The draft guidance from the Center for Biologics Evaluation and Research outlines safety considerations throughout the clinical development program timeline.
The FDA’s Center for Biologics Evaluation and Research has issued draft guidance for industry players developing gene therapy products that involve gene editing. The document, which is currently open to comments, is a reflection of the concern surrounding safety of gene-editing strategies—namely off-target effects—for the treatment of a range of disorders.1
Specifically, the document outlines the information that should be included in a sponsor’s investigational new drug (IND) application in order for the agency to effectively evaluate safety and efficacy.
The guidance document, which includes information on product design, manufacturing, and testing, as well as preclinical safety assessment and clinical trial design, follows a similar document released in 2020 that addressed these potential issues within the gene replacement therapy category.2
Although excitement abounds with the potential of these new therapeutic strategies, safety, especially over the long-term, is largely unknown. As such, the FDA recommends that industry sponsors follow clinical trial participants who undergo gene editing for a minimum of 15 years to better capture both immediate and long-term safety developments that can be a direct result of gene editing, including “off-target editing, unintended consequences of on- and off-target editing, and the unknown long-term effects of on- and off-target editing,” the agency wrote.
In preclinical studies, the agency suggests that studies be designed to detect safety risks, including toxicity associated with delivery of the therapy, modification of the genomic structure, and expression of the gene product. In addition, safety analyses should account for any off-target activity and chromosomal rearrangements, and the consequences of such. In vivo preclinical safety studies should reflect elements of the planned clinical trial where feasible to best characterize potential toxicities, the timing of onset and resolution, and effects of dose levels.
Recognizing that additional risks of a gene editing product may be realized at the clinical stage, the agency places emphasis on risk-benefit when selecting an appropriate study population for first in human trials, noting that they “should be designed to enroll only subjects for whom no other treatment options are available or acceptable.” Although some participants with more advanced disease may be more willing to participate in these trials despite the risks, they may also be a greater risk of AEs. Therefore, “in some instances, subjects with less advanced or more moderate disease may be appropriate for inclusion in first-in-human clinical studies” so as to not complicate interpretation of safety or efficacy data.
To further mitigate risks associated with administration of the gene editing product, the agency suggests study sponsors stagger participant enrollment, with clearly specified intervals of time between product administration among trial participants.
Beyond monitoring for off-target editing and unintended effects of on- and off-target editing, the agency recommends that sponsors monitor for AEs related to “aberrant cellular proliferation, immunogenicity, and tumorigenicity.” Ideally, these AEs should be anticipated based on preclinical findings, with management strategies outlined in study protocols.
Overall, with this document in place as well as an emphasis on communication with the FDA early and often, the agency hopes to simplify the IND process and minimize safety findings that can potentially derail clinical programs working to address high unmet clinical needs.