The document is a Step 4 document signed off on March 14, 2023, for implementation by ICH Regulatory Members.
Developed based on an approved Concept Paper and Business Plan in November 2019.
ICH S12 Key Principles:
Biodistribution (BD): Refers to the in vivo distribution, persistence, and clearance profile of the administered gene therapy (GT) product.
Nonclinical BD Data: Contribute to the interpretation and design of nonclinical pharmacology and safety studies for investigational GT products in early-phase clinical trials.
Key Design Elements: Recommendations for designing nonclinical BD studies for GT products.
3Rs Principle: Emphasizes the reduction, refinement, and replacement of animal use in studies.
Harmonized recommendations for assessing BD during nonclinical development.
Recommendations for overall design of nonclinical BD studies.
Consideration points for interpretation and application of BD data.
Facilitation of nonclinical development of GT products while adhering to 3Rs principles.
Table of Contents:
Definition of Nonclinical BD
Timing of Nonclinical BD Assessment
Design of Nonclinical BD Studies
Application of Nonclinical BD Studies
Harmonized recommendations for nonclinical BD assessment of GT products.
Nonclinical BD data contributes to the interpretation and design of studies supporting early-phase clinical trials.
Encourages early discussions on nonclinical programs for GT products.
Describes the scope of ICH S12, excluding shedding and genomic/germline integration evaluation.
Definition of Nonclinical BD:
Nonclinical BD involves in vivo distribution, persistence, and clearance at the site of administration and in tissues and biofluids.
Timing of Nonclinical BD Assessment:
BD data should be available when evaluating nonclinical pharmacology and toxicology findings.
Nonclinical BD data can inform the design of first-in-human clinical trials.
Assessment should be completed before initiating clinical trials.
Design of Nonclinical BD Studies:
General Considerations, Test Article, Animal Species or Model, Group Size, and Sex of Animals, Route of Administration, Dose Level Selection, Sample Collection are key components.
Emphasis on GLP compliance for in-life procedures.
Consideration of factors like animal species, sex, age, and physiological conditions.
Assay methodologies for determining BD, with a focus on nucleic acid amplification methods.
Quantification of genetic material and expression products in tissues/biofluids.
Spike and recovery experiments for method validation.