The time towards the implementation of the so-called “New Approach Methodologies” (NAMs) in pharmaceutical development is drawing closer, as evidenced by recent initiatives on both sides of the Atlantic.
In the US, the Food & Drug Administration has launched its roadmap to phase out animal testing in three to five years, starting with an explorative pilot project for the development of monoclonal antibodies aimed to assess the possibility of shortening pre-clinical development times by incorporating some NAMs. In the EU, the European Medicines Agency (EMA) and the Heads of Medicines Agencies published an Horizon scanning report focusing on the current status and opportunities of NAMs. We will focus on this latter report to highlight the many issues that remain to be addressed, particularly from a regulatory perspective.
Open issues in NAMs for regulatory decision-making
The horizon scanning initiative is the result of a continuous screening of scientific abstracts on the 3Rs (replacement, reduction, refining) principles published in the period 2009-2024, coupled with a search of EMA internal databases. The main objective of the exercise was to assess the regulatory acceptance of NAMs in the development of human medicines.
Animal testing remains the gold standard for preclinical testing, mainly for quality testing (54%, e.g. batch potency and batch safety) and toxicity and safety testing (40%, including pharmacology). According to the report, animal uses for regulatory purposes accounted for 17% (1.4 million) of the total 8.05 million uses in research and testing in 2020. The vast majority of these were referred to basic research (41%), followed by translational and applied research (31%). A small proportion (5%) of uses are also related to routine production, such as the production of monoclonal antibodies by the mouse ascites method.
NAMs aim to at least reduce the use of animal testing. They include a growing number of different 3R-compliant technologies that have been developed since the early 2000s to support regulatory decisions. NAMs span across the in silico, in vitro, ex vivo and in chemico domains. While some applications, such as computational modelling leading to Quantitative Structure-Activity Relationships (QSARs) have a long tradition of regulatory acceptance, newer and more complex in vitro methods (e.g. tissue engineering, organoids) or organ-on-chip systems still require further validation in order to support regulatory decision-making. Nevertheless, according to the EMA’s report, the level of readiness of many technologies allows them to be considered initially in some selected contexts of use for regulatory purposes, including weight-of-evidence submissions.
Key open issues
The application of the 3Rs is mandatory in the EU since the entry into force of Directive 2010/63/EU on the protection of animals used for scientific purposes. The EMA activated a dedicated 3Rs Working Party (3RsWP) in 2022; other initiatives active at the EU level include the Non-Clinical and New Approach Methodologies European Specialised Expert Community, the Batch Release Testing Operational Expert Group and the EMA’s Innovation Task Force, which acts as a first point of contact for 3R innovators. A specific Qualification of New Methodologies procedure is also available to obtain an opinion from EMA on the acceptability of a particular NAM method for a specific context of use.
The lack of communication and data sharing with regulators is the first, critical challenge preventing the regulatory use of NAMs, according to the Horizon scanning report. This is linked to the fact that NAMs are mainly developed in academia and therefore lack a regulatory perspective. Scientific robustness and alignment with regulatory requirements should be the higher priority in the development of NAMs, followed by the identification of the appropriate advice mechanism to interact with regulators on 3R issues and the transparent sharing of data with regulators to keep them informed of any progress or challenges that arise during development.
In this respect, SMEs, academia and EU-funded consortia are more likely to seek advice on NAMs from the EMA, while the industry prefers to share data on a need-to-know basis and using weight-of-evidence approaches, particularly in the area of toxicological assessment. It would also be essential to harmonise regulatory requirements at the international level to avoid the risk that certain countries still require animal testing. At the EU level, different competent authorities may differ in their application of Directive 2010/63/EU and the 3Rs, and improved cooperation would be needed.
Clearer terminology and claims and improved flexibility
Clarification of the terminology could avoid problems with the understanding of what is meant by qualification and validation of NAMs, as well as by “context of use” or “efficacy testing”. These issues often arise in the interactions between developers and the ITF. Ambiguity in the potential areas of application of a particular NAM should also be clarified, as this ensures versatility for developers but, on the other hand, it does not support the specific context of use required to assess and validate the NAM from a regulatory perspective.
Regulatory flexibility based on the provision of available NAM data to the authorities could favour the omission of certain toxicological studies from the development plan. The availability of an explicit regulatory framework for platform technologies inclusive of 3Rs considerations would facilitate a wider use of this type of development strategy, which is currently mainly used by larger companies.
NAMs based on a variety of different cell-culture models, representative of different populations, could provide data closer to the real human target population. A similar goal could be achieved by using in silico and AI models built with robust and representative data.
The final recommendations
The EMA-HMA Horizon scanning report also makes a number of recommendations to improve the development and implementation of NAMs to reduce animal testing. While there is a need to build trust among organisations representing patients, healthcare professionals and animal welfare, there is also a need for closer interaction between developers and regulators to improve knowledge sharing and understanding of this highly complex area of R&D. This could be supported by the publication of a specific guidance document on regulatory flexibility by EMA. A clearer definition of the validation and qualification of NAMs could also be part of the evolving regulatory framework, with greater attention to translational and clinically relevant endpoints. Expert knowledge on NAMs should also be improved at the level of the European Medicines Regulatory Network (EMRN) and its assessors. This would also allow for appropriate representation of the EMA/EMRN in international working groups.
Learned societies or public-private partnerships could be considered to act as intermediaries to facilitate the dissemination of knowledge on the 3Rs and NAMs and the sharing of data. Better cooperation between the EMRN assessors and those responsible for the application of Directive 2010/63/EU should also be sought in order to avoid duplication of animal testing. Publication and data sharing should be promoted across all the different EU legislation that has an impact on animal testing (i.e. pharmaceutical, food, chemical). The funding of the above mentioned proposals should be supported by specific EU calls focusing on the validation and qualification of NAMs in relation to clear end-goals and contexts of use.
