EMA consults on ICH S12 guideline, shares comments on PFDD reflection paper

Regulatory NewsRegulatory News | 24 June 2021 |  By 

The European Medicines Agency (EMA) on Thursday opened a public consultation on the International Council for Harmonisation’s (ICH) S12 guideline on nonclinical biodistribution (BD) considerations for gene therapies.
The S12 guideline recently reached Step 2b of the ICH process after being endorsed at the ICH Assembly virtual meeting earlier this month. (RELATED: ICH reports ‘significant milestones’ reached on guidelines ranging from impurity testing to eCTD standards, Regulatory Focus 14 June 2021)
While other regulators have issued guidance containing recommendations on nonclinical biodistribution studies, ICH writes that the S12 guideline, “Provides a harmonised definition for nonclinical BD and conveys overall considerations for assessing BD for [gene therapy] products.” The guideline also provides recommendations on how to interpret and apply BD data to support a nonclinical development program and endeavors "to facilitate the development of GT products while avoiding unnecessary use of animals, in accordance with the 3Rs (reduce/refine/replace) principles.”
The guideline says that understanding the BD of a gene therapy product following in vivo administration is an “important element” in the nonclinical development program and helps sponsors design nonclinical pharmacology and toxicology studies to support early phase clinical trials.
BD is defined as the “in vivo distribution, persistence, and clearance of a GT product at the site of administration and in target and non-target tissues, including biofluids (e.g., blood, cerebrospinal fluid, vitreous fluid), in biologically relevant animal species.”
According to the guideline, BD studies can either be conducted as “stand-alone” studies or in conjunction with other nonclinical pharmacology and toxicology studies.
The guideline covers the design of nonclinical BD studies including the test article to use, the animal or species to study, the group size and sex of the animals to be used, the route of administration and dose level selection and sample collection time points. Also covered are the assay methods to quantify the amount of genetic materials in the product’s tissues and biofluids, immunogenicity and triggers for additional nonclinical BD studies.
The scope of the guideline covers products that express transferred genetic materials and includes purified nucleic acid, as well as microorganisms that have been genetically modified to express transgenes. It also applies to products that are intended to alter the host cell genome in vivo without specific transgenes.
ICH anticipates that a Step 4 guideline will be implemented by regulators in June 2023, according to its summary of the guideline. The deadline to comment for EMA’s consultation is 24 October.
Patient-focused drug development
EMA also released a summary of the comments received on ICH’s reflection paper on patient-focused drug development (PFDD).
The reflection paper, which was endorsed by the ICH Assembly in November 2020, identifies key areas where incorporating patient perspectives could improve the quality, relevance, safety and efficiency of drug development and inform regulatory decision making. The deadline for commenting was March 2021. (RELATED: ICH updates focus on patient-focused drug development, nitrosamines, Regulatory Focus 11 December 2020)
Comments were submitted from 313 individuals and 38 stakeholders, including 12 private companies, 11 societies, seven patient organizations, three ICH members, three individuals and two industry associations.
The summary notes there was “strong support” for the guideline overall. Yet several modifications were proposed in a number of areas, such as the criteria that will be used to determine what constitutes “acceptable” or “desirable” data. Several comments requested the paper clarify what constitutes acceptable criteria for quantitative data and the criteria regulators will use to determine data robustness. Respondents also questioned whether patient preferences would be weighed and incorporated into evidence-based decision making.
There were also multiple comments requesting clarification on the terminology used, including such terms as: patient, patient centricity, patient experience data, patient engagement and patient involvement.
Also “many” comments stressed the need to consider additional groups in patient data collection such as inclusion of all ethnic groups and different age groups and suggested that data should be collected from all disease areas and disease states.
Other comments suggested the “importance” of engaging with patients at the start of drug development when defining the goals of the program and to continue this engagement throughout the drug’s lifecycle.
EMA ICH S12 consultation
ICH S12 Step 2 presentation
EMA summary report of comments on PFDD


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