FDA post ICH S12: Nonclinical Biodistribution Considerations for Gene Therapy Products

 Dated for May, the FDA releaseed on 28April2023, the final version of ICH S12:

Nonclinical Biodistribution Considerations forGene Therapy Products

ICH released this in March of this year, so this was processed by the FDA rather quickly compared to other ICH guidelines. The objectives of the guideline are:

A. Objectives of the ICH S12 Guidance (1.1)

The objective of this guidance is to provide harmonized recommendations for the conduct of nonclinical biodistribution (BD) studies in the development of gene therapy (GT) products. This document provides recommendations for the overall design of nonclinical BD assessments. Considerations for interpretation and application of the BD data to support a nonclinical development program and the design of clinical trials are also provided. The recommendations in this guidance endeavor to facilitate the development of GT products while avoiding unnecessary use of animals, in accordance with the 3Rs (reduce/refine/replace) principles.

The Scope is interesting as it defines what is covered and what it does not (prophylactic vaccines. Chemically synthesized oligonucleotides or their analogues, which are not produced using a biotechnology-based manufacturing process):

Scope (1.3)

GT products within the scope of this guidance include products that mediate their effect by the expression (transcription or translation) of transferred genetic materials. Some examples of GT products can include purified nucleic acid (e.g., plasmids and RNA), microorganisms (e.g., viruses, bacteria, fungi) genetically modified to express transgenes (including products that edit the host genome), and ex vivo genetically modified human cells. Products that are intended to alter the host cell genome in vivo without specific transcription or translation (i.e., delivery of a nuclease and guide RNA by nonviral methods) are also covered in this guidance. Although not currently considered GT in certain regions, the principles outlined in this guidance are also applicable to oncolytic viruses that are not genetically modified to express a transgene.

This guidance does not apply to prophylactic vaccines. Chemically synthesized oligonucleotides or their analogues, which are not produced using a biotechnology-based manufacturing process, are also outside the scope of this guidance.

The release of a GT product outside the body via excreta and secreta (feces, urine, saliva, nasopharyngeal fluids, etc.), or through the skin (pustules, sores, wounds) is termed shedding. Evaluation of the nonclinical shedding profile of a GT product is outside the scope of this guidance. Assessment of genomic integration and germline integration of GT products is also outside the scope of this guidance. Considerations for these aspects of nonclinical data can be found in existing International Council for Harmonisation (ICH) consideration documents (1, 2).

 If you are working in gene therapy development, a must read.