CMC considerations

Changes from the draft guidance:

In January 2024, FDA published the final guidance “Human Gene Therapy Products Incorporating Human Genome Editing,” finalizing a March 2022 draft guidance of the same name. Notable changes in the final version include an explicit definition of "GE component" (any material essential for the intended genomic modification, including those not appearing in the final drug product), a revised definition of "therapeutic editing threshold" (degree of genome modification needed for the desired therapeutic effect), additional clarifications to potency assay expectations, and additional flexibility on timing for certain evaluations or assessments of GE components and assays.

Webinar discussion:

In discussing Drug Product (DP) definitions during its February 2024 webinar on “Human Gene Therapy Products Incorporating Human Genome Editing,” FDA elaborated on the considerations for various types of GE products. For GE products administered via nanoparticles, FDA clarified that the nanoparticle containing the components in its final formulation constitutes the DP. Similarly, for GE products expressed in vivo through directly administered vectors, the vector encoding the GE components in its final formulation is deemed the DP. Finally, for ex vivo modified products, such as modified cells, the final formulation including the modified cells serves as the DP.

The agency also provided recommendations for gRNA purity analyses, including the purity requirements for full length gRNA and characterization of impurities, alternative techniques to G-banding analyses for confirming chromosomal stability following gene editing, and considerations for lot release characterization when using donor templates or performing multiplex GE.

Nonclinical considerations

Changes from the draft guidance:

The final guidance provided examples of in vitro models and possible biological consequences of on- and off-target editing on cell physiology, clarified what cells can be used to characterize on- and off-target editing, and changed the phrase “chromosomal rearrangements” to “chromosomal abnormalities.”

Webinar discussion:

FDA emphasized the need for sponsors to carefully evaluate the functionality of GE products, assessing whether editing occurred at the intended locus and whether it translated into the desired functional outcome. These evaluations can be done in vitro or in vivo using animal models that are representative of the target cell types. Importantly, the choice of animal model should be biologically relevant to the intended therapeutic effect, and aid in determining the level of editing necessary for clinical activity (the “therapeutic threshold”).

Sponsors should also conduct comprehensive on- and off-target editing assessments to analyze the safety of the investigational GE product. FDA generally recommends using multiple methods for this analysis to reduce bias, starting with in silico methods before moving to biochemical and cellular assays.

For biodistribution studies, FDA explained these can be done either standalone or in conjunction with proof of concept or safety studies. Once the sponsor can pinpoint the type, genomic location, and frequency of genomic alterations through biodistribution data, sponsors should then assess the impact of the editing on the physiology of these cells. This includes how the edits may impact cellular function, survival, and differentiation and proliferation capacity. Finally, if the biodistribution data show distribution or editing in gonadal tissues, FDA will likely require additional assessments for germline transmission and reproductive toxicity.

FDA also discussed considerations for nonclinical assessments of immunogenicity, tumorgenicity, and how to specifically conduct an assessment of distribution or editing activity seen in reproductive organs.

Clinical considerations

Changes from the draft guidance:

Notable changes from the 2022 draft guidance include additional clarification that sponsors should conduct clinical assessments of the outcomes of off-target editing and unintended consequences of on-target editing, clarification on monitoring and staggering within clinical trials, and a requirement that sponsors obtain voluntary consent to long-term follow up before trial enrollment. The agency also emphasized that accelerated approval can be appropriate for GE products in certain circumstances.

Webinar discussion:

FDA discussed clinical study population selection and the need for careful consideration of the risk-benefit profile. While it was noted that the decision ultimately lies with the sponsors, FDA recommended that where appropriate, early and first-in-human trials should primarily enroll subjects with no other treatment options available. However, FDA acknowledged that this may not always be feasible, and recommended sponsors focus on maximizing benefit while minimizing potential risks when enrolling patients for first-in-human trials. For pediatric patients, FDA also emphasized the importance of enrolling subjects that can understand and consent to study procedures and risk, wherever possible.

Regarding dose and dose schedules, FDA noted the importance of minimizing adverse events from product delivery to target tissues. Sponsors should support delivery and proposed dose schedules with nonclinical and, where possible, clinical experience for similar cell and/or gene therapy products. The agency also recommended treatment plans include stagger intervals that provide sufficient time to detect both acute and subacute adverse events prior to dosing additional patients, taking into account the expected duration of activity of the GE product.

Monitoring and follow-up strategies should include a well-defined toxicity grading system and management plan, and should focus on off-target and unintended consequences of on-target editing identified through nonclinical studies. The agency stated that sponsors should conduct long-term follow-up for up to 15 years following administration, and should have a plan to ensure subject safety in the event an IND is discontinued.

The agency also discussed the availability for the accelerated approval pathway for GE products, considerations when choosing efficacy endpoints, and emphasized the importance of engaging with the agency early in the study design process to get agency input early on.

Authored by Michael N. Druckman, Bryan Walsh, and Katie Kramer