Pharma industry wants clarity on plausible mechanism framework
The US pharmaceutical industry expressed support for the US Food and Drug Administration’s (FDA) proposed framework for increasing access to treatments for ultra-rare diseases yet raised questions concerning various aspects of the program.
Industry was particularly interested in the framework’s practical implementation and how it would integrate with other programs and requested more clarity regarding the role of chemistry, manufacturing, and controls (CMC) in the framework.
Additionally, multiple groups proposed expanding the program to include treatments for diseases that are not classified as ultra-rare.
The agency received 154 comments on its proposed guidance to establish a plausible mechanism program for rare diseases.
FDA released draft guidance on the framework in February 2026, proposing a potential pathway for the agency to authorize the use of individualized drugs and biologics for specific genetic conditions that have known biological causes. (RELATED: FDA proposes plausible mechanism pathway for ultra-rare disease therapies, Regulatory Focus 23 February 2026)
The Pharmaceutical Research and Manufacturers of America (PhRMA) summed up the sentiments of many in their comments. The group wrote that “the Draft Guidance represents an important step toward providing predictability and regulatory clarity for sponsors developing gene-editing, RNA-based, and other targeted therapies for patients, including those with rare diseases.”
Questions on implementation
Several groups, including the Biotechnology Innovation Organization (BIO) and the Alliance for Regenerative Medicine (ARM), stated that the guidance lacked practical examples illustrating how the program would function.
BIO wrote that “we respectfully request the Agency to provide clearer how-to implementation of the guidance with case studies on how to utilize this framework as an evidentiary approach within existing statutory authorities.”
ARM had similar comments. “While the draft guidance reflects flexibility in principle, it does not sufficiently outline how this approach will be applied in practice for sponsors, particularly at critical development, investment, and manufacturing decision points. This may lead to uncertainty in how the framework is applied across review divisions.”
Relation to existing programs
BIO, PhRMA, and the National Organization for Rare Disorders (NORD) questioned how the program would work with existing programs such as accelerated approval, breakthrough, fast-track, the Regenerative Medicine Advanced Therapy (RMAT) program, and the platform technology designation program.
BIO statee that “to avoid misinterpretation, we request clearer articulation of this distinction and recommend the Agency clarify how the Plausible Mechanism Framework aligns with existing regulatory programs.”
PhRMA and NORD had similar comments.
Groups suggest scope should be expanded
PhRMA and BIO suggested that the scope of the program be expanded beyond rare diseases.
PhRMA said that “the framework may be appropriate for other therapies with high unmet medical need, e.g., some chronic diseases where the scientific rationale and prior knowledge are strong and the benefit-risk profile is favorable (i.e., low-risk with the potential for meaningful benefit).”
BIO wrote that “as written, the draft guidance appears narrowly focused on genome‑editing technologies, antisense oligonucleotides, and rare, severely debilitating, or life‑threatening diseases. We encourage the FDA to clarify that the framework’s applicability extends beyond individualized products and is principle‑based and modality‑agnostic, making it suitable for other therapeutic modalities and disease contexts with serious life-threatening conditions, where a strong mechanistic rationale exists and feasibility constraints similarly limit the ability to conduct traditional clinical trials.”
Greater clarity needed on CMC
There was also consensus among the Friends of Cancer Research, ARM and the American Society for Cell and Gene Therapy (AESGT) regarding the need for greater clarity on how chemistry, manufacturing and controls (CMC) would function within the plausible mechanism program.
FOCR wrote that “additional clarity around Chemistry, Manufacturing, and Controls (CMC) expectations is needed across the full product lifecycle, particularly regarding the transition from IND to Biologics License Application (BLA)/New Drug Application (NDA) stages.”
FOCR further recommended that FDA allow rolling CMC submissions to reduce the burden on sponsors and support compressed clinical timelines. The group also recommended that FDA clarify how CMC expectations scale as drug development progresses from investigational new drug applications (INDs) to new drug applications (NDAs).
ARM concurred that “while the draft guidance reflects flexibility, the CMC section does not yet lay out a scalable path to licensure, particularly given the need to align early-stage development with manufacturing and validation expectations typically associated with later-stage programs.”
AESGT further weighed in that “the Society believes the scope of the CMC section in this guidance warrants reconsideration. This section does not yet provide the kind of focused, practical advice that would be most helpful in this setting. A separate, more focused FDA discussion or guidance on CMC expectations for individualized therapies may be more useful, particularly if it addresses the need for additional clarity on Phase 1 CGMP exemptions applicable to individualized therapies where patient numbers are very low, including n=1 settings, and where Phase 1 studies may contribute to the efficacy dataset rather than serving only a safety role.”
NORD wants assurances that FDA won’t reject natural history studies
NORD said it is skeptical about the FDA’s claims in the guidance that it will accept natural history data as an external control when clinical outcomes are not easily observable.
The guidance states that “in patients for whom the natural history of the disease in the untreated state can be reasonably characterized, it may be possible for an externally controlled clinical investigation that assesses a patient’s change following treatment compared to baseline to serve as the adequate and well-controlled clinical investigation necessary to support approval/licensure.”
NORD said that “despite FDA’s existing guidance on natural history studies, the Agency’s acceptance of those studies remains unclear. We have seen FDA reject natural history studies for various reasons, even those conducted by NIH or other august bodies. This issue may be exacerbated in the context of individualized therapies for very rare diseases and patients with unique mutations.”
NORD said that its IAMRARE platform supports the establishment of natural history registries for over 140 disease states.
NORD questions program’s scale
NORD also raised concerns about how the program can scale beyond “highly specialized” academic centers.
The group states that “the path to commercialization for products under the Plausible Mechanism Framework – which will be the ultimate mechanism for equitable access and reimbursement – is not clear.”
NORD said that KJ Muldoon, the first patient treated with an individualized gene editing product, was treated through a single patient investigational new drug application.
The group states that “NORD envisions a future where patients who are not at highly specialized academic medical centers can access these therapies. However, scaling and commercializing them is a challenge - the researchers who treated Baby KJ have reported that they cannot scale their own work due to FDA’s manufacturing requirements.”
