ICH adopts S12 guideline for gene therapies
The International Council for Harmonisation (ICH) last week announced that its S12 guideline on nonclinical biodistribution (BD) considerations for gene therapy products has reached Step 4 of the ICH process, meaning it’s ready for regulators to adopt in their jurisdictions.The guideline provides considerations for the design, timing and conduct of preclinical BD studies, and offers various recommendations for sponsors on the animal species or model to be used, the group size and sex of study animals, route of administration and dose selection, as well as sample collection.
Specific considerations are provided for assay methodology, measurement of expression, immunological considerations, ex vivo genetically modified cells, the assessment of biodistribution in gonadal tissues, situations where additional BD studies might be required and alternative approaches.
“Characterisation of the BD profile following administration of a [gene therapy] GT product in animals is a critical component of a nonclinical development programme. The nonclinical BD data contribute to the overall interpretation of the study findings by enabling a better understanding of the relationship of various findings (desired and undesired) to the administered GT product,” ICH writes.
The regulatory harmonization body adds that the guideline adheres to the “3Rs” principles (reduce/refine/replace) to minimize the use of animals in nonclinical testing.
The guideline was released for public consultation in 2021, and in comments to the US Food and Drug Administration (FDA), industry stakeholders requested changes to the document’s scope and sought clarification on several technical matters. (RELATED: Industry calls for technical, scope changes in ICH S12 guideline, Regulatory Focus 10 November 2021)
As with the draft version, the final guideline considers chemically synthesized oligonucleotides and viral shedding to be outside the document’s scope. Both Novartis and the Alliance for Regenerative Medicine (ARM) had said these topics should be considered for inclusion in their comments to FDA.
The final guideline does, however, remove references to preliminary biodistribution studies that were found in the draft version, which Novartis had requested. In its comments, Novartis said that such preliminary studies would go against the 3Rs principles the guideline is intended to adhere to.
Additionally, the final guideline includes revisions related to sample collection time points, which commenters had raised questions about during the public comment period.
Now, ICH states that “Sample collection time points during the nonclinical BD study should be selected to sufficiently characterise the time-related changes in GT product levels over appropriate time points.” Previously, ICH said the time points “should reflect the anticipated time following GT product administration to reach peak, steady-state (i.e., plateau), and declining (if feasible) GT product levels in target and non-target tissues/biofluids.” The document still notes that additional time points can be included as appropriate, and that additional time points should be considered for products that involve repeat administrations.
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