Final ICH Guide Supports Nonclinical Development Of Gene Therapy Products
Executive Summary
The International Council for Harmonisation has finalized guidance that aims to facilitate the nonclinical and clinical development programs of gene therapy products, while avoiding the unnecessary use of animals.
The International Council for Harmonisation has issued harmonized recommendations for conducting nonclinical biodistribution (BD) studies to support the development of gene therapy products.
Such studies are an important component of the nonclinical program for a gene therapy product as BD data are considered informative and necessary to support gene therapy product administration and safety monitoring in early clinical trials.
The ICH recommendations are outlined in the S12 guideline, which was finalized on 14 March and is ready for adoption by ICH regulatory members in their respective jurisdictions. It is the first ICH guideline that specifically addresses an important nonclinical development component of gene therapy products.
S12 has been drawn up to address the different expectations on the BD assessment of gene therapy products in existing regulatory guidance, which create a challenge for both regulators and industry when developing a gene therapy product.
It provides recommendations for the overall design of nonclinical BD assessments and aims to facilitate the development of gene therapy products while avoiding unnecessary use of animals in accordance with the 3R (reduce/refine/replace) principles. It addresses aspects such as animal species selection, dose levels, sample collection time intervals and types of samples to be collected.
On the timing of such studies, the S12 guideline states that BD data should be available when evaluating the nonclinical pharmacology and toxicology findings. Such data can inform design aspects of a first-in-human clinical trial and subsequent clinical trials such as the dosing procedure (ie, dosing intervals between subjects), the monitoring plan, and long-term follow-up assessment.
Gene therapy products within the scope of the guideline include products that mediate their effect by the expression (transcription or translation) of transferred genetic materials. Examples include purified nucleic acid (eg, plasmids and RNA), microorganisms (eg, viruses, bacteria, fungi) genetically modified to express transgenes (including products that edit the host genome), and ex vivo genetically modified human cells.
S12 also covers products that are intended to alter the host cell genome in vivo without specific transcription or translation (ie, delivery of a nuclease and guide RNA by non-viral methods). Although not currently considered gene therapy in certain regions, the “principles outlined in this guideline are also applicable to oncolytic viruses that are not genetically modified to express a transgene,” the document states.
The guideline does not apply to:
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Prophylactic vaccines.
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Chemically synthesized oligonucleotides or their analogs, which are not produced using a biotechnology-based manufacturing process.
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Evaluation of the nonclinical shedding profile of a gene therapy product.
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Assessment of genomic integration and germline integration of gene therapy products.