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ICH S12: Nonclinical Biodistribution Considerations for Gene Therapy Products

Updated: Feb 16


ICH S12 is a new guideline that provides harmonized recommendations for the nonclinical biodistribution (BD) assessment of gene therapy (GT) products. The guideline covers a wide range of topics, from the definition of nonclinical BD to the application of nonclinical BD data in clinical trials.  One of the key takeaways from ICH S12 is that nonclinical BD data can be used to inform the design and conduct of first-in-human clinical trials. For example, BD data can be used to determine the optimal dosing regimen, identify potential target tissues and organs for toxicity, and assess the potential for systemic toxicity.

ICH S12 is a new guideline that provides harmonized recommendations for the nonclinical biodistribution (BD) assessment of gene therapy (GT) products. The guideline covers a wide range of topics, from the definition of nonclinical BD to the application of nonclinical BD data in clinical trials.


One of the key takeaways from ICH S12 is that nonclinical BD data can be used to inform the design and conduct of first-in-human clinical trials. For example, BD data can be used to determine the optimal dosing regimen, identify potential target tissues and organs for toxicity, and assess the potential for systemic toxicity.


Another key takeaway from ICH S12 is that the design of nonclinical BD studies should be tailored to the specific GT product being evaluated. For example, the route of administration, dose level, and target tissue of the GT product will all affect the design of the BD study.


ICH S12 also provides guidance on the specific considerations that should be taken into account when designing and conducting nonclinical BD studies for GT products. These considerations include the following:

  • The type of GT product (e.g., viral vector, non-viral vector)

  • The route of administration

  • The dose level

  • The target tissue

  • The potential for immune response

  • The potential for germline modification

ICH S12 is an important resource for researchers who are developing GT products. The guideline provides harmonized recommendations for the nonclinical BD assessment of GT products, which can help to ensure the safety and efficacy of these products.


Here are some additional key takeaways:

  • BD assessment of ex vivo genetically modified cells of haematopoietic origin is not critical based on expected widespread distribution following systemic administration.

  • BD of the administered GT product in the gonads should be evaluated for both sexes unless justified.

  • Persistent GT product detection in non-germline cells in gonadal tissues (e.g., leukocytes, Sertoli cells or Leydig cells) can warrant additional consideration of its potential effect on the function of the affected non-germline cells, particularly if the cell type is important to successful reproduction.

  • Existing BD data from the same GT product for a different clinical indication can potentially suffice with considerations such as the dose level(s), dosing regimen, ROA, and change in promotor factored into this decision.

  • BD data obtained with a previously characterised GT product that has the same vector structure and other characteristics that determine its tissue tropism, but a different transgene, can potentially support waiving an additional nonclinical BD study.

  • When a biologically relevant animal species that can inform the BD profile in the clinical population does not exist, provide a comprehensive discussion of the issue and justification to support an alternative approach to evaluation of nonclinical BD.

Overall, ICH S12 provides valuable guidance for researchers who are developing GT products. The guideline helps to ensure that nonclinical BD studies are conducted in a way that is informative and relevant to the safety and efficacy of these products.

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