FDA: Genome editing therapies may use accelerated approval pathway

The US Food and Drug Administration (FDA) has finalized guidance to assist sponsors developing gene therapy products that incorporate genome editing (GE) of human somatic cells; the final version revises the draft by stating that the accelerated approval pathway may be used for these products.

The final guidance, issued on 29 January, addresses the information that should be provided in an investigational new drug (IND) application to assess the safety and quality of investigational GE products, and covers product manufacturing and testing, nonclinical safety assessment, and clinical trial design. It also provides more clarity on the criteria for enrolling pediatric patients in clinical trials and provides clearer expectations for potency testing.

The guidance finalizes a draft version issued in March 2022. (RELATED: FDA drafts guidance on genome editing, CAR T cell therapies, Regulatory Focus 16 March 2022)

FDA received 26 comments on the draft guidance; and reactions were mixed. While some groups supported the guidance, others did not. The Biotechnology Innovation Organization (BIO) wrote that “in general, this is a well-written guidance that will be useful until more experience is gained with these therapies. The guidance puts forward reasonable expectations for off-target analysis and safety in the context of gene editing.”

Novartis wrote that “we agree with general recommendations to communicate early and often during GE product development. We note that once a product is approved, there are additional product development activities to optimize manufacturing processes to improve patient outcomes. It is critical for Sponsors to be able to engage with FDA throughout a GE product’s life cycle, including post approval.”

Yet the Alliance for Regenerative Medicines (ARM) objected to the :tone" of guidnace. FDA, said the group, "seems to regard gene editing technologies as having a different (less favorable) benefit-risk foundation than gene replacement technologies. We encourage the Agency to revise the tone and content of the guidance with this feedback in mind if it was not the Agency’s intent to communicate that gene editing products may have a higher hurdle to overcome to establish a positive benefit-risk profile.”

Accelerated approval

The final guidance states that sponsors can use the accelerated approval pathway for gene editing products if these products are intended to treat a serious or life-threatening disease where there is a lack of available alternative treatments.

“FDA is supportive of the use of accelerated approval for GE products and encourages sponsors to discuss the potential eligibility of a GE product for such program, including the proposed surrogate endpoints or intermediate clinical endpoints, early in development of the clinical trial,” the agency wrote.

Under the accelerated approval pathway, sponsors may need to use a surrogate endpoint or marker that is “reasonably likely to predict clinical benefit” or use an intermediate clinical endpoint that that is “reasonably likely to predict an effect on irreversible morbidity or mortality.”

Products approved under this pathway may be subject to postapproval studies to verify and describe the product’s predicted effect.

BIO and other companies had requested the use of the accelerated approval pathway for GE products. BIO in its comments stated that “to avoid confusion, we would recommend that FDA incorporate specific language regarding Accelerated Approval and appropriate endpoints for genome editing products that is consistent with language used in other FDA guidances for cell and gene therapy products.”

FDA’s Peter Marks, head of the Center for Biologics Evaluation and Research (CBER) had previously indicated a willingness to expand the accelerated approval program to include gene therapy products, especially for those that treat rare diseases. (RELATED: FDA plans to launch communications pilot for promising rare disease gene therapies, Regulatory Focus 27 February 2023)

More clarity on when to enroll pediatric patients

The guidance also provides more clarity on when to enroll pediatric patients in GE trials. BIO asserted that the draft did not address circumstances where young children, and possibly infants, should be the primary intended population for these trials, especially in cases of such diseases as infant-onset Pompe and spinal muscular atrophy (SMA).

FDA’s finalized guidance said manufacturers should consult a draft guidance issued in September 2022 which addresses the ethical considerations and the risk benefit calculation of enrolling children in clinical trials. The guidance is called “Ethical Considerations for Clinical Investigations of Medical Products Involving Children; Draft Guidance for Industry, Sponsors and IRBs.” (RELATED: New FDA guidance offers ethical roadmap for including children in clinical trials, Regulatory Focus 26 September 2022)

More clarity on potency assays

The guidance also provides more clarity on the use of potency assays for in vivo gene editing products. Pfizer wanted examples of such potency testing for in vivo gene editing products.

The final guidance states that sponsors should develop potency assays to measure multiple aspects of activity for in vivo human GE products. For early phase studies, potency assays should evaluate the ability of GE components to perform the desired genetic sequence modification. And for studies intended to provide primary evidence of effectiveness to support a marketing application, potency assays should assess the intended downstream biological modification. FDA states that “we recommend that, whenever possible, the potency assays be performed in the target cells or tissues (or a representative surrogate). We also recommend inclusion of such a potency assay in the DP stability studies.”

FDA rejects suggestion to expand GE treatments

Yet in other areas, FDA rejected industry’s suggestion to expand GE first-in-human trials to include patients that have other treatment options. The draft stated that “first-in-human trials involving such products generally should enroll only subjects for whom no other treatment options are available or justified.” The final guidance retained this provision.

In its comments, BIO wrote that “we are concerned that the language used in the Draft Guidance appears very restrictive with respect to clinical enrollment for GE trials. The Guidance recommends enrolling subjects for whom no other treatments options are available or acceptable. This is contrary to the transformative potential of GE for patients and does not reflect a proper benefit/risk assessment that should be taken based on the specific product and the specific patient population.”

The final guidance also changes the term “preclinical studies” to “nonclinical studies in the text.

Difficulties in meeting with FDA

In other areas, Novartis in its comments on the draft cited its difficulties in scheduling meetings with the Office of Tissues and Advanced Therapies (OTAT) on their applications, and that many of their meeting requests have been denied or recommended for a Written Response Only (WRO) communication.

The company said that “we look forward to when there are opportunities to meet with FDA directly again.”

Final guidance, Federal Register notice, public docket

FDA: Genome editing therapies may use accelerated approval pathway

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