The recent wave of Alzheimer’s Disease (AD) drug approvals and promising pivotal trial data from various drug manufacturers has been celebrated by physicians, patients, caregivers, and advocacy groups across the U.S. The scientific breakthroughs that led to these new therapies came after decades of research in AD and studies of more than 200 drug candidates. After significant time and resources have been dedicated to AD research, hope of slowing disease progression is, at long last, within our grasp.
In a July 17 statement, Maria C. Carrillo, PhD, Chief Science Officer of the Alzheimer’s Association, called the benefits of slowing disease progression “real and meaningful, giving people more time to participate in daily life, remain independent, and make future healthcare decisions.”1 And at a House Energy and Commerce Health Subcommittee meeting the same month, Alzheimer’s advocate Sue Wronsky, whose mother was diagnosed with AD, testified, “The idea that these individuals can take a medication that can possibly help slow this disease, even for just a few months, is enormous.”2
Yet the largest payer in the U.S. has seemingly taken a different point of view.
Drug Approval ≠ CMS Coverage
In April 2022, in advance of FDA approval of then-investigational monoclonal antibodies directed against amyloid treatments for AD, the Center for Medicare and Medicaid Services (CMS) issued a National Coverage Determination (NCD) related to all such amyloid treatments.3 NCDs are regulations that outline the conditions under which a medical service, procedure, medication, or device is covered or not; NCDs apply to all Medicare providers under the Medicare system.4 In this instance, one primary driver of CMS’ decision was the question of whether or not amyloid reduction, a surrogate marker, meaningfully improved cognitive outcomes.
The NCD for amyloid treatments for AD is unique in that AD is one of few conditions in which the patient population is made up of almost exclusively those age 65 and older, meaning that CMS (Medicare) would be the primary payer for these medications, with commercial health plans being significantly less impacted by the drugs’ approval.
The CMS coverage criteria for Alzheimer’s amyloid treatments can be summarized as follows:3
- When used in a randomized, controlled trial conducted under an investigational new drug (IND) application.
- When used in CMS-approved prospective comparative studies, the data for which may be collected in a registry. (Additional criteria relating to the diversity of the trial population, description of instruments used for assessment of cognition and function, and other specifics apply here.)
- When the treatments are furnished according to the FDA-approved indication in National Institutes of Health (NIH)-supported trials.
Many patients and advocacy organizations have expressed concern over these criteria, noting that limiting Medicare coverage of these drugs to only when used as part of clinical or prospective trials severely limits patient access, ensuring that the huge unmet need in the Alzheimer’s community will remain unmet.
Where Do We Go from Here?
It’s important for drug manufacturers to take a step back and view this CMS decision as a learning opportunity. The reality is that when unprecedented situations arise in healthcare, how those moments are handled by regulators, payers, and policymakers sets the precedent for what to expect going forward. It’s therefore not unrealistic to assume that CMS may issue similar NCDs for entire classes of medications that aim to treat such large populations in the future—in therapeutic areas beyond AD.
Some circumstances in which an NCD is possible include trials that involve surrogate endpoints, or those in which endpoints are not easily interpreted, are variable, or are subjective (such as cognitive scales)—or in disease states in which clinical meaningfulness is not clearly established or those that have a sizable target patient population.
With that in mind, here are some key learnings that may help drug manufacturers anticipate, avoid, and/or earn reconsiderations of such NCDs in the future:
1) Plan ahead and avoid assumptions: Don’t assume that FDA approval, even in a category with significant unmet need, equates to CMS coverage. Drug manufacturers should begin thinking about the possibility of an NCD and consider ways to protect against it from beginning to end—in trial design, inclusion/exclusion criteria, recruitment/enrollment, and pricing. If an NCD is possible, it may be worthwhile to create a team (and partner with external experts) that will be responsible for navigating this process and communicating with CMS. This team should include experts in policy, health outcomes, trial design, and enrollment, as well as scientists and clinicians.
2) Ensure diverse, representative study populations: The FDA has increased its focus on ensuring enrollment of more participants from underrepresented racial and ethnic populations. If that’s not reason enough to prioritize diversity, consider that CMS looks for not only racial and ethnic inclusion, but also for study populations that are fully representative of the Medicare population, especially in therapeutic areas in which a large portion of patients are Medicare/Medicaid recipients. Creative or novel recruitment strategies may therefore be necessary.
3) Ensure clinical trial data are robust: CMS looks for strong, relevant scientific data as they evaluate treatment options. To reduce likelihood of an NCD (or help earn a reconsideration decision for one already in place), data should clearly demonstrate improved outcomes not only in the overall population, but in relevant subgroups as well. It’s important to strategically plan subgroup analyses, as inability to demonstrate a positive impact across the board could lead to restrictions.
4) Clearly identify your target population: One of the factors that may be part of CMS’ coverage decision is the size of the potential market and the subsequent total cost for CMS. Critically analyze your clinical trial inclusion/exclusion criteria and any subgroups where your drug performed especially well, or underperformed. If novel diagnostic tools were used to identify patients, this may be a limiting factor in real-world practice. Be realistic—a minority of patients may be eligible for your therapy. An important factor in the NCD for amyloid treatments for AD was the inaccurate assumption that a large majority of people with AD would be eligible for treatment, which would lead to an overwhelming/unsustainable budget impact on CMS.
5) Prioritize proactive communications: The best way to avoid an unexpected NCD is to maintain open lines of communication with CMS. In recent years, CMS has been open to meeting with manufacturers in certain circumstances and has demonstrated that they value clinical data and other information. Manufacturers should understand what types of data CMS is looking for and be able to supply those data quickly.
Keep the Focus on Patients
Innovation in healthcare is a marathon, not a sprint. We’ve seen treatments, procedures, and technologies evolve over time to help patients with many conditions—from heart transplants to chemotherapy drugs to personalized cell and gene therapies. Progress is not perfection. Progress is incremental. To maintain this progress, drug manufacturers must continue to pursue innovation because they are in the business of helping patients lead healthier lives.
References:
1. Alzheimer’s Association. “Alzheimer’s Association statement on donanemab phase 3 data reported at AAIC 2023.” https://aaic.alz.org/releases_2023/donanemab-phase-3.asp. Accessed August 10, 2023.
2. Alzheimer’s Association. “Alzheimer’s advocate testifies on access to innovative Alzheimer’s treatments.” https://www.alz.org/news/2023/testify-congress-cms-innovative-treatments. Accessed August 10, 2023.
3. Centers for Medicare and Medicaid Services. “Monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease.” https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=N&ncaid=305. Accessed August 10, 2023.
4. Blaser R, Singer D, Schmidt RJ, “Nephrologist leadership in advocacy and public policy.” Adv Chronic Kidney Dis. 2018. 25(6): 505-513. https://doi.org/10.1053/j.ackd.2018.08.020.
