Stakeholders seek clarification, flexibility, expansion of CGT guidance

Stakeholders want more clarity, detail, and flexibility in a recent guidance proposed by the US Food and Drug Administration (FDA) for sponsors developing cell and gene therapies (CGTs). Some specific areas the commenters addressed include alignment with past policies, the use of surrogate endpoints, and expanding and updating the guidance as FDA gains more experience in this field.

In November, FDA asked sponsors for feedback on a draft guidance addressing key questions for drugmakers developing cell and gene therapies (CGTs). The guidance also addresses interactions with the agency, as well as considerations for conducting clinical and non-clinical studies. (RELATED: FDA drafts Q&A guidance on cell and gene therapy development, Regulatory Focus 19 November 2024)

FDA received 18 comments on the guidance before the docket closed on 18 February, including feedback from the pharmaceutical lobby group PhRMA. The groups said it wants the agency to update policy on requesting meetings with the agency on CGT development to align with commitments agreed upon under the latest iteration of the Prescription Drug User Fee Act (PDUFA VII).

PhRMA said that some of the expectations and limitations regarding the meetings in the draft guidance aren’t aligned with what FDA has already agreed to do, including proposed page limitations for briefing packages.

"PhRMA is aware that FDA has previously mentioned limits on the number of meeting questions in Standard Operating Procedures and Policies (“SOPPs”) and other Draft Guidance," said PhRMA. "Nevertheless, such limitations are not present in the PDUFA VII Commitment Letter and are not consistent with the non-binding nature of guidance."

"Accordingly, PhRMA thus recommends that FDA revise the guidance to provide flexibility with respect to expected page counts," the group added. "At the very least, we encourage FDA to clarify that it will exclude a submission’s appendix from any page limits."

PhRMA also objected to the FDA's proposed requirement that sponsors complete some proof-of-concept studies before holding an Initial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs (INTERACT) meeting. The group said that proof-of-concept studies are topics that have already been deemed acceptable for INTERACT meetings as agreed upon in PDUFA VII and CBER SOPPs and a draft guidance on formal meetings. It also asked FDA to clarify when the design and conduct of definitive toxicology studies are an appropriate topic for the meetings and provide more details on what topic areas are not appropriate compared to pre-investigational new drug (pre-IND) meetings.

PhRMA also asked for more clarity on Chemistry Manufacturing and Controls (CMC)-specific issues during meetings, more certainty on timelines for protocol submission feedback, eligibility of CGT products for FDA's Split Real Time Application Review (STAR) pilot program, and more.

The lobby group further asked FDA to allow more flexibility in using non-traditional study designs. The group said natural history controls are important for sponsors developing CGT products but asked the agency to allow sponsors to reference other examples of external controls available in guidances, including data from other trials and sources of real-world data (RWD), and consider them on a case-by-case basis.

"Moreover, since gene therapy treatments are often designed for a single dose and FDA has approved gene therapies where a dose-response relationship has not been identified, we encourage the agency to clarify its expectation for evaluating more than one dose, including expectations for establishing a dose-response relationship and for dose selection for the pivotal trials," said the group.

PhRMA asked for more clarity on endpoint selection for accelerated approval drugs and considerations for developing CGTs for rare diseases. The group also asked FDA to expand the questions addressed in the guidance to include topics such as clinical immunogenicity assessments, role of viral vectors in CGTs, and non-conforming chimeric antigen receptor (CAR) T-cell products.

While FDA said it plans to keep updating the guidance with additional FAQs over time, the biotechnology lobby group, BIO, asked for more detail about how it plans to do that.

"For this guidance to be an effective tool, we recommend the agency enact a pathway to promptly update the FAQs information and have effective responsiveness when necessary modifications and instances occur as this would be most useful for sponsors," said the group.

BIO made several recommendations to the guidance regarding manufacturing, CMC-specific issues, and non-clinical and clinical considerations. Specifically, the group asked for clarity on the acceptability of Master Files for IND and biologics license application (BLA) applications, considerations for discipline-specific pre-IND meetings and other meetings before pre-BLA, expectations for chain of custody and chain of identity for IND and BLA applications, and information expected in IND or marketing applications for investigational devices and companion diagnostics.

"We agree with the use of non-clinical lots to support stability for Phase 1 studies and suggest including more questions on CMC-specific issues, control strategy considerations for raw materials, and phase-appropriate method qualification/validation," said BIO. "It would also be helpful to provide guidance on whether lentiviral vectors used in CAR-T cell therapy manufacture is a critical starting material or a Drug Substance."

"Additionally, we recommend addressing considerations for clinical immunogenicity assessments, including risk-based and phase-appropriate approaches," the group added. "As well as clarification on whether updates after clinical development are supported, especially for products using patient-derived starting material."

Bio asked FDA to amend its policy on clinical holds so that sponsors can formally engage with FDA using means such as brief phone calls so that sponsors can get clarity on non-hold comments. The group also asked the agency to consider in vitro and in silico models as an alternative for tumorigenicity studies when animal models are not pharmacologically relevant, and to include guidelines on using surrogate endpoints for new CGT treatment and modalities.

The American Society of Gene and Cell Therapy (ASGCT) wrote to FDA recommending changes regarding its policies on product development considerations and when sponsors conduct human trials. The group addressed the agency's policy on differentiating between product characterization testing and release testing.

ASGCT asked for more detail on why characterization assays are necessary as part of an IND submission when considering FDA's perspective that characterization tests do not need to be qualified or included for product release.

"Our concern is that including elements that are not necessary for characterization assays, without providing additional guidance on their positive use, may be confusing," said ASGCT. "In addition, this contributes to ongoing confusion around the need to establish acceptance criteria for and include non-critical, unqualified characterization assays in important development studies such as comparability studies."

In the draft guidance, FDA states that when an animal model of the target disease is unavailable or if the CGT product in development is incompatible with an animal model, the sponsor should look for supporting data from other sources. ASGCT noted that most CAR T-cell therapies do not have established animal models and asked the agency to clarify whether its reviewers will consider using a combination of varying sources to address the lack of animal models.

For accelerated approval, FDA said in the guidance that it would accept proven evidence surrogate endpoints that are likely to predict a clinical benefit or an intermediate clinical endpoint. ASGCT said it wants more information specific to intermediate clinical endpoints.

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Stakeholders seek clarification, flexibility, expansion of CGT guidance

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