March 25, 2022

Safety First! Much-Anticipated FDA Draft Guidance Provides Additional Advice on the Development of Human Genome Editing Products

Last week the U.S. Food and Drug Administration (FDA) issued a long-awaited draft guidance, Human Gene Therapy Products Incorporating Human Genome Editing, that addresses key considerations for the development of gene therapy products incorporating genome editing (GE) of human somatic cells, including information that should be provided in an Investigational New Drug (IND) application. FDA defines “human GE” for purposes of this guidance as a process in which DNA sequences are added, deleted, altered or replaced at specified location(s) in the genome of human somatic cells, ex vivo or in vivo, using nuclease-dependent or nuclease-independent GE technologies.

Building on its prior cellular and gene therapy guidance documents, this draft guidance describes FDA’s current thinking on product design, manufacturing, preclinical safety testing, and clinical trials of human GE products. Importantly, the guidance acknowledges that because this field is “rapidly evolving,” these recommendations may change as human GE products advance and more safety information becomes available.

Product design

The draft guidance starts with an emphasis on intentional and thoughtful product design. Specifically, the FDA advises sponsors of human GE products to consider the (i) genome editing method, (ii) type and degree of genomic modification needed for the desired therapeutic effect, and (iii) method of delivery. When selecting a genome editing method (e.g., nuclease-dependent or nuclease-independent), the guidance recommends considering the mechanism of action, the ability to specifically target the desired DNA sequence, and the ability to optimize the GE component(s) to improve efficiency, specificity or stability. To justify the degree of genome modification needed to achieve the desired therapeutic effect, the guidance recommends detailing in the IND available clinical data or other justification for the product’s modification threshold. With respect to product delivery, the guidance recommends that sponsors consider the product’s intended use, as well as the advantages and limitations of each potential delivery method (including, for example, the persistency of GE components which may increase the risk of off-target editing, and the potential for vector-mediated toxicity).

Chemistry, manufacturing, and controls (CMC)

The guidance includes numerous CMC recommendations for human GE product components, including that a sponsor should optimize GE component(s) to reduce the potential for off-target editing and describe the optimization strategy in detail. An IND should also include extensive component-specific information, such as how each component is manufactured, purified, and tested, and stability studies for all GE components. In addition, the guidance offers several specific recommendations for drug product manufacturing and testing, including the development of applicable assays and specifications, and outlines varying considerations for in vivo-administered vs. ex vivo-modified human GE products. For example, for an in vivo GE product delivered by nanoparticles, the guidance suggests that under certain circumstances these nanoparticles may be considered a delivery device. For an ex vivo allogeneic GE product, the guidance notes that additional donor screening and testing may be needed beyond the requirements set forth in FDA’s current regulations for human cellular and tissue-based products.

Preclinical studies

The guidance recommends that preclinical in vitro and in vivo proof-of-concept studies evaluating the activity of a human GE product include assessments of specificity and efficiency of editing in target and non-target cells, functionality of the corrected or expressed gene product, editing efficiency required to achieve the desired biological effect, durability of genome modification, and effects of genetic variation on editing activity. To assess safety, preclinical studies should identify and characterize the risk of editing at on- and off-target loci, including by using multiple orthogonal methods to identify potential off-target sites, evaluating the biological consequences of on- and off-target editing, and assessing the potential for inadvertent germline modification. 

Clinical trials

This section of the guidance focuses on minimizing risks to clinical trial study subjects and adequately assessing the risks of human GE products. At the current time, FDA notes that “[h]uman GE products may have significant risks and an uncertain potential for benefits,” thus the agency generally recommends that first-in-human clinical trials be conducted in patients with no other available or acceptable treatment options. On the other hand, the agency recognizes that patients with more severe disease, who may be more willing to participate in clinical trials of GE products, may also be predisposed to more adverse events or may be receiving several concomitant treatments, which could make the data from a clinical trial of a GE product more difficult to interpret. The guidance also underscores the agency’s prior recommendation for staggered subject enrollment, with a pre-specified interval between product administration to sequential study participants, to allow for monitoring of adverse events and mitigation of anticipated risks. The FDA emphasizes it is “crucial” to have a “thorough” safety monitoring strategy in the clinical trial protocol, including a well-defined toxicity grading system and toxicity management plan. Monitoring plans should capture adverse events related to aberrant cellular proliferation, immunogenicity and tumorigenicity. To identify long-term effects that may be unknown at the time of GE product administration, the guidance recommends that sponsors seek study subjects’ consent to long term follow-up (LTFU) prior to enrolling in a clinical study, and reiterates that sponsors should conduct LTFU for at least 15 years after administration of GE products. 

To discuss the numerous product-specific considerations that may arise when moving a human GE product into clinical development, the guidance encourages sponsors to consult early with the Office of Tissues and Advanced Therapies within the Center for Biologics Evaluation and Research, before submitting an IND application. The guidance suggests pre-IND or INTERACT meetings, depending on the timing and nature of the advice sought by the sponsor.


Comments on this draft guidance should be submitted to the docket by June 14, 2022.

There is much more in this draft guidance than what we have highlighted here. For questions about this guidance and its implications for your human GE product development program, or for assistance with commenting on this guidance, contact the authors or your regular Goodwin lawyer.