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FDA Details Expectations for Gene-Editing Therapy IND Applications

FDA sign at its headquarters in Washington D.C.

NEW YORK – US Food and Drug Administration staff discussed in a public webinar on Thursday what information the agency expects drugmakers to include in applications seeking permission to begin first-in-human trials for therapies that involve human gene editing, including recommendations on proposed clinical trial designs, product manufacturing and testing, and safety assessments.

Prior to this webinar, the FDA had finalized a guidance in January for drugmakers on these topics, updating recommendations it proposed in a draft form in March 2022. "This guidance is intended to provide sponsors, industry members, and other stakeholders with recommendations on what to include in an investigational new drug application," said Denise Gavin, director of the Office of Gene Therapy in the Office of Therapeutic Products (OTP) at the FDA's biologics division, during the webinar.

The recommendations the FDA makes in guidance documents aren't legally binding on industry players but represent the agency's current thinking on how sponsors can best meet regulatory expectations. Sponsors can use approaches not included in guidelines, but the FDA advises sponsors to discuss them with agency staff.

Representatives of the biopharmaceutical industry have been supportive of the FDA's efforts to provide greater clarity into its expectations for drugmakers developing gene-editing therapies. "In general, the FDA guidance strikes an appropriate balance between setting baseline expectations and providing flexibility where needed to account for the evolving science and benefit-risk profile of gene-editing products," said Janice Chen, cofounder and chief technology officer of CRISPR therapy company Mammoth Biosciences.

Andrew Powaleny, senior director of public affairs at the industry lobbying group Pharmaceutical Research and Manufacturers of America, noted that the FDA's final guidance on IND submissions for medicines incorporating human gene editing comes at a time when this field of medicine is evolving rapidly. "PhRMA believes guidance in this area will not only help inform this advancing science but also aid sponsors developing these cutting-edge medicines for patients with the potential to treat, or even cure, serious diseases," Powaleny said. 

The commercial market for gene-editing-based therapeutics is in its infancy, but it is poised to grow quickly. Last year, the FDA approved the first CRISPR gene-edited therapy, Vertex Pharmaceuticals and CRISPR Therapeutics' Casgevy (exagamglogene autotemcel) for sickle cell disease, and there are many others in clinical and preclinical development that rely on gene editing using CRISPR, base editing, zinc finger nucleases, and other techniques.

Anticipating that a bolus of applications for gene therapy products is headed its way, the FDA has said it wants to explore ways of expediting the entry of such therapies to the market. For example, the agency has previously expressed interest in getting more rare disease gene therapies to market through the accelerated approval pathway, and in the latest final guidance, the FDA made explicit its support for this approach in products that use gene editing.

The accelerated approval pathway allows the FDA to shepherd drugs for serious conditions without available treatment options to market quickly by approving them based on surrogate endpoints — or biomarkers that are expected to predict clinical benefit — rather than requiring direct evidence of clinical benefit.

Even at the IND application stage, it's not too early to start thinking about accelerated approval. "We're quite supportive of the use of accelerated approval for genome-editing products, and we encourage sponsors to discuss the use of accelerated approval with us early in their clinical development programs," said Gavin Imperato, chief of the general medicine branch in the division of clinical evaluation general medicine within OTP's office of clinical evaluation, during the webinar. "Accelerated approval is a powerful tool, and we strongly encourage sponsors who are developing genome-editing products to consider it."

The reference to accelerated approval in the final guidance is a new addition that wasn't in the 2022 draft version, an omission that organizations such as the American Society of Gene & Cell Therapy had flagged. "The final guidance includes significant additional language on the use of surrogate endpoints for GE products, including an explicit statement that the agency is supportive of accelerated approval for GE products," Christina Mayer, ASGCT's senior manager of government affairs, wrote in a statement published online Wednesday.

The FDA defines genome editing in the guidance as the process by which DNA sequences are added, deleted, altered, or replaced at specified places in the genome. "We tried to be as inclusive as possible in this definition, so as not to limit this guidance to only currently available GE technologies," Anna Kwilas, chief of the gene therapy branch in the Office of Gene Therapy at the FDA, said during the webinar.

The final guidance focuses on what the FDA refers to as "GE components," which encompass any material needed for an intended genetic modification, including the editing technology, DNA template, delivery method, and DNA targeting element, such as a guide RNA. In an IND application, sponsors should include detailed descriptions of the manufacturing processes and testing for all these components. 

The FDA specified that components administered in vivo are considered active pharmaceutical ingredients or drug substances, whereas components used to modify cells ex vivo are considered critical components for manufacturing.

In the finalized guidance, the FDA also stressed that clinical trials of these products not only need to address risks associated with gene therapy, for which there are already established guidances, but also address additional risks specifically associated with gene editing. That can include the potential for off-target mutations, as well as potential unintended consequences of on-target edits.

"The benefit-risk profile for each product depends on the proposed indication and patient population, the extent and duration of therapeutic benefit achieved, and the availability of alternative therapeutic options," the FDA wrote.

To identify potential risks, the FDA suggested sponsors undertake nonclinical safety studies to identify any chromosomal abnormalities that could arise, evaluate the distribution and persistence of edits, and analyze on- and off-target edits with multiple methods, such as in silico analyses and cellular-based assays. Based on these analyses, sponsors of IND applications should describe how they have optimized the editing and targeting components in their products to reduce the likelihood of off-target mutations and how they plan to monitor off-target mutations in clinical trials.

Products in which genes are edited in vivo and ex vivo carry different challenges for preclinical studies. When evaluating an in vivo product, the FDA acknowledged that typical animal studies might not work to assess safety, since genomic sequences can differ between animals and humans. In that case, sponsors can consider a surrogate gene-editing product, substituting promoters or transgenes with species-specific elements, though they should also provide the scientific justification for that surrogate product in their application. For ex vivo products, the FDA said that the targeted clinical cell type should be used in nonclinical studies, with a justification provided if an alternative cell type is used.

Another area of focus in the guidance is assessing potency of a gene-editing product, for which the FDA suggested a phased approach. That includes initially using potency assays to measure a product's ability to perform the intended genetic sequence modification, which the agency said could be sufficient for earlier-phase clinical studies, in addition to assessing downstream biological modifications, which will be expected in later-stage clinical studies used to support marketing applications.

In late 2023, the FDA published a separate draft guidance on potency assurance for cell and gene therapy products, which was meant to replace a version that hadn't been updated since 2011. Previously, drugmakers had expressed confusion about what information they needed to demonstrate to regulators that they could reliably and consistently produce each dose and batch of precision cell and gene therapies, treatments that are manufactured for individual patients. 

That phased approach to potency testing, among other language in the finalized guidance on gene-editing therapies, showcases the FDA's understanding that the gene-editing field is rapidly evolving, and that the agency will need to be flexible in its expectations, said Shawn Davis, CEO of Liberate Bio, a biotech company developing non-viral delivery technologies for genetic medicines. He said he also appreciated the FDA's acknowledgement that IND-enabling materials should be representative of final materials, rather than requiring that they be fully comparable.

These recommendations "all allow developers of genetic medicines to move at the pace of discovery while still maintaining high-quality standards," Davis said. The finalized guidance doesn't change his company's development plans, he noted, but it "gives us the confidence to build our internal pipeline with greater clarity regarding the agency's expectations."

When designing first-in-human trials, the FDA said sponsors should consider the anticipated "magnitude" of therapeutic benefit and the "availability, safety, tolerability, and effectiveness" of alternative therapeutic options already on the market. The agency further stressed that sponsors should consider a narrow study population based on a product's mechanism of action, expected benefits, and availability of alternative treatments. Given that gene-editing products have "significant risks and an uncertain potential for benefits," the agency suggested that first-in-human trials should generally enroll patients who don't have other treatment options.

"It's really important, particularly for genome-editing products where there are many unknowns, that the benefit-risk profile of the patient population is optimized," the FDA's Imperato said. "This is again another plug for sponsors to engage with us early in their development programs."

The FDA advised caution when considering administering gene-editing treatments to children, noting that investigators, when possible, should enroll patients who can "understand and consent to the study procedures and risks." In cases where a treatment is intended for a disease affecting children, the FDA suggested that a sponsor initially enroll a cohort of adult subjects to obtain data on safety and feasibility and enroll adolescents or older children prior to younger children and infants.

To mitigate anticipated safety risks, after administering a gene-editing product to a patient, sponsors should stagger subject enrollment to ensure there's time to detect potential adverse events before treating additional patients, as well as before increasing the dose in subsequent cohorts. And, since some risks will be unknown when clinical trials begin, the FDA recommends that sponsors conduct long-term follow-up of participants for up to 15 years after treatment.

"Overall, it's a reasonable guidance document," said Jerry Vockley, who sits on the American College of Medical Genetics and Genomics' board of directors. "It provides some very specific guidance where possible but also leaves flexibility as necessary given the variance in gene-editing therapies. [This] guidance will likely need to be updated often as both preclinical platforms and clinical trial models evolve."