Alzheimer’s Disease Monoclonal Antibodies with Traditional Approval: Clarifying the Pathway for Medicare Postmarket Evidence Development and Use

With at least two Alzheimer’s disease (AD) amyloid-targeting monoclonal antibodies (mAbs) treatments potentially reaching traditional approval by the Food and Drug Administration, questions remain about how best to generate additional evidence about the effects of these treatments on Medicare recipients to ensure:

1. these treatments are safe and appropriate for real-world use by Medicare beneficiaries and
2. the best ways to advance such evidence development in the context of Medicare’s 2022 National Coverage Determination (NCD).

This Duke-Margolis report explores options to generate evidence for AD mAbs treatments—efficiently and in the least burdensome way—to answer key questions that may remain after traditional FDA approval is received.

Under the NCD, the Centers for Medicare & Medicaid (CMS) will cover mAbs treatments that have received FDA approval under coverage with evidence development (CED) provisions. But the extent of the post-market evidence requirements for this coverage, and the infrastructure available to support evidence development, is unclear. This uncertainty adds urgency to questions about what steps can be taken now to enable evidence development, while supporting appropriate access to these products under Medicare’s coverage standards.

This Duke-Margolis paper outlines three policy options for CMS coverage and ongoing evidence development, while providing appropriate evidence-based access to AD mAbs treatments after traditional FDA approval:

1. eliminate CED for a fully-approved drug that meets “reasonable and necessary” standards for some Medicare populations, but impose coverage requirements and restrictions where the standard is not yet met, while evidence develops outside of CED;
2. implement CED using a limited registry that includes all Medicare beneficiaries eligible for AD mAbs treatments but requires relatively few data elements that are feasible to collect reliably; or
3. implement CED through a differential data collection structure, with limited requirements at many sites and supporting more sophisticated evidence development such as important cognitive and functional outcome measures at a subset of sites with greater capabilities.

Duke-Margolis describes steps that CMS and other stakeholders can take in advance of a potential FDA approval to make implementing these options easier, mitigate uncertainty, and create a more robust foundation for developing AD evidence and improving AD care.

Executive Summary

Evidence on the safety and efficacy of Alzheimer’s disease (AD) amyloid-targeting monoclonal antibodies (mAbs) has continued to emerge through pivotal randomized control trials (RCTs). However, with at least two mAb treatments potentially reaching traditional approval by the Food and Drug Administration (FDA) based on clinical endpoints, questions remain about additional evidence from postmarket settings that could help ensure these treatments’ safe and appropriate real-world use for Medicare beneficiaries and the best ways to advance such evidence in the context of Medicare coverage.

According to the Centers for Medicare & Medicaid (CMS) final National Coverage Determination (NCD) issued in 2022, Medicare will cover mAbs that have received traditional FDA approval based on clinical endpoints under coverage with evidence development (CED) through prospective comparative studies. But the extent of the postmarket evidence requirements for coverage and the infrastructure available to support evidence development is unclear, adding urgency to questions about what steps can be taken now to enable evidence development while supporting appropriate access to these products under Medicare’s coverage standards. Most stakeholders support the goals of better data collection and evidence generation on AD mAbs without imposing excessive costs or other burdens that could inappropriately limit access to treatment. There is less consensus on how best to achieve these goals.

Reflecting recent analysis and stakeholder convenings, this paper explores options to conduct evidence generation for AD mAbs in the most efficient and least burdensome way to answer key questions that may plausibly remain after their traditional FDA approval. In contrast to “pivotal” RCTs conducted prior to approval to clearly answer questions about a medical product’s effectiveness and safety in a cohort of enrolled patients who are randomized under carefully controlled conditions, real-world evidence (RWE) methods focus on community-based contexts of care delivery. The methods are complementary in that the former is designed for determining causal relationships using rigorous data collection and randomization, while the latter can provide evidence on generalizability to patient groups and circumstances that are less feasible to study using traditional RCT methods–e.g., to understand experiences of different types of patients in their usual settings of care over the duration of their disease.

For example, data on rates of serious safety events associated with AD mAb use in different types of patients in community practices are relatively less burdensome to collect on a broad scale, and often can be captured through claims data. With additional progress in the coming months and years, CMS-supported updates to electronic health records (EHRs) could facilitate reporting of key clinical data elements that providers would be expected to track according to the AD mAbs’ label.

However, it is typically more difficult to develop matched comparison groups, especially without randomization, potentially raising questions about whether associations of outcomes with treatment use actually represent causal relationships. In addition, real-world data may be missing or unreliable in ways that introduce “noise” or bias. Current challenges in AD RWE generation include the lack of routine, consistent administration of cognitive function testing and lack of documentation of results in actual practice outside of clinical trials, as well as the limited collection in clinical practice of validated outcome measures used in clinical trials. These factors create concerns not only about the availability of data but also about the comprehensiveness of community-based care for patients with AD who will consider using newly approved mAbs.

Recognizing the limitations in the existing evidence-generation infrastructure for AD mAbs, this paper describes two potential registry approaches for AD mAb CED. The first is a large-scale registry that includes all Medicare beneficiaries eligible for mAbs but specifies relatively few data elements, for example not requiring extensive reporting on cognitive and functional status due to the insufficient infrastructure to do so in broad clinical practice. The second registry option would provide for more extensive data collection with richer data elements, such as important cognitive and functional outcome measures, for both treated patients and similar non-treated patients. But such data collection would realistically be more limited in terms of participating sites since many practices are not currently equipped to provide such reliable, longitudinal clinical data. With a focused effort, enough sites might be able to participate in developing additional needed evidence for Medicare subpopulations in a reasonable time period. Relevant initiatives are underway now to develop such evidence and could potentially be supported and expanded outside of CED.

As the existing infrastructure is mostly limited to claims-based collection and analysis, CMS could prioritize additional steps through a stakeholder process (e.g., notice and comment of a proposed path to expanding data collection) in the coming months to broaden this infrastructure while further clarifying the three CED questions and identifying ways to support their resolution. Such steps are described throughout this report and include engagement to address the important evidence questions that may have already been answered by the full evidence package leading to traditional approval; important further questions that can reliably be answered by a broad registry; support for existing and planned RWE systems for addressing questions that require more clinical data; identifying and promoting ways to increase the feasibility of and reduce the burden for comprehensive data collection; and in the meantime, placing appropriate coverage requirements and restrictions given the available evidence.

In particular, payers consider the strength of available evidence to make coverage decisions regarding the appropriate populations (patient selection), providers, and sites of service, and may initially restrict coverage based on available evidence relevant to these concerns. Indeed, the “reasonable and necessary” coverage standard for Medicare requires consideration of whether the treatment is as safe and effective as alternative approaches for beneficiaries that might be covered, which potentially includes diverse beneficiaries receiving care in a wide range of settings.

In the case of AD mAbs, CMS and other payers, such as the Veterans Administration (VA), have raised concerns about current gaps in the available evidence. For example, initial mAb coverage at the VA includes significant restrictions reflecting major patient subgroups and care settings where the available evidence on the risk-benefit profile is currently less favorable or less clear. Further evidence and patient experience developed through other, non-CED means would lead to updates on these restrictions over time and would encourage the development of more evidence. Even in the absence of a broad CED requirement, CMS could pay for mAb treatment in additional registries or trials involving Medicare beneficiaries and settings where evidence gaps exist. We describe opportunities to support an effective RWE infrastructure to accelerate that process.

This analysis leads to three policy options, detailed below, for CMS coverage and ongoing evidence development while providing appropriate evidence-based access to AD mAbs after traditional FDA approval. The options include: 1) eliminate CED for a fully-approved drug that meets “reasonable and necessary” standards for some Medicare populations, but impose coverage requirements and restrictions where the standard is not yet met, while evidence develops outside of CED; 2) implement CED but through a limited registry that includes a few critical data elements that are feasible to collect reliably; or 3) implement CED through a differential data collection structure, with limited requirements beyond claims at many sites that meet “reasonable and necessary” requirements, and support more sophisticated evidence development at a subset of sites with greater capabilities. We describe steps that CMS and other stakeholders can take in advance of a potential FDA approval to make it easier to implement these options, mitigate uncertainty, and create a more robust foundation for developing AD evidence and improving AD care.