Industry asks FDA to expand prior knowledge guidance
Industry stakeholders want the US Food and Drug Administration (FDA) to expand the scope of its recent draft guidance on the types of scientifically valid prior knowledge sponsors may consider when developing gene therapies that involve genome editing to explicitly apply to other types of cell and gene therapies (CGT).
In June, FDA published the draft guidance that details its thinking on how to leverage chemistry, manufacturing, and controls (CMC), and nonclinical and clinical prior knowledge when developing GT products that incorporate ex vivo and in vivo genome editing (GE) of human somatic cells. The agency said the information may be especially helpful when developing GT products for rare diseases. (RELATED: FDA aims to speed gene therapy development with prior scientific knowledge guidance, Regulatory Focus 2 June 2026)
While the guidance notes that its recommendations may apply to CGTs more broadly in some cases, industry commenters have asked FDA to clarify how the guidance applies to CGTs beyond genome editing products.
Adding CGTs, focusing on risk
“While this draft guidance specifically focuses on GE products, some of the recommendations, when finalized, are or may be applicable to other CGT products, such as adeno-associated viral (AAV) vectors, nanoparticle-based GT products, and ex vivo-modified cell-based GTs that do not incorporate GE," said FDA. “However, additional considerations may also apply to these related product types, based on the specific product and manufacturing process, that are beyond those recommended in this guidance.”
Several industry stakeholders requested that FDA to broaden the scope of the draft guidance, particularly the title, to include CGT products more broadly.
"If the title of the Draft Guidance remains limited to GE products, it may inappropriately suggest that the opportunities for leveraging prior knowledge are largely confined to those technologies, notwithstanding FDA’s acknowledgment that many of the recommendations are relevant to other CGT products," said drug lobby group PhRMA. Both PhRMA and the Biotechnology Innovation Organization (BIO) suggested the title be changed to “Leveraging Prior Knowledge in the Development of Human Cell and Gene Therapy Products.”
“BIO members believe the principles described in the guidance are applicable across a broad range of cellular and gene therapy products and are not unique to genome editing technologies,” said BIO. “Many of the underlying considerations related to manufacturing platforms, analytical methods, nonclinical testing strategies, clinical trial design, comparability assessments, and lifecycle learning are shared across CGT modalities…. We also suggest the FDA clearly articulate which recommendations are applicable to non-genome-editing modalities and provide examples demonstrating their application across a broader range of CGT products.”
PhRMA also argued that expanding the scope of the guidance would advance FDA’s commitment under the Prescription Drug User Fee Amendments (PDUFA VII) agreement to seek stakeholder feedback on improving CGT regulations.
PhRMA and BIO also asked FDA to adopt a more structured, risk-based framework for leveraging prior knowledge. BIO noted that throughout the guidance, FDA states that the ability to leverage prior knowledge depends on the similarity of products, manufacturing processes, formulations, delivery systems, and other attributes. The group said that the agency should clarify how sponsors should evaluate, document, and justify those similarities.
"BIO recommends that FDA provide a risk-based decision framework or set of guiding principles to help sponsors determine when products, or aspects of products, may be considered sufficiently similar to support leveraging activities," said BIO, which also listed elements in the framework that may be evaluated for similarity, including product structure and composition, editing components and mechanisms, manufacturing processes, and more.
"Providing these factors would improve predictability, consistency, and efficiency during regulatory interactions," the group added.
PhRMA said a more structured framework for evaluating when and how prior knowledge may appropriately be leveraged would be beneficial and similarly asked FDA to take a risk-based approach.
"Although FDA acknowledges that the scientific soundness of leveraging depends on multiple considerations, the Draft Guidance describes individual factors that may be relevant without providing a clear framework for assessing the degree of reliance that may be appropriate in each circumstance," said PhRMA. "As a result, sponsors may face uncertainty regarding when prior knowledge is sufficient to support full reliance, when targeted bridging data should be generated, and when de novo data generation remains necessary.
PhRMA
PhRMA asked FDA to clarify the scope and application of public and platform knowledge in the guidance; and to clarify the factors regulators will consider when assessing the scientific soundness of leveraging prior knowledge. Furthermore, the group asked the agency to ease restrictions on the use of master files and referenced information in biologics license applications (BLAs).
"PhRMA is concerned that the Draft Guidance’s discussion of leveraging prior knowledge is in tension with FDA’s continued restrictive approach to the use of Master Files and referenced information in BLAs," said PhRMA. "The Draft Guidance appropriately recognizes that prior knowledge may be generated and maintained in a variety of ways and that sponsors may need to rely on information developed by third parties or across multiple development programs.
"However, the Guidance’s discussion of BLAs suggests that key practical limitations on such reliance remain, potentially undermining the efficiencies that the Draft Guidance otherwise seeks to promote," the group added.
PhRMA asked FDA to reaffirm protections for proprietary information and rights of reference. The guidance states that platform knowledge may be considered proprietary and may require written permission from the entity that owns the knowledge if used in a submission. The group says that while it agrees with the principles in the guidance, the agency should be clearer and more consistent that knowledge leveraging must be done within existing legal protections for sponsor-owned information.
"The Draft Guidance repeatedly encourages the use of prior knowledge across development programs and applications, but it does not always clearly distinguish between information that is generally accepted public knowledge and information that remains proprietary to a sponsor or other entity," said PhRMA. "Without additional clarification, the Draft Guidance could be interpreted as suggesting that the scientific utility of information alone is sufficient to justify reliance, regardless of whether the sponsor has a legal basis to use the information.
"FDA should make clear that leveraging prior knowledge is not intended to undermine existing protections for proprietary data, confidential commercial information, trade secrets, nor to create an alternative pathway that circumvents established statutory approval frameworks," the group added. "Accordingly, where a sponsor seeks to rely upon platform knowledge that is not [generally accepted scientific knowledge (GASK)], FDA should expressly recognize and indicate that it will consider whether the knowledge is proprietary, and, if so, permit the leveraging only if the sponsor has the appropriate authorization to rely on the prior knowledge."
Additionally, PhRMA asked FDA to clarify how to appropriately use published literature and publicly available data; avoid categorical limitations on leveraging prior knowledge in the guidance; clarify how prior knowledge may be leveraged throughout the product lifecycle; and create a more explicit process for reconsidering long-term follow-up (LTFU) requirements. The group said the agency, while stating it will be flexible on its LTFU requirements, doesn't provide much detail on how it plans to operationalize that flexibility.
"Although the Agency indicates that it may reconsider existing LTFU expectations, the Draft Guidance does not identify a process, criteria, or evidentiary framework for doing so," said PhRMA. "FDA should clarify when it might consider modifications to existing monitoring requirements, what types of information would support such reconsideration, and how requests for changes should be presented to the Agency.
"Specifically, FDA should build upon the principles articulated in the Draft Guidance by establishing a risk-based framework for revisiting LTFU requirements over time," the group added. "Such a framework could recognize that the appropriate duration, frequency, and scope of follow-up may change as additional product-specific, platform-specific, and field-wide safety experience accumulates."
PhRMA also asked FDA to clarify that it is willing to engage with sponsors about leveraging prior knowledge at any point in the drug development process and after the drug’s approval; and encourage the use of off-target assessment frameworks and methodologies.
BIO
BIO also listed several additional considerations for FDA, including clarifying expectations for bridging and confirmatory evidence, providing additional examples and decision-making factors to improve regulatory predictability, and echoing PhRMA’s request to clarify the use of prior knowledge across the product lifecycle. The group said it appreciates the agency’s willingness to host INTERACT and pre-IND meetings to help sponsors answer questions early, but it wanted more details on what to expect from regulators.
"While early FDA engagement can be valuable, the guidance should provide sufficient clarity and specificity to enable sponsors to make informed development decisions without necessarily requiring an INTERACT meeting to interpret FDA's expectations,” said BIO. “To facilitate such understanding, FDA should provide additional examples, decision matrices, and descriptions of the factors reviewers may consider when evaluating leveraging proposals.
“Greater transparency regarding FDA's expectations would help sponsors develop more focused regulatory strategies and reduce uncertainty across development programs,” the group added. “We also encourage the agency to remain receptive to discussions on the use of prior knowledge through other meeting formats, including Type C and Type D meetings, throughout product development.”
Additionally, BIO asked FDA to provide terminologies and clarify how the guidance interfaces with existing regulatory frameworks. In particular, it noted that the agency's use of the term "platform" differs from the statutory concepts of "platform technology" and "designated platform technology". The group said that the use of similar yet distinct terminology for regulatory purposes may create confusion.
BIO also asked FDA to expand on the examples of clinical development in the guidance.
"BIO members support FDA's recognition that prior knowledge may inform clinical trial design, dose selection, monitoring strategies, and other aspects of development," said BIO. "However, compared to the CMC and nonclinical sections, the clinical section contains relatively few examples describing how actual clinical data may be leveraged across programs."
More specifically, the group asked for examples where prior clinical data may help support streamlined development programs, optimized assessment schedules, safety monitoring approaches, dose selection strategies, and the use of external or historical data sources.
Friends
Friends of Cancer Research (Friends) asked FDA to establish a structured framework to leverage prior knowledge. The group said the agency should provide a voluntary framework for presenting prior knowledge that can be leveraged, along with the scientific justifications for its applicability.
"A common structure could improve consistency, transparency, and early alignment with the FDA without replacing case-by-case review," said Friends. "The framework could also include a mechanism for revisiting the approach as additional product-specific, clinical, or postmarket evidence becomes available."
Friends said FDA should clarify that similarity assessments should be considered in the context of the specific inference being supported instead of as a determination based on whether two products are broadly similar or dissimilar. The groups said that limiting determinations to differences between two products may limit the ability to leverage prior knowledge, and that the agency should provide more examples of prior knowledge sponsors can use.
Friends also asked FDA to clarify how prior knowledge may be used to streamline clinical development. More specifically, the group said the agency should clarify how prior knowledge may support modifications to the scope or sequence of clinical development and provide more concrete examples.
"This clarity may be particularly important for individualized or highly targeted therapies, where repeating conventional development activities for each related product may be infeasible and/or scientifically unnecessary," said Friends.
Like other commenters, Friends also asked the FDA to clarify how its guidance can be applied across programs and submissions. The group said the agency could provide more clarity on cross-referencing information across INDs, using investigational versus licensed product experience, common platform dossiers, updates across related programs, and using consortium-generated datasets.
"The FDA should also clarify the distinction between leveraging prior knowledge to support scientific conclusions and formally cross-referencing previously submitted information to satisfy application requirements, particularly where current BLA regulations require information to be submitted directly in the application," said Friends. "Greater procedural clarity would help ensure that prior knowledge can be reused efficiently even when the underlying information must be resubmitted in a particular application.
"The FDA could also clarify how leveraging prior knowledge relates to the Platform Technology Designation Program and other emerging frameworks for individualized therapies, including how these mechanisms may be used independently or together," the group added.
