Background In 2022, the Centers for Medicare & Medicaid Services (CMS) issued its final national coverage policy for aducanumab, a novel FDA-approved treatment for Alzheimer’s disease, deciding to ‘Cover with Evidence Development’ (CED). CMS will thus only pay for the treatment of AD patients enrolled in an approved randomized controlled trial (RCT). We sought to understand whether, given current evidence, CED was best from a societal perspective.

Methods We conducted a modeling-based expected value of sample information analysis to estimate the expected net decision-theoretic value of a further RCT to evaluate the clinical efficacy of high-dose (10 mg/kg) aducanumab and to determine what sized trial, if any, is optimal conditional on an initial decision to cover or not. We also evaluated the expected net benefit of the manufacturer’s proposed RCT (‘ENVISION’). We considered two post-trial decision criteria: cost-effectiveness given updated evidence (‘efficiency’) and does the new trial demonstrate a statistical significant (p<0.05) clinical benefit. Results were used to calculate the expected population net monetary benefit (NMB) of four decision alternatives (including CED) depending on an initial coverage and trial decision. We ranked alternatives and calculated the expected opportunity loss of a suboptimal decision. We used a societal perspective and focused on willingness-to-pay (WTP) values for a quality-adjusted life year (QALY) between $50K-$200K. We conducted scenario analyses using different assumptions about population size, efficacy, and drug cost.

Findings CMS’s decision to not cover aducanumab avoids an expected societal loss (NMB) of $15B-$110B. Even an optimally designed RCT would confer no or negative decision-theoretic value for WTP≤$100K or with statistical significance as a post-trial decision criterion, respectively, and thus denying coverage without a trial (rather than CED) is clearly preferable. For WTP=$150K (WTP=$200K) and assuming an efficiency criterion, CED with ENVISION or a similar trial is reasonable (decidedly optimal). The case for future research would become less ambiguous if the manufacturer again voluntarily dropped the price ≥50%.

Interpretation The societal net value of a future trial (and thus CED) depends on how CMS would use the trial results to update its coverage decision and the WTP per QALY. Assuming CMS policymakers can avoid the pitfalls of a legal framework that limits their ability to consider costs in coverage decisions, the CED decision is at least reasonable, if not optimal, if a QALY is valued ≥$150K.

The authors have declared no competing interest.

Jutkowitz was funded in part by 1R21AG059623-01 and 1R01AG060871-01. Popp was partially supported for methods development by U01CA265750.

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