Rare Disease Focus: FDA's Trio Of Cell And Gene Therapy Draft Guidances Highlight Expedited Programs, Innovative Trial Designs, And Postapproval Evidence Generation

FDA's Center for Biologics Evaluation and Research ("CBER") recently issued a trio of new draft guidances to assist sponsors who are developing and conducting postapproval studies of cell and gene therapies ("CGTs"):

1. Expedited Programs for Regenerative Medicine Therapies for Serious Conditions ("Expedited Programs Draft Guidance")
2. Innovative Designs for Clinical Trials of Cellular and Gene Therapy Products in Small Populations ("Innovative Designs Draft Guidance")
3. Postapproval Methods to Capture Safety and Efficacy Data for Cell and Gene Therapy Products ("Postapproval Methods Draft Guidance")

These draft guidances address commitments FDA made as part of the seventh authorization of the Prescription Drug User Fee Act ("PDUFA"), PDUFA VII: Fiscal Years 2023–2027, to promote greater transparency and increase efficiency in the development of CGTs. This Alert describes the key takeaways for industry from the new draft guidances, which largely reference and expand upon principles articulated in previous agency guidances and address their specific application to CGT products intended to treat rare diseases.

Notably, CBER published these draft guidances as rare disease companies, researchers, providers, and patients await more detailed information about a potential new "plausible mechanism" pathway for certain rare disease products to come to market, touted in public remarks by FDA Commissioner Dr. Marty Makary and Chief Medical and Scientific Officer and CBER Director Dr. Vinay Prasad.¹ Ropes & Gray will continue to monitor these developments, with a focus on whether and how the promised new pathway aligns with or departs from the principles reflected in the new draft guidances described in this Alert.

I. Draft Guidance on Expedited Programs for Regenerative Medicine Therapies for Serious Conditions

The Expedited Programs Draft Guidance consolidates and updates expectations for sponsors of regenerative medicine therapies seeking to take advantage of the agency's distinct Fast Track, Breakthrough Therapy, Priority Review, and Accelerated Approval programs. When finalized, this new draft guidance is intended to supersede the 2019 final guidance of the same name.

Like the earlier final guidance, the new draft guidance describes the agency's various expedited programs and their requirements. The new draft provides more detailed recommendations about the eligibility of regenerative medicine therapies for these expedited programs, describes expanded flexibilities, and showcases updated examples in the following key areas:

• preliminary clinical evidence to demonstrate product potential;
• use of real-world evidence ("RWE")/real-world data ("RWD") and data standards;
• expectations for chemistry, manufacturing, and controls ("CMC") readiness;
• ensuring comparability between the product used to generate preliminary clinical evidence and the product planned for clinical development; and
• postapproval plans for confirming clinical benefit, where appropriate

The Expedited Programs Draft Guidance also emphasizes that regenerative medicine therapies need not have received a Regenerative Medicine Advanced Therapy ("RMAT") designation to be eligible for the other expedited programs described.

Key updates from the 2019 Expedited Programs Guidance include:

• Expanded and clarified scope of "Regenerative Medicine Therapies." The newly released Expedited Programs Draft Guidance reflects a somewhat broader understanding of the scope of the statutory term "regenerative medicine therapy." Specifically, it omits the prior draft's suggestion that human gene therapies, including genetically modified cells, should have a "sustained effect on cells or tissues" to meet the statutory definition in section 506(g) of the Federal Food, Drug, and Cosmetic Act ("FDCA"). The updated guidance reflects FDA's recognition that cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using such therapies, with limited exceptions, can be "regenerative medicine therapies." It also specifically notes that all xenotransplantation products may potentially qualify, rather than just xenogeneic cells.
• Emphasis on CMC readiness for early-phase clinical studies. When relying on early-phase data to support expedited designations or a marketing application, FDA expects appropriate product quality controls, grounded in defined critical quality attributes and critical process parameters, to be in place early in development. The Expedited Programs Draft Guidance emphasizes the importance of ensuring comparability as manufacturing changes are made through the development process, explicitly recognizes the challenge of CMC readiness when developing CGTs on an expedited timeline, and "strongly" encourages sponsors "to discuss CMC readiness, including any perceived manufacturing challenges" through the increased interactions with FDA that expedited programs provide.²
• Greater openness to use of externally controlled trials and RWE —with stricter quality guardrails—for RMAT designation. The Expedited Programs Draft Guidance clarifies that, while external controls, retrospective studies, or case series may be used to support an RMAT designation, these forms of preliminary clinical evidence should not be merely hypothetical and should demonstrate the potential to address an unmet medical need. For accelerated approval, RWE from registries and electronic health records may be acceptable as confirmatory evidence if data reliability, relevance, and common biases are rigorously addressed. This draft guidance repeatedly cross-references other FDA guidance documents drafted or finalized since 2019 that illustrate FDA's current thinking on these themes.³
• Continued clinical trial design flexibilities and multi-site approaches. In the new draft, FDA signals continued flexibility for adaptive trial designs, novel endpoints, natural‑history comparators, and externally controlled trials, especially in rare diseases. FDA also continues to support collaborative multi‑site models—encouraging early alignment of protocols, sites, and data systems with scale‑out in mind.
• Strengthened safety monitoring and long‑term follow‑up expectations. In the Expedited Programs Draft Guidance, FDA highlights the need for product‑specific short‑ and long‑term safety monitoring. The guidance points to leveraging digital health technologies for collecting the requisite safety information.

II. Innovative Designs for Clinical Trials of Cellular and Gene Therapy Products in Small Populations

CBER's new Innovative Designs Draft Guidance reflects FDA's understanding of the "importance of innovative and efficient trial designs" to address the "urgent need for safe and effective products to treat serious and severely debilitating diseases in small populations."⁴ The guidance seeks to assist sponsors developing drugs and biologics for rare diseases to overcome the significant challenges that arise when limited data, small patient populations, or manufacturing complexities constrain traditional trial approaches. It builds upon principles articulated in existing agency guidance related to rare disease drug development⁵ and trial design, and provides recommendations with the goal of aiding FDA's evaluation of product effectiveness.

The suggestions and recommendations in the Innovative Designs Draft Guidance are high-level; this draft guidance functions more as a survey of the landscape than as an all-in-one prescriptive guide. Detailed footnotes point sponsors to pre-existing draft and final guidances on numerous themes, such as adaptive design clinical trials and master protocols.⁶ These references can be of use as sponsors navigate the myriad issues that will undoubtedly arise as researchers seek to implement the innovative designs described. Nonetheless, in this draft guidance, FDA clearly describes the basic concepts and rationale underlying the proposed designs, how they might be implemented, and the contexts in which they may be appropriate. It also addresses considerations for patient selection.

Proposed Innovative Designs

The draft guidance provides a non-exhaustive list of innovative design options, summarized below. It also urges sponsors to engage with the agency as early as possible to discuss the innovative design approaches they are considering.

• Single‑arm trials using participants as their own control. In this design, a participant's response to the investigative therapy on a given measure is compared to their own baseline status for that measure and no external control arm is required. FDA explains that self‑controlled designs can be persuasive where the target conditions are universally degenerative and improvement is expected with therapy, but notes that to be useful, baselines must be reliably established via prospective lead‑in or validated retrospective data.
  • Sponsors should mitigate the potential for regression to the mean that could confound the results by avoiding enrollment at peak symptom severity and by prioritizing objective, non‑effort‑dependent endpoints to support interpretability.
  • For waxing‑and‑waning diseases, or when the goal is to slow progression, concurrent controls may still be needed to distinguish treatment effect from natural variability.
  • This type of trial design requires a comprehensive understanding of the overall course of an illness and the goal of treatment.
  • Additional methodological considerations that may be relevant are contained in the July 2020 International Council for Harmonisation ("ICH") E10 guideline: Choice of Control Group in Clinical Trials.
• Disease progression modeling to inform design and analysis. This design strategy uses a quantitative approach to characterize a disease or condition's natural history—integrating biomarkers, clinical endpoints, and covariates such as baseline severity, demographics, and concomitant treatments—and can be of use to guide endpoint selection, power assumptions, and subgroup evaluation. FDA cautions that variability in disease trajectories, evolving standards of care, and limited representation of key subgroups can complicate the validation and extrapolation of results. Lengthy observation periods required to capture meaningful change can also present a challenge. Robust model development, transparent assumptions, and sensitivity analyses are essential to support regulatory decision‑making based on this type of design approach.
• Externally controlled studies using historical or real‑world data. This study design uses historical or RWD from patients who did not receive the study therapy as a comparator group. Such data can serve as the sole control for a study or be used in addition to a concurrent control arm. External comparators may be appropriate when concurrent controls are impracticable, but require tight alignment on baseline characteristics, outcome definitions, ascertainment methods, and follow‑up. Suitability is a case‑by‑case determination informed by disease heterogeneity, preliminary product evidence, and whether superiority or non‑inferiority is sought. The central question is whether the design can credibly separate drug effect from confounding and bias inherent in nonrandomized comparisons. The Innovative Designs Draft Guidance refers sponsors and investigators to the agency's February 2023 draft guidance, Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products, for more detailed information.
• Adaptive designs permitting preplanned modifications during study. This design approach involves the prospective identification of modifications to be made to one or more aspects of a clinical trial, during the trial, based on accumulating data from participants as the trial progresses. These types of designs can be particularly helpful when limited pre-trial clinical data are available, enabling investigators to take advantage of new learnings from empirical evidence collected during the trial. The Innovative Designs Draft Guidance identifies four adaptive methodologies:
  • Group sequencing: permits early trial termination if convincing evidence accumulates, showing effectiveness of an investigational therapy or that further study will not be useful;
  • Sample size reassessment: modifications to study size based on data;
  • Adaptive enrichment: enrollment modification to focus on the population most likely to benefit from the therapy based on interim analysis; and
  • Adaptive dose selection: protocol that allows for selection and confirmation of dose effectiveness in the same study.
• Bayesian trial designs allowing for use of external data. These designs can reduce the size of the sample population and otherwise leverage existing data to improve analyses. One example of a Bayesian trial design would be adding existing control data from outside the study to data collected from a concurrent control group. Bayesian designs can also assist with adaptive designs, for example, by leveraging adult effectiveness data when seeking to demonstrate efficacy in a pediatric population and to improve estimates of treatment effects in patient subgroups.
• Master protocol designs allowing for multiple sub-studies within one trial. As examples, a master protocol might provide for the evaluation of multiple cohorts with different manifestations of a disease treated with the same investigational product, different interventions for the same disease or condition, or the same investigational product used for different conditions.

Participant Selection

The Innovative Designs Draft Guidance also addresses considerations for the selection of patients for rare disease trials in which there is significant unmet need and existing therapies may provide only limited improvement of certain symptoms without impacting the course of the underlying disease. Key messages include:

• Participant selection should be aligned with the treatment landscape. Entry criteria that require exhaustion of all available therapies may be unnecessarily exclusive where existing options confer limited benefit and could compromise generalizability if the product is approved. FDA encourages sponsors to calibrate entry criteria to the real‑world standard of care and medical need, balancing safety with inclusive access to maximize information yield. Clear justification of restrictions is important to withstand review and to support downstream labeling.
• Participant selection reflecting symptom status and representativeness. For conditions with pre‑symptomatic phases or variable onset, sponsors should align endpoints and analyses to disease stage and consider appropriate surrogate, biomarker, or intermediate clinical endpoints, including digital health measures where suitable. When determining efficacy endpoints in studies that include patients with early stage disease, sponsors are strongly encouraged to consult with FDA. Broadly representative early enrollment can aid dose finding, safety characterization, and potential extrapolation across variants and phenotypes, with added safeguards for pediatric subjects consistent with 21 CFR part 50, subpart D.
• Speeding development in the pediatric population. Sponsors should pursue approaches to patient selection that speed the safe development of CGTs to treat diseases in the pediatric population. Recognizing that disease manifestation may be different in children, sponsors should consider whether, and in what circumstances, adult clinical data and nonclinical data will be relevant to assessing likely clinical benefit in the pediatric population. In select cases, pediatric enrollment without prior adult investigation may be appropriate where scientifically necessary and supported by an IRB‑approved design and robust safety monitoring.

III. Postapproval Methods to Capture Safety and Efficacy Data for Cell and Gene Therapy Products

FDA's new Postapproval Methods Draft Guidance reflects consideration of issues raised in a CBER Office of Therapeutic Products virtual public listening meeting, held on April 27, 2023.⁷ As its name suggests, it focuses on methods and data sources, particularly with respect to RWD, that can be marshaled for tracking postapproval safety and efficacy outcomes for CGT products, and describes the relative benefits and limitations with respect to their use.⁸ While FDA has previously addressed the importance of long-term follow up studies to assess safety in gene therapy products,⁹ this new draft guidance also addresses the utility of different types of data and data collection methods in assessing post-market effectiveness.

At the outset of the Postapproval Methods Draft Guidance, FDA makes two key recommendations for long-term monitoring studies of CGTs, which often extend 15 years. FDA urges sponsors to plan for pediatric-to-adult care transitions and establish contingency plans—including by allocating funding—to ensure continued follow-up if the sponsor ceases to operate the study before its completion.

Use of Real-World Data and Real-World Evidence

A. Electronic Health Record ("EHR"), Medical Claims, and Vital Statistics Data

These sources are "not typically designed to collect data for evaluation of safety or effectiveness," and sponsors should carefully assess fitness for use—particularly in rare diseases.¹⁰ However, with "adequate strategies for study sample selection, data validation, and ascertainment of exposures, outcomes and covariates," they may be appropriate to support targeted analyses.¹¹

• Key constraints include missing key variables, unstructured data or lagging coding, fragmented longitudinal records, and limited power to detect rare outcomes, even in large databases.
• Appropriate uses of such data include utilization studies, outcome assessments in treated patients, estimating adverse event background rates, multi-population outcome observations, and training Artificial Intelligence and Natural Language Processing machine-learning models to develop computable phenotypes.
• FDA encourages feasibility assessments for representativeness, protocol-level specification of computable phenotype definitions and algorithms, attention to data lags and practice changes, plans for long-term follow-up, and methods to extract and validate unstructured or patient-generated data, including approaches to missingness and data linkage.

B. Use of Registry Data

The Postapproval Methods Draft Guidance encourages use of, and describes the following benefits of, registry data for postapproval monitoring.

• Registries can capture clinical and laboratory data, plus genetic data, histopathology specimens, imaging, and in-home digital health technology inputs.
• They facilitate standardized longitudinal datasets that include patient-reported outcomes, adherence, and disease severity, offering advantages over EHR/claims sources.
• Priority use cases include assessing long-term durability (including biomarker-based endpoints), pediatric growth and developmental milestones, malignancy surveillance, and fertility/pregnancy outcomes in those exposed to conditioning regimens.

Decentralized data collection

Decentralized approaches can make data capture "more accessible and less burdensome,"¹² enhancing generalizability and retention in small CGT populations. This Postapproval Methods Draft Guidance refers sponsors to FDA's September 2024 final guidance on conducting clinical trials with decentralized elements,¹³ summarized in a prior Ropes & Gray Alert.

• FDA's core strategies are high-level: identify necessary data elements, ensure robust methods to support accuracy and reliability, and "incorporate flexibility in the study design" tailored to therapy, treatment, and patient journey.
• Protocols using local HCPs and telemedicine should specify how activities are tracked, how outcomes and adverse events will be captured and assessed, where participants can access local care and follow-up, and how urgent or in-person care will be provided.
• IRB review and informed consent requirements continue to apply in the postapproval setting.

Conclusion

The comment periods for the draft guidances described in this Alert remain open until November 24, 2025. Ropes & Gray will continue to monitor regulatory developments related to CGT products, and will watch for more information on whether and how the promised new "plausible mechanism" pathway aligns with the principles reflected in the draft guidances described above. If you have any questions, or wish to discuss submitting comments on one or more of these draft guidances, please contact any member of our FDA regulatory practice or your usual Ropes & Gray advisor.

Footnotes

1. Nyah, Phengsitthy, FDA Prepares Approval Pathway Plan for Rare Disease Treatments, Bloomberg Law (Sept. 3, 2025), https://news.bloomberglaw.com/health-law-and-business/fda-prepares-approval-pathway-plan-for-rare-disease-treatments; Interview with Commissioner Makary on Megyn Kelly Show, https://www.youtube.com/watch?v=Jd9u6ckPjvI (April 2025).

2. Expedited Programs Guidance at 2.

3. See infra n. 8.

4. Innovative Designs Draft Guidance at 2.

5. The Innovative Designs Draft Guidance refers sponsors to its December 2023 final guidance, Rare Diseases: Considerations for the Development of Drugs and Biological Products and its March 2019 draft guidance, Rare Diseases: Natural History Studies for Drug-Development.

6. The Innovative Designs Draft Guidance points sponsors to a variety of draft and final guidances related to clinical trial design, such as the September 2024 final guidance on Conducting Clinical Trials With Decentralized Elements, the December 2023 draft guidance on Master Protocols for Drug and Biological Product Development, the February 2023 draft guidance on Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products, and the November 2019 final guidance on Adaptive Design Clinical Trials for Drugs and Biologics Guidance for Industry.

7. This meeting was held to meet a commitment made by FDA as part of the seventh authorization of the Prescription Drug User Fee Act ("PDUFA"), PDUFA VII: Fiscal Years 2023-2007. Following the meeting, FDA opened a docket (FDA-2023-N-0398) to solicit input on methods and approaches for capturing postapproval safety and efficacy data for CGT products.

8. The Postapproval Methods Draft Guidance builds on the existing body of guidance related to RWD and RWE approaches, including the July 2024 final guidance on Real-World Data: Assessing Electronic Health Records and Medical Claims Data To Support Regulatory Decision-Making for Drug and Biological Products, the December 2023 final guidance on Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products, and the August 2023 final guidance on Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products.

9. The Postapproval Methods Draft Guidance references its 2020 final guidance Long Term Follow-up After Administration of Human Gene Therapy Products ("LTFU Guidance") which provided recommendations for the design of long-term follow-up studies for collection of data on delayed adverse events, following the administration of a gene therapy product. This guidance was discussed in a Ropes & Gray Alert that addressed six FDA final gene therapy guidances FDA published in January 2020.

10. Postapproval Methods Draft Guidance at 3.

11. Id.

12. Id. at 5.

13. FDA, Guidance for Industry: Conducting Clinical Trials With Decentralized Elements (Sept. 2024).

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