should be made available for patients generally. We urge CMS to uphold this comprehensive, patient-centered proposed decision when finalizing their national coverage determination.
Angie Bakke, MBA
Executive Director, Doctors for America
Krishnan Narasimhan, MD
President, Board of Directors, Doctors for America
- Jensen TS, Chin J, Baldwin J, et al. Proposed National Coverage Determination for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease. Published online January 11, 2022. https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&NCAId=305
- Office of the Commissioner. FDA Grants Accelerated Approval for Alzheimer’s Drug. FDA. Published June 7, 2021. Accessed February 7, 2022. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug
- Biogen. 221AD301 A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects With Early Alzheimer’s Disease. clinicaltrials.gov; 2021. Accessed October 24, 2021. https://clinicaltrials.gov/ct2/show/NCT02477800
- Biogen. 221AD302 A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects With Early Alzheimer’s Disease. clinicaltrials.gov; 2021. Accessed October 24, 2021. https://clinicaltrials.gov/ct2/show/NCT02484547
- Andrews JS, Desai U, Kirson NY, Zichlin ML, Ball DE, Matthews BR. Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer’s disease clinical trials. Alzheimers Dement (N Y). 2019;5:354-363. doi:10.1016/j.trci.2019.06.005
- Food and Drug Administration. Peripheral and Center Nervous System Drugs Advisory Committee Meeting. Published online November 6, 2020. Accessed January 29, 2022. https://www.fda.gov/media/145691/download
- Feuerstein A, Herper M, Garde D. Inside ‘Project Onyx’: How Biogen used an FDA back channel to win approval of its polarizing Alzheimer’s drug. STAT News. https://www.statnews.com/2021/06/29/biogen-fda-alzheimers-drug-approval-aduhelm-project-onyx/. Published June 29, 2021. Accessed July 31, 2021.
- Alexander GC, Knopman DS, Emerson SS, et al. Revisiting FDA Approval of Aducanumab. New England Journal of Medicine. 2021;385(9):769-771. doi:10.1056/NEJMp2110468
- Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019;15(2):73-88. doi:10.1038/s41582-018-0116-6
- Salloway S, Chalkias S, Barkhof F, et al. Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease. JAMA Neurology. 2022;79(1):13-21. doi:10.1001/jamaneurol.2021.4161
- Belluck P. Concerns Grow Over Safety of Aduhelm After Death of Patient Who Got the Drug. The New York Times. https://www.nytimes.com/2021/11/22/health/aduhelm-death-safety.html. Published November 22, 2021. Accessed February 7, 2022.
- Manly JJ, Glymour MM. What the Aducanumab Approval Reveals About Alzheimer Disease Research. JAMA Neurology. 2021;78(11):1305-1306. doi:10.1001/jamaneurol.2021.3404
- Center for Drug Evaluation and Research. Clinical Review(s): Aduhelm (aducanumab). Published online June 7, 2021. Accessed August 10, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/761178Orig1s000MedR_Redacted.pdf
14. Anderson TS, Ayanian JZ, Souza J, Landon BE. Representativeness of Participants Eligible to Be Enrolled in Clinical Trials of Aducanumab for Alzheimer Disease Compared With Medicare Beneficiaries With Alzheimer Disease and Mild Cognitive Impairment. JAMA. 2021;326(16):1627-1629. doi:10.1001/jama.2021.15286