February 10, 2022
The National Center for Health Research (NCHR) appreciates the opportunity to provide public comments on the National Coverage Analysis Proposed Decision Memo from the Centers for Medicare and Medicaid Services (CMS). This decision relates to monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease.
As a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, we have a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. Our aim is to ensure that patients and consumers are equipped with information that can help them chose treatments that are proven safe and effective. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.
The Food and Drug Administration (FDA) approval of Aduhelm (aducanumab), a member of this drug class, has generated enormous controversy. The manufacturer, Biogen, submitted clinical trial data that did not meet FDA standards of safety and efficacy. One randomized clinical trial indicated a small benefit that was not clinically significant and the other indicated that the placebo patients did somewhat better. In addition to a lack of efficacy, brain swelling and brain bleeds were experienced by 41% of patients, as well as nausea, headaches, dizziness, confusion, and an altered mental state. Unfortunately, FDA ignored the advice of their Advisory Committee and instead approved Aduhelm on the basis of a biomarker that has not been shown to not be associated with significant improvement in terms of memory or cognition.1
We strongly support the CMS proposed decision to limit the coverage of this class of drugs while requiring additional clinical trials to ensure safety and effectiveness for the Medicare population. This compromise strategy will help ensure that patients and family members can make decisions based on unbiased information demonstrating the known risks and the lack of certainty about any benefit.
Approximately 1 million American’s are diagnosed with Alzheimer’s disease each year,2 which has been found to be more prevalent among older Black and Hispanic communities.3 And yet, less than 4% of the patients in the Aduhelm clinical trials were Black or Hispanic, making it impossible to determine safety of efficacy for those populations. The proposed decision memo takes important steps to protect vulnerable Americans by requiring diversity in the clinical trials.
In addition to excluding patients who were over the age of 85, the Aduhelm trials also excluded individuals with many prevalent chronic conditions such as heart disease, blood clots, kidney disease, impaired liver function, and individuals taking blood thinners. Overall, 85% of Medicare beneficiaries with mild cognitive impairment were not represented in the Aduhelm clinical trials conducted by Biogen.4 The new clinical trials should include as many of these co-morbidities as can be done safely.
NCHR recommends the following as CMS finalizes the coverage decision for this class of drugs and develops the clinical trial guidance:
- The clinical trial guidance must articulate how CMS will enforce their requirements for diversity.
Criticisms of the CMS decision have focused on limiting access of Aduhelm to people of color. These criticisms ignore the fact that Aduhelm was not adequately tested on people of color, so that neither safety nor efficacy has been established in any of the Biogen studies. It also ignores the fact that people of color tend to seek treatment for Alzheimer’s disease at a later stage than Whites, thus making it less likely that they would seek treatment for the mild cognitive impairment for which Aduhelm is approved.3
While numerous racial and ethnic groups have been underrepresented in clinical trials for Alzheimer’s disease, CMS’s proposal explicitly addressed that problem.5 The proposed decision memo mandates that CMS-funded clinical trials must include patients that are representative of the national population diagnosed with Alzheimer’s disease. We would suggest a slight revision: Rather than being concerned about the percentage of patients in specific racial and ethnic groups, we propose that CMS include sufficient numbers of patients in different racial, ethnic, and age groups to ensure that there is enough statistical power for subgroup analyses to determine safety and efficacy for each of the major demographic groups. Equally important, CMS should specify how they will ensure that the study participants represent the co-morbidities of typical Alzheimer’s patients, while ensuring that patients at high risk of harm are not included in the trial. Because CMS plans to restrict clinical trials to the best possible treatment centers, they can help ensure the diversity that is needed.
CMS should specify how clinical trial recruitment will overcome barriers such as mistrust, lack of clinical trial awareness, lack of transportation and access to the clinical trial sites, and lack of comfort with the clinical trial process.6 Principal Investigators and physicians who have already built trust by serving diverse populations will be key.
- CMS guidelines must establish a strict monitoring strategy to track and limit adverse effects.
There are significant safety concerns associated with Aduhelm. In the original clinical trials 41% of patients experienced brain swelling or brain bleeds.7 Other side effects included headaches, nausea, dizziness, confusion, and an altered mental state. It is critical that there are adequate data monitoring guidelines in the final CMS coverage decision to help protect clinical trial participants, including easy, free access to brain scans and other necessary safeguards.
- Drug manufacturers should share the cost burden of future CMS clinical trials for this drug class.
The financial burden of these clinical trials studies should not be paid entirely by the American taxpayer through Medicare. The cost of Aduhelm at $28,000/patient/year is far too expensive for an unproven drug in or outside of a clinical trial, and Aduhelm requires numerous brain scans that would be very costly for patients and for Medicare. Biogen should reduce the cost of Aduhelm in the trials and share the costs of brain scans and administrative fees. CMS must ensure transparency in all costs to the public and patients.
- CMS must uphold this decision with future monoclonal antibody drugs in development that are targeting amyloid.
Several companies decided to submit applications to FDA for similar drugs as soon as Aduhelm was approved. They followed the misguided precedent of defining efficacy as amyloid plaque reduction rather than clinically meaningful benefits to memory and cognition. CMS must uphold this coverage decision so that it applies to all Alzheimer’s treatment drugs pending results from clinical trials.
NCHR strongly supports CMS’s effort to make the best of the bad situation that was created when the FDA ignored the advice of its own independent scientific advisors and instead approved Aduhelm. Rather than have Medicare pay for patients to risk their lives by providing coverage for an unproven drug with clear risks, CMS’s proposed plan would safeguard many Alzheimer’s patients while at the same time protecting the Medicare program from financial ruin. Given the lack of scientific evidence that the benefits of Aduhelm outweigh the risks for most Medicare patients, well-designed clinical trials that ensure patients’ access to brain scans are urgently needed. These trials will eventually make it possible for patients to make an informed decision for their own health and for loved ones. The inclusion of diverse populations, initially excluded from clinical trials of Aduhelm, will ensure safety and efficacy data is representative of all groups with access to drugs within this class.
We appreciate the opportunity to provide insight into this decision and strongly encourage CMS to consider our recommendations aimed to protect the public health.
- Zuckerman, D.M., Jury, N.J., Silcox, C.E. (2015) 21st Century Cures Act and similar policy efforts: at what cost? BMJ ;351:h6122 doi: 10.1136/bmj.h6122
- Rajan, K.B., Weuve J., Barnes, L.L., Wilson, R.S., & Evans, D.A. (2019) Prevalence and incidence of clinically diagnosed Alzheimer’s disease dementia from 1994 to 2012 in a population study. Alzheimer’s Dement;15(1):1-7.
- Lines, L.M., Sherif, N.A., & Wiener, J.M. (2014) Racial and ethnic disparities among individuals with Alzheimer’s disease in the United States: A literature review.
- Anderson, T.S., Ayanian, J.Z., Souza, J., Landon, B.E. (2021) 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;326(16):1627–1629. doi:10.1001/jama.2021.15286
- Indorewalla, K.K. et al. (2021) ‘Modifiable Barriers for Recruitment and Retention of Older Adults Participants from Underrepresented Minorities in Alzheimer’s Disease Research’: 927 – 940.
- Clark, L.T., Watkins, L., Piña, I.L., Elmer, M., Akinboboye, O., Gorham, M., Jamerson, B., McCullough, C., Pierre, C., Polis, A.B., Puckrein, G., (2019) Increasing diversity in clinical trials: overcoming critical barriers. Current Problems in Cardiology;44(5):148-72.
- Salloway, S., Chalkias, S., Barkhof, F., et al. (2021) Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease. JAMA Neurol ;79(1):13–21. doi:10.1001/jamaneurol.2021.4161