Loyola University Chicago School of Law, JD 2023
As my colleague at Inside Compliance discussed here in September, the FDA approved Aducanumab for the treatment of Alzheimer’s Disease on June 7, 2021. Aducanumab, marketed as Aduhelm, is intended to reduce beta-amyloid levels. This compound is responsible for forming a “plaque” which inhibits neuron function and eventually triggers neuronal apoptosis (death of neurons). Now, a recent decision by CMS on insurance reimbursement for aducanumab has increased the compliance responsibilities of providers.
FDA approval and surrogate endpoints
In recognition of aducanumab’s potential to treat the approximately 6.2 million American’s living with Alzheimer’s Disease (AD) the FDA reviewed aducanumab through its Accelerated Approval Program. The Accelerated Approval Program uses a “surrogate endpoint” in lieu of confirmatory trials, where a surrogate endpoint is some biological or clinical marker correlated to disease pathology. Since increased levels of beta-amyloid are correlated with AD pathology and are present in later stages of AD, reduced levels of beta-amyloid were able serve a surrogate endpoint in the accelerated approval of Aducanumab. However, as the FDA provides, a surrogate endpoint is not the same as proving a drug is safe, effective, and potent. In turn, after receiving accelerated approval, a drug must undergo additional trials known as phase 4 confirmatory trials which validate the surrogate endpoint and confirm the drug offers patients a clinical benefit. As part of the accelerated approval process, the FDA is requiring Biogen, aducanumab’s manufacturer, to conduct a post-approval clinical trial to confirm the anticipated clinical benefit of aducanumab.
CMS’s Decision on Aducanumab
On January 11, 2022 the Centers for Medicare and Medicaid Services (CMS) released its coverage decision on aducanumab. CMS’s decision to offer Coverage with Evidence Development (CED) means a patient must be in a CMS approved trial in order to receive insurance reimbursement. Additionally, CMS mandates that all trials be conducted in a hospital-based outpatient setting, which may present barriers to access for patients who cannot access hospital based services due to financial or travel related needs. CMS’s CED decision in turn imposes a clinical compliance requirement on providers, where providers must ensure a patient is properly enrolled in a CMS approved trial in order to prescribe aducanumab with subsequent reimbursement. The National Institute on Aging (NIA) also released a statement regarding CMS’s decision on January 11, 2022 which reiterated the role of beta-amyloid in AD, FDA approval, and CMS’s CED decision.
The Alzheimer’s Association’s statement on Aducanumab
The Alzheimer’s Association, a leading organization dedicated to supporting patients, providers, and caregivers, released a formal statement on CMS’s decision by Alzheimer’s Association CEO Harry Johns. While further evidence of aducanumab’s clinical benefit is both anticipated and required by the FDA, the Alzheimer’s Association raises a compelling point, that “access to treatment would not only be available to a privileged few, those with access to research institutions, exacerbating and creating further health inequities.” The Association’s reference to access to research institutions connects to CMS requiring patients to be enrolled in a trial conducted in a hospital-based outpatient setting. Access to this may be challenging for patients in advanced disease stages who are unable to travel and enroll and who would otherwise stand to benefit from aducanumab. The Alzheimer’s Association points out that despite CMS citing to the Alzheimer’s Association 2021 Alzheimer’s Disease Facts and Figures report covering barriers faced by underrepresented communities when attempting to enroll in clinical trials, the CED requirement imposes an additional barrier to access.
The Alzheimer’s Association’s position on CMS’s CED requirement for aducanumab may also be motivated by the infrequent use of CED requirements for coverage, as described by Dr. Caleb Alexander, co-director of the Center for Drug Safety and Effectiveness at Johns Hopkins Medicine. Regarding CED, Dr. Alexander states “I’m not aware that they’ve [CMS] ever required coverage with evidence development for a prescription drug before.” Turning to the need for validation of the clinical benefit suggested by the surrogated endpoint of beta-amyloid reduction, Dr. Alexander noted “to some degree, their hand [CMS] is forced by the absence of evidence whether or not this product even works.”
What Steps Ought Providers and Patients Take?
Due to CMS’s decision and the trend of hospitals and universities to decline prescribing aducanumab, patients and providers should consider what steps will best align with compliance requirements and treatment goals. To ensure compliance with CMS’s coverage decision, providers must prescribe only if the patient is enrolled in a CMS approved trial. Additionally, patients and providers might choose to advocate for CMS allowing expanded enrollment where CMS will offer reimbursement for patients receiving treatment who are not enrolled in a CMS approved trial. Data from patients who are prescribed aducanumab could in turn be reported to the FDA, NIA, and CMS to support the phase 4 confirmatory trials required by the FDA. With more robust data, the clinical benefit of aducanumab can be validated or rejected, allowing patients easier access to this drug should it prove to offer the clinical benefit anticipated.