FDA Guidance on Preclinical Proof-of-Concept Studies for Human Gene Therapy for Neurodegenerative Disease

 Preclinical evidence to support a prospect of direct benefit is most important when clinical evidence of effectiveness is not available from adult subjects with the same disease. Further details for general considerations in preclinical studies of these investigational GT products are available in a separate guidance document. The Food and Drug Administration issued draft guidance for "Human Gene Therapy for Neurodegenerative Diseases" for the development of a preclinical program for an investigational GT product intended for the treatment of neurodegenerative disease.

Objectives of Preclinical Studies:
A preclinical program that is tailored to the investigational product and planned early-phase clinical trial contributes to the characterization of the product’s benefit/risk profile for the intended patient population. The overall objectives of a preclinical program for a GT product include: 

    1) identification of a biologically active dose range; 

    2) recommendations for an initial clinical dose level, dose-escalation schedule, and dosing regimen; 

    3) establishment of feasibility and reasonable safety of the proposed clinical route of administration         (ROA); 

    4) support of patient eligibility criteria; and 

    5) identification of potential toxicities and physiologic parameters that help guide clinical monitoring for a particular investigational product. 

Preclinical in vitro and in vivo proof-of-concept (POC) studies 

The proof-of-concept study should be conducted to establish feasibility and to support the scientific rationale for the administration of the investigational GT product in a clinical trial. The animal species and/or models selected should demonstrate a biological response to the investigational GT product that is expected to be similar to the response in humans.

Biodistribution studies

Biodistribution studies should be conducted to assess the distribution, persistence, and clearance of the vector and possibly the expressed transgene product, from the site of administration to target and non-target tissues, including applicable biofluids (e.g., blood and cerebrospinal fluid (CSF)). 

Toxicology studies 

Toxicology studies for an investigational GT product should incorporate elements of the planned clinical trial (e.g., dose range, ROA, dosing schedule, and evaluation endpoints), to the extent feasible. Study designs should be sufficiently comprehensive to permit identification, characterization, and quantification of potential local and systemic toxicities, their onset (i.e., acute or delayed) and potential mitigation and/or resolution, and the effect of dose level on these findings.

Animal Models

Due to differences in anatomy in rodents as compared to the central and peripheral nervous systems in humans, animals with larger brains or spinal columns, such as pigs or nonhuman primates, may provide additional safety information and facilitate dose extrapolation. The inclusion of larger animals may also allow for the evaluation of the surgical dosing procedures and delivery device systems intended for clinical use. The scientific justification should be provided to support the selection of animal models.

Functional endpoints

Functional endpoints for POC studies in models of neurodegenerative disease often require neurobehavioral testing to demonstrate activity following administration of the investigational GT product. Adequate training of personnel, inclusion of appropriate controls, masked assessment of study endpoints, and use of well-defined scoring systems are recommended to avoid potential bias in these studies. FDA supports the principles of the “3Rs,” to reduce, refine, and replace animal use in testing when feasible.

Additional nonclinical studies may be needed to address such factors as: 

    1) the potential for developmental and reproductive toxicity; and 

    2) significant changes in the manufacturing process or formulation that may impact comparability between the product administered in clinical trials and the product intended for licensure.

For Details, visit

FDA Guidance- "Human Gene Therapy for Neurodegenerative Diseases, 2021"

FDA Guidance- "Preclinical Assessment of Investigational Cellular and Gene Therapy Products; Guidance for Industry, November 2013"