Our FDA Comment: Plausible Mechanism Framework Draft Guidance

Dear Sir or Madam:

Cureledger, Inc. (Cureledger) appreciates the opportunity to submit the following comments to the U.S. Food and Drug Administration (FDA or Agency) in response to the draft guidance “Considerations for the Use of the Plausible Mechanism Framework to Develop Individualized Therapies That Target Specific Genetic Conditions With Known Biological Cause” (the draft guidance). Cureledger is a life data trust dedicated to advancing the development of safe and effective therapies for people living with rare diseases.

I. GENERAL COMMENTS

Cureledger commends the Agency on the issuance of the draft guidance and believes the Plausible Mechanism Framework (PMF) has significant potential to accelerate the development of therapies for rare diseases. By accepting mechanism-anchored evidence as substantial evidence of effectiveness, the draft guidance addresses a long-standing barrier in rare disease drug development: the difficulty of generating traditional randomized controlled trial evidence in small, heterogeneous, and widely dispersed patient populations. Cureledger believes this framework, if implemented with appropriate supporting infrastructure, can meaningfully expand the number of rare conditions for which viable development pathways exist.

Cureledger notes that the draft guidance’s methodology depends substantially on the availability of high-quality natural history data. The guidance contemplates data leveraging across product variants, master protocols, and cross-program interoperability (lines 312–330, 492–497), and recommends the early initiation of observational protocols (lines 429–437). Cureledger supports these provisions and believes they reflect an appropriate recognition that longitudinal, shareable data is central to the framework’s scientific logic.

Cureledger believes that the natural history data on which the framework relies must satisfy three conditions simultaneously: structural validity under recognized interchange standards such as FHIR and CDISC; regulatory compliance with 21 CFR Part 11, HIPAA, and applicable cGMP requirements; and persistent legal contractual viability. The specific comments that follow address each of these conditions, together with the related question of data custody when a sponsor exits a program, and offer recommendations for the Agency’s consideration.

II. SPECIFIC COMMENTS

1. Need for Consolidated Data Standards Guidance for Natural History Studies

Cureledger notes that the current regulatory landscape for natural history data is distributed across multiple provisional guidance documents, CFR titles, and industry specifications, including FHIR, CDISC, SNOMED CT, and LOINC. Cureledger further notes that the March 2019 draft guidance Rare Diseases: Natural History Studies for Drug Development remains the Agency’s primary reference on natural history data standards and continues to be designated “not for implementation;” and that the natural history section of the December 2023 final guidance Rare Diseases: Considerations for the Development of Drugs and Biological Products was removed during finalization.

Cureledger believes the absence of a consolidated pathway for compliance concentrates capacity among well-resourced sponsors and academic institutions and creates barriers for the patient organizations, family foundations, and independent researchers who have historically driven rare disease science. Cureledger believes the final guidance would benefit from addressing the standards applicable to such data because the PMF explicitly contemplates the use of natural history data generated from diverse sources.

Cureledger recommends that the final guidance either consolidate existing Agency positions on natural history data standards or reference a forthcoming companion guidance that does so, and that the Agency prioritize finalization of the March 2019 draft guidance on natural history studies.

2. Privacy Framework for Small Populations

Cureledger notes that the draft guidance contemplates populations of fewer than 200 patients but does not address the privacy framework applicable to such populations beyond standard IRB review and the informed consent requirements of 21 CFR 50.20. Cureledger is concerned that HIPAA Safe Harbor de-identification, as currently defined, may not provide meaningful protection for patients in populations of this size. Published research indicates that re-identification risk in small cohorts can be substantial (see Rocher, Hendrickx, & de Montjoye, “Estimating the success of re-identifications in incomplete datasets using generative models,” Nature Communications 10:3069 (2019)).

Cureledger further notes that the Department of Justice final rule implementing Executive Order 14117 on bulk sensitive data (28 CFR Part 202, effective April 8, 2025) reflects a federal determination that genomic data cannot be meaningfully de-identified and that bulk access by countries of concern presents a national security risk. Cureledger believes this determination is relevant to the privacy framework applicable to data generated under the PMF and should be reflected in the final guidance.

Cureledger recommends that the final guidance address privacy protections appropriate to rare disease populations, and that the Agency consider incorporating recognition of privacy-preserving technical approaches, including cryptographic commitments, pseudonymous linkage, and conditional reidentification mechanisms, as acceptable components of a data infrastructure for patient-contributed evidence.

3. Data Lifecycle, Reuse, and Custody

Cureledger notes that the draft guidance’s provisions on data leveraging (lines 312–330, 492–497) presume that natural history data generated in one context will remain available, verifiable, and usable in subsequent contexts. Cureledger supports this principle and believes data reuse is central to the framework’s capacity to make rare disease development feasible at scale. Natural history data generated for one program may serve as external control data for the next, and the value of such data to future programs depends on its persistence and verifiability over time.

Cureledger is concerned that the draft guidance assigns custody of data to the sponsor by default and does not address the circumstances under which a sponsor exits a rare disease program. Under ICH-GCP, sponsor retention obligations are enforceable only so long as the sponsor exists. No federal requirement currently specifies the disposition of natural history data when a sponsor becomes insolvent, is acquired, or discontinues a program. Cureledger believes that in the rare disease context, sponsor discontinuation is a predictable rather than exceptional event, and that the current custody model therefore creates a risk that the longitudinal evidence base the framework depends on will not survive the sponsors who generate it. Cureledger further notes that current consent frameworks, including the broad consent provisions adopted in the 2017 revisions to the Common Rule, address only the initial authorization of data use and do not address the downstream conditions necessary for continuous, data-driven rare disease development.

Cureledger recommends that the final guidance address the conditions under which natural history data generated under the framework remains reliably persistent, verifiable, and validatable for use by future programs. Cureledger believes patients and families are the most consistently motivated stakeholders in rare disease outcomes. Cureledger further recommends that the Agency consider data custody models in which participation of the individual data contributor is encouraged, and operational custody rests with a fiduciary capable of delivering data to qualified researchers on demand.

III. CONCLUSION

Cureledger appreciates the opportunity to submit these comments and supports the Agency’s commitment to advancing drug development for rare diseases. Cureledger believes the PMF represents an important step forward and that the final guidance will be strengthened by addressing the data standards, privacy, and data lifecycle considerations outlined above. Cureledger looks forward to working with the Agency and other stakeholders to advance these objectives.

Respectfully submitted,

Cureledger, Inc.
Nina Kilbride, CEO/Founder