The development of a gene therapy (GT) product has many considerations that differ from those of a traditional biologic or new chemical entity (NCE) program. CBER has issued many guidances that relate to GT products in whole or in part, with the key guidance relating to the nonclinical aspects issued in November 2013 (Preclinical Assessment of Investigational Cellular and Gene Therapy Products | FDA). Based on the concepts in this FDA guidance document and Rho’s experiences with INTERACT (INitial Targeted Engagement for Regulatory Advice on CBER producTs) and pre-IND meetings for GT products, it is clear that the Agency places a high value on several key points in the guidance; failure to appropriately address these points can derail a GT program.

The guidance is full of statements regarding the use of disease/injury models for evaluation of GT products. While use of such models are encouraged by the Agency to better define the risk-benefit ratio and to possibly identify activity-risk biomarkers that may be applicable for monitoring in clinical trials, several limitations of preclinical animal models exist that are noted in the guidance and that developers should be mindful of when considering their use. Multiple animal models, sometimes in non-standard species (such as genetically modified rodents or large animals), may be necessary to adequately characterize the human condition and thus test the GT product. It is highly important to understand the disease progression in the animal model(s) because the activity and safety profiles of the GT product may be influenced by the timing of administration; this point was highlighted by the Agency in its review of the now FDA-approved GT product Zolgensma, where in the FDA Pharm/Tox reviewer noted that limitations of the proof-of-concept studies included timing of vector administration (May 24, 2019 Summary Basis for Regulatory Action – ZOLGENSMA (fda.gov)). Additionally, we often see the FDA request additional information and explanation of the relevancy of the animal model(s) used in a GT program throughout early product development, up to and including the initial IND review period. Therefore, ensure any animal models used to support a GT product are well characterized and representative of the human pathology, and that sufficient information is provided in any briefing packages when meeting with the Agency and in the IND itself. Keep in mind that it may be necessary to conduct a natural history study to characterize the animal model and/or the human disease, and these studies generally have long timelines.

The nonclinical program supports clinical dose selection, which often presents unique challenges for GT developers. The proof-of-concept nonclinical studies should investigate a dose range (identifying the minimally effective dose and optimal biological dose), various routes of administration (to confirm the GT product reaches the target anatomic site/tissue/cell), optimal timing of product administration relative to disease onset, optimal dosing schedule (often single dose only, though not always), and the putative mechanism of action or hypothesized biological activity of the GT product. For the safety (i.e., toxicity) studies, the overall design should mimic the proposed clinical trial design as closely as possible. Multiple dose levels of the investigational GT product, which should bracket the proposed clinical dose range, should be tested. The route of administration and dosing schedule that reflects the intended clinical route and dosing regimen, to the extent possible, should be used in these nonclinical safety studies. A point that is often overlooked by GT developers is that they are responsible for providing sufficient data in the IND to allow the FDA to determine the safety of the delivery device system. If possible, the delivery device system used in the definitive preclinical studies should be identical to the planned clinical product delivery device, and the device will typically need to be cleared for the specific route of administration in the proposed clinical trial. Considerations regarding allometric scaling of the dose from the nonclinical studies to the clinic is often challenging, and unlike NCE programs, body weight may not be the most appropriate measure. Allometric scaling can depend on the tissue targeted, the route of administration, and also potentially on the vector. Accurate scaling of the dose can only be obtained when validated methods were used to assess the titer of the GT product in the nonclinical studies; this point too was highlighted by the FDA review of Zolgensma in which several nonclinical studies could only be included as supportive data because validated methods were not used to assess titer. Delays in developing a validated analytical method will likely delay clearance of the IND.

Overall, nonclinical programs for GT products are diverse and customized. Consult the FDA guidance documents and take advantage of the various meetings FDA offers sponsors of GT products. Importantly, heed the FDA’s recommendations when provided and seek professionals, such as those at Rho, with experience in navigating the complexities of GT products.

Brenda Faiola, Ph.D., DABT, Senior Director, Nonclinical Development, has over 15 years of experience in the pharmaceutical and medical device industries. She received her Ph.D. in Immunology from Duke University in 2001 and has been a Diplomate of the American Board of Toxicology since 2004. At Rho, Dr. Faiola oversees and provides support regarding nonclinical aspects of Integrated Product Development and Integrated Regulatory Submissions for pharmaceutical, biologics, and medical device programs.

Joseph Watson, Ph.D., RAC, Director, Regulatory Strategy, has served as a contributor, lead, and expert reviewer for products targeting rare diseases across multiple neurological, musculoskeletal, and infectious disease indications. He has experience in both regulatory submissions and clinical document preparation, with over fifteen years of experience in scientific writing and editing clinical and nonclinical documents, including numerous publications in peer-reviewed journals.  Dr. Watson has led the preparation, review, and coordination of a variety of regulatory and clinical documents, including protocols; clinical study reports; integrated summaries of biopharmaceutics, safety, and efficacy; CMC and nonclinical documents; draft product labels; and 120‑day safety updates.  His writing and editing experience covers a broad range of therapeutic areas, including multiple orphan drug indications and rare pediatric disease designation applications.  

Kelsey Behrens, Ph.D., Research Scientist, supports regulatory submissions and product development. She has a decade of experience in writing, reviewing, and editing scientific documents and has prior experience in the design and management of both clinical and nonclinical studies. Dr. Behrens has participated in the authoring and preparation of US NDA and IND modules, clinical study reports, clinical study protocols, and briefing packages to support regulatory meetings.