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ICH S12 Nonclinical BiodistributionConsiderations for Gene TherapyProducts

Updated: Feb 19


Key Takeaways.  Background:   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.

Key Takeaways.


Background:
  • 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.


Guideline Objectives:
  • 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:
  • Introduction

  • Definition of Nonclinical BD

  • Timing of Nonclinical BD Assessment

  • Design of Nonclinical BD Studies

  • Specific Considerations

  • Application of Nonclinical BD Studies

  • Glossary


Introduction:
  • 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.


Specific Considerations:
  • 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.


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