Industry calls for technical, scope changes in ICH S12 guideline

Regulatory NewsRegulatory News | 10 November 2021 |  By 

In response to the US Food and Drug Administration's (FDA) consultation on the International Council for Harmonisation's (ICH) S12 guideline on nonclinical biodistribution considerations for gene therapy products, two industry groups and drugmaker Novartis have suggested changes to the document.
The guideline reached Step 2b of the ICH process in June and has been released for comment by regulators, including the European Medicines Agency (EMA), to gather feedback before the international guideline can be adopted. (RELATED: EMA consults on ICH S12 guideline, shares comments on PFDD reflection paper, Regulatory Focus 24 June 2021)
FDA issued the draft version of the document, which is intended to "facilitate the development of investigational [gene therapy] products, while avoiding unnecessary use of animals, in accordance with the 3Rs (reduce/refine/replace) principles, for public comment in September.
Two industry groups, the Alliance for Regenerative Medicine (ARM) and the American Society of Gene and Cell Therapy (ASGCT) welcomed the harmonized guidance and suggested several changes.
"ARM supports the advancement of guidance and policies that promote clear, timely communication and ensure predictable and efficient regulatory paths to market for gene therapy products as scientific understanding evolves. The creation of guidance at the ICH level is particularly welcome as it is expected to provide globally harmonized recommendations," ARM wrote.
In its comments, ARM suggested several changes to the document's scope and specific technical recommendations. ARM asked that the guideline's scope be restricted to in vivo gene therapy and not to ex vivo genetically modified cells. The group also asked for "greater clarity on the global expectations for assay methodologies," as some recommendations contained in US and EU guidance on gene therapies are not reflected in the S12 document.
ARM also asked for some additional clarification on the regulatory expectations for bioanalytical assays and suggested that the guideline specify that, "The bioanalytical methods used should be qualified (fit-for-purpose) for their intended uses."
Both ARM and drugmaker Novartis, which recently reshuffled its gene therapy division, asked whether chemically synthesized oligonucleotides, such as lipid-nano particles (LNPs) with DNA encapsulated, and viral shedding should be considered within the scope of the document.
"Viral shedding is listed as 'out of scope'. We believe that it is a missed opportunity in not including this topic, particularly as some would consider shedding as part of the 'distribution' of a gene therapy vector. In addition, there exists significant health authority divergence in opinion with respect to whether shedding should be assessed in nonclinical studies," Novartis wrote.
The company also questioned why chemically synthesized oligonucleotides, or their analogues, are outside the scope of the guidance, with Novartis arguing that, "There are circumstances where a chemically synthesized (i.e., an LNP incapsulated) could be delivered and qualified as a gene therapy."
Additionally, Novartis points out that the one of the statements in the guideline emphasizing the value of preliminary studies to evaluate gene transfer efficacy or assay methodologies goes against the 3Rs principles. "[The] statement implies that preliminary studies are useful when very often these would not be necessary."
All three commenters also raised questions about the sample collection time points noted in the guideline. While ARM suggested recommending a maximum duration and allowing for deviation where appropriate, ASGCT noted that, "For replication competent vectors, sample collection time points should also cover the detection of the second peak level due to vector replication and the subsequent clearance phase." In its comments, Novartis recommended stating that the final sample collection panel should also "be guided by an understanding of the [gene therapy] GT product."
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