Discover the ICH S12 guidelines for nonclinical biodistribution (BD) testing of gene therapy products. Learn how BD data supports clinical trial design and safety assessments, ensuring effective regulatory pathways for innovative therapies.
ICH S12 is a recent guideline on nonclinical biodistribution (BD) testing of gene therapy (GT) products. The publication has a lot of information in it, from what nonclinical BD actually is to how nonclinical data of BD should be used in drug development.
By extension, an important conclusion of ICH S12 is that nonclinical BD data can also be used to support the design and conduct of first-in-human clinical trials. This, in turn, could be assessed for a safe starting dose, select the potential target organs and tissues of toxicity, and evaluate for systemic toxicological possibility such as BD data.
The design of BD studies should be developed according to the individual GT product under investigation, which is another major lesson learnt from ICH S12. This include the route of administration, dose level and target tissue of the GT product for which a BD study plan will be specifically designed.
ICH S12 also describes additional considerations that should be considered for development and conduct of nonclinical BD studies to assess safety for GT products. These are some of the few considerations:
The GT product (e.g., viral vector, non-viral vector)
The route of administration
The dose level
The target tissue
Potential of establishing an immune response
The prospect of germline engineering
It is a good source of information for researchers planning to develop GT products and to help in navigating the various regulatory pathways that may be applicable. The guideline provides aligned recommendations for the nonclinical BD assessment of GT products in order to facilitate marketing applications that may result in approval of these first-in-class type of products.
Key takeaways
Nevertheless, as ex vivo genetically modified cells of haematopoietic lineage are most likely to be distributed universally following systemic administration, there is a less need for Bio Distribution assessment in this regard.
The BD of the gonads (both for males and females unless inadequate) should be assessed when the GT product is administered
Given that Gene therapy T products were detectable in non-germline cells of gonadal tissues (leukocytes, Sertoli or Leydig cells), the potential impact on function of these cells may require further evaluation if the non-germline cell is known to be critical for successful reproduction.
It may be possible to use Bio distribution data for this Gene Therapy product in another clinical indication if the dose level(s), dosing regimen, ROA and promotor are changed.
BD data generated using a GT product that has an identical vector but different transgene as compared to a previously characterised GT product will be suitable for the waiver of an additional nonclinical BD study.
Conclusion
If a biologically relevant animal species that could inform the BD profile in the clinical population does not exist, include an extensive discussion and rationale to administer nonclinical BD in one or more nonbiologically relevant species.
In general, ICH S12 offers a useful guidance for scientists working on GT product development. This guideline describes a process to help ensure that nonclinical BD studies are pursued, conducted, and reported in a manner that provides assurance related to the safety and effectiveness of these products.
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