Cell and gene therapies (CGT) encompass a variety of products with potentially limitless clinical applications and a non-traditional development journey1. With every success and every failure, the field collectively learns and evolves to give these innovative products a fighting chance in making a meaningful difference in the lives of countless patients. Here, we provide considerations in navigating a critical step in the process – nonclinical (preclinical) development.
Developing a Nonclinical Program for CGT Products
An important pillar in the development of investigational CGT products is an adequate nonclinical development program. Typical nonclinical studies evaluate the pharmacology, biodistribution, and toxicity profiles of these innovative products. Data from these studies are intended to support their development and the design of clinical trials 2-7.
Pharmacology Studies
Given the complexity of CGT products, nonclinical pharmacology studies should provide insights into their mechanism of action (MOA) and effect on the intended therapeutic target3. These studies may be conducted in vitro and/or in vivo, and are not typically performed in compliance with Good Laboratory Practice (GLP) standards.
TIP: As part of regulatory submissions (e.g., IND), study reports are needed for these studies as well as for biodistribution and toxicology studies. Key components of these study reports include, but are not limited to:
- Study Report Identifier – study numbers may be used to refer to the appropriate study report when the studies and their findings are described in relevant nonclinical modules.
- Materials and Methods – information on study personnel, key dates, the materials used (e.g., cells and reagents), and a description of how the study was conducted are important to provide context to the study and meaning to the findings. Note that study reports for GLP-compliant studies also include other aspects such as compliance and quality assurance (QA) statements.
- Data – individual and mean data are typically included in the study reports, with a clear indication of the statistical method(s) used, as well as the interpretation of the results and discussion.
Biodistribution Studies
The biodistribution profile of a CGT product may be useful in understanding its efficacy and safety. Biodistribution is defined as the distribution, persistence, and clearance of a CGT product following administration in vivo, and is typically determined at the site of administration as well as in various tissues and biofluids using sensitive and reproducible analytical methods5. A biodistribution assessment may be performed on a panel of tissues (e.g., heart, liver, kidney, spleen, and gonads) and biofluids (e.g., blood) collected from control and treated animals at specified timepoints.
TIP: The biodistribution profile of CGT products may be assessed as part of GLP-compliant toxicology studies.
Toxicology Studies
Understanding the toxicity profile is crucial in the development of CGT products. Typically conducted under GLP regulations, findings from toxicology studies can provide invaluable information (e.g., adverse effects, off-target toxicities, and dose response) which may be supportive of the proposed clinical dose level and dosing regimen.
Key considerations in the design of toxicology studies include, but are not limited to:
- Species Selection – identification of adverse effects in a relevant animal model(s)
- Route of Administration (ROA) – to the extent possible, using the proposed clinical ROA
TIP: Consider the FDA’s focus on the 3 Rs – replace, reduce, and refine – when designing toxicology studies8. In addition to fewer animals, alternative but relevant animals (e.g., use of non-rodent species other than nonhuman primates [NHP]) and alternative methods (e.g., in vitro assays) may be used instead.
Key Takeaways in CGT Development
The nonclinical development of CGT products is a process that requires flexibility and a data-driven approach, with clinical trial designs specific to the investigational product itself6. Given the complexity of the product and the less-defined path forward, it is important to develop a nonclinical program that keeps the end objective in mind – developing CGTs that are reasonably safe to conduct the proposed clinical trial3,7.
As CGT products continue to evolve, staying informed about the latest nonclinical development strategies is crucial. Whether navigating biodistribution and pharmacology studies or designing GLP-compliant toxicology assessments, these insights are key to shaping an effective development strategy. Additionally, understanding the regulatory landscape and clinical trial requirements is critical for ensuring compliance and streamlining the approval process for CGT products. For more information on these topics, explore our recent blog, A Regulatory Perspective on Cell and Gene Therapy in Oncology, or view our webinar, Cell and Gene Therapy Clinical Trials: How to Successfully Operationalize a Trial of Prolonged Duration.
References
1 “The Office of Therapeutic Products (OTP): A New Way Forward for Cell and Gene Therapies.” Resources. Allucent. https://www.allucent.com/resources/blog/office-of-therapeutic-products.
2 U.S. Food & Drug Administration. Guidance for Industry. Drug Products, Including Biological Products, That Contain Nanomaterials. Apr 2022. https://www.fda.gov/media/157812/download .
3 U.S. Food & Drug Administration. Guidance for Industry. Preclinical Assessment of Investigational Cellular and Gene Therapy Products. Nov 2013. https://www.fda.gov/media/87564/download.
4 U.S. Food & Drug Administration. Guidance for Industry. Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products. Jun 2015. https://www.fda.gov/media/106369/download.
5 U.S. Food & Drug Administration. Guidance for Industry. S12 Nonclinical Biodistribution Considerations for Gene Therapy Products. May 2023. https://www.fda.gov/media/167605/download.
6 Husain SR, Han J, Au P, Shannon K, Puri RK. Gene therapy for cancer: regulatory considerations for approval. Cancer Gene Ther. 2015 Dec;22(12):554-63.
7 “A Regulatory Perspective on Cell and Gene Therapy in Oncology.” Resources. Allucent. https://www.allucent.com/resources/blog/regulatory-perspective-cell-and-gene-therapy-oncology.
8 U.S. Food & Drug Administration. Focus Area: Novel Technologies to Improve Predictivity of Non-clinical Studies and Replace, Reduce, and Refine Reliance on Animal Testing. Content current as of 06 Sept 2022. https://www.fda.gov/science-research/focus-areas-regulatory-science-report/focus-area-novel-technologies-improve-predictivity-non-clinical-studies-and-replace-reduce-and.
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