Comment on CMS-2026-2080-0001

I respectfully submit this comment on proposed section 429.125(b)(4)(i). CMS has identified a legitimate program-integrity concern. Under the general fixed-combination policy, an original qualifying single source drug and a later fixed-combination formulation containing the same shared active moiety, active ingredient, or antigen component could be treated as separate potential qualifying single source drugs. CMS explains that this could affect selection for negotiation and application of an agreed-upon maximum fair price if utilization shifts to the new formulation. This proposal fits within a broader federal concern about new formulations. In Medicaid, the line-extension and new-formulation framework reflects a similar concern that follow-on formulations may be used to avoid pricing consequences tied to an original drug. In Vanda Pharmaceuticals, Inc. v. Centers for Medicare & Medicaid Services, 98 F.4th 483 (4th Cir. 2024), cert. denied, 145 S. Ct. 1047 (2025), the Fourth Circuit upheld CMS’s Medicaid line-extension regulation, including CMS’s definition of “new formulation” as “a change to the drug” that includes an extended-release formulation or other change in release mechanism, dosage form, strength, route of administration, or ingredients. Product-hopping cases, such as New York v. Actavis PLC, 787 F.3d 638 (2d Cir. 2015), illustrate a related concern: introducing a follow-on formulation is not necessarily unlawful, but shifting the market away from the original product can raise competition concerns when it forces patients to switch and impedes generic competition. These authorities are not controlling here, but provide useful context for CMS's concern. Proposed 429.125(b)(4)(i) is narrower than a general line-extension rule. CMS is not aggregating every new formulation or fixed-combination product with overlapping ingredient. It applies only where an added component creates a new formulation and enables an alternative route for the shared component. That limit should be preserved. To make the rule more predictable, CMS should consider defining "enables" to mean that the added component materially enables or materially facilitates the alternative route of administration for the shared component. A strict but-for standard would be too narrow because route changes may depend on concentration, excipients, injection volume, stabilizers, device design, or manufacturing processes. A mere-association standard would be too broad because the presence of an added component in a differently administered product does not necessarily mean the added component enabled the new route. A "materially enables or facilitates" standard would best capture the functional inquiry CMS appears to intend. Any factual-submission process should be narrow and time-limited so that it does not delay the selection process or convert CMS’s identification of qualifying single source drugs into a broader adjudicatory proceeding. The submission should be limited to the specific factual issues raised by proposed 429.125(b)(4)(i): the function of the added component, whether it materially enables or facilitates the alternative route of administration, and whether the product is better understood as a distinct therapeutic combination rather than a route-changing formulation of the shared component. CMS should retain final decision-making authority and may reasonably rely on public sources and FDA consultation where the record is clear. CMS should address mixed-causation cases. A new route may be made possible by the added active ingredient together with other product features. The added component should not have to be the sole cause if it materially enables or facilitates the new route. Otherwise, manufacturers could avoid aggregation by arguing that the route also depended on excipients, device design, injection volume, concentration, or manufacturing changes. Conversely, CMS should avoid over-aggregation where the added ingredient has an independent therapeutic role and the product is more appropriately understood as a distinct therapeutic combination rather than a route-changing formulation of the shared component. Finally, CMS should separate aggregation for selection purposes from valuation during negotiation. Aggregation under 429.125(b)(4)(i) should be understood as a program-integrity rule, not as a conclusion that the new formulation lacks value. A product may be properly aggregated to prevent circumvention and still provide value, such as reduced administration time, reduced infusion-center burden, improved adherence, or improved access. CMS states that clinical benefit may be considered during negotiation under proposed 429.510(e). The final rule should make clear that when a product is aggregated under 429.125(b)(4)(i), CMS will still consider evidence of clinical and practical benefits. These refinements preserve CMS's objective while improving predictability and administrability for affected parties.