Overview of comments received on ICH guideline S12 on nonclinical biodistribution considerations for gene therapy products - EMA/CHMP/ICH/318372/2021 - Overview

Sep 30, 2026

Uploaded by Jacob

Overview of comments submitted in response to the ICH S12 guideline covering nonclinical biodistribution considerations for gene therapy products, within the EMA/CHMP/ICH/318372/2021 framework. The document records organizational input, including general concerns about guideline layout and the role of animal models for relevance to human translation. It highlights gaps in recognition of species differences and calls for clearer justification, prioritization of non-animal methods, and future-proofing as scientific evidence evolves.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages35

Reading Time1 h 28 min

AccessFree to download

Overview of comments received on ICH guideline S12 on nonclinical biodistribution considerations for gene therapy products

1. General comments – overview

2. Relevance/value of animal models

3. Lack of examples and guidance provided on non-animal testing methods

Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to [www.ema.europa.eu/how-to-find-us](www.ema.europa.eu/how-to-find-us)[ ](www.ema.europa.eu/how-to-find-us)Send us a question Go to [www.ema.europa.eu/contact](www.ema.europa.eu/contact) Telephone +31 (0)88 781 6000 An agency of the European Union 25 October 2021 EMA/628681/2021 Overview of comments received on ICH guideline S12 on nonclinical biodistribution considerations for gene therapy products EMA/CHMP/ICH/318372/2021 Please note that comments will be sent to the ICH S12 EWG for consideration in the context of Step 2b of the ICH process. 1. General comments – overview | Name of organisation or individual | Line
from | Line to | Section
number | Comment and rationale | Proposed changes / recommendation | | --- | --- | --- | --- | --- | --- | | International Council on Animal Protection in Pharmaceutical Programs (ICAPPP) | 0 | 0 | | The International Council on Animal Protection in Pharmaceutical Programs (ICAPPP) understands that the purpose of this guideline is to provide internationally harmonized recommendations for the conduct of nonclinical biodistribution studies to facilitate the development of gene therapy products. While we appreciate that one of the stated objectives of the guideline is to avoid “unnecessary use of animals, in accordance with the 3Rs”, we are concerned that this goal is not reflected throughout the guideline.
We have some concerns regarding; 1) the layout of the guideline, 2) the relevance of animal models in the development of innovative medicines (such as gene therapy products) and 3) the lack of examples and guidance on non-animal testing methods. | | | International Council on Animal Protection in Pharmaceutical Programs (ICAPPP) | 0 | 0 | | 1. Guideline layout
Since one of the main objectives of this guideline is to avoid the unnecessary use of animals (1.1 Objectives of the ICH S12 Guideline), it would seem sensible to begin with recommendations on situations where non-clinical biodistribution studies may not be needed or feasible (which are described in section 5.8. towards the end of the guideline) followed by situations that would trigger the need for biodistribution studies (covered in section 5.7.) before proceeding with recommendations on how these studies should be conducted. We therefore suggest that sections 5.8. and 5.7. be moved in front of section 4. | | © European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged. Page 1 / 35 | Name of organisation or individual | Line
from | Line to | Section
number | Comment and rationale | Proposed changes / recommendation | | --- | --- | --- | --- | --- | --- | | International Council on Animal Protection in Pharmaceutical Programs (ICAPPP) | 0 | 0 | | 2. Relevance/value of animal models
Because of the complexity and innovative nature of gene therapy products, their development poses new scientific and regulatory challenges and more human-relevant test systems are sorely needed. Animal models come with many limitations with regards to their relevance and extrapolation to humans, which must be clearly stated in the guideline.
The prioritization of more human-relevant test systems is urgent when it comes to the development of innovative medicinal products such as gene therapy products because of the human specificity of their activity and the lack of relevant animal models. According to a recent review article “the use of irrelevant test systems, including animal models, healthy or diseased, might be as deleterious as their nonuse, because they could lead to misinterpretation of study outcomes and thus human risk overestimation or underestimation, which could lead to either exclusion of useful candidates or triggering of unidentified, severe, or even potentially fatal reactions in humans”(ref 1) .
While the guideline does mention the

FAQs

What is the purpose of the ICH S12 guideline referenced in the comments?

It provides internationally harmonized recommendations for conducting nonclinical biodistribution studies to support development of gene therapy products.

What concerns are raised about the use of animal models in the guideline?

The comments argue that species differences and limitations of animal models for translational relevance are not adequately addressed and that standalone animal biodistribution studies lack sufficient justification.

What change is suggested regarding the guideline’s structure?

The comments recommend repositioning sections so guidance on situations where studies may not be needed or feasible is presented before recommendations that describe when biodistribution studies would be triggered.

Sep 30, 2026

Uploaded by Jacob