MHRA approach to medicines using non-animal methods
Approach to MHRA’s assessment of applications for medicines that use alternative methods to replace animals in science
Overview
The MHRA is the regulator of medicines, medical devices and blood components for transfusion in the UK, rigorously using science and data to inform its decisions, enable medical innovation and make sure that medicines and healthcare products available in the UK are safe and effective.
The use of animals in science has been historically pivotal to ensuring safety of new medicinal products prior to their human use. However, advancements in non-animal-based testing methods make it possible to reduce reliance on animals in development of medicines. The MHRA is committed to the 3Rs principles to replace, reduce or refine animal use in medicinal product development. We also recognise that, like studies in animals, current alternative methods also have limitations in predicting effects in humans.
The UK government policy is to move towards phasing out animal testing in the UK. This guidance sets out the approach the MHRA will take in supporting developers to understand requirements.
Each application reviewed by the MHRA is considered individually and where scientifically justified, exceptions to international guidelines have been always acceptable, in principle.
This guidance applies to the MHRA’s approach to its review of Clinical Trial Authorisation applications and of Marketing Authorisation applications for medicinal products. It does not relate to animal use in quality control testing for batch release of products.
International context
International guidelines on drug development have traditionally recommended use of animals in testing and while these guidelines are not legally binding, regulators and developers of new medicinal products have generally agreed to follow them. For instance, the World Health Organization indicates that in vaccine development, immunisation studies in animals should be conducted (see Section 3 Immunogenicity and other pharmacodynamic studies). Furthermore, ICH M3 R2 contains recommendations for the duration of studies in animals (for example, clinical trials of at least 6 months duration should be supported by 6 and 9 month general toxicity studies in rodents and non-rodents, respectively ( see Table 2 of the ICH Harmonised Tripartite Guideline).
The MHRA acknowledges global advancements in drug development methods that do not rely on the use of animals, including incorporation of such methods into guidelines. The MHRA has worked collaboratively with other regulators and industry to support this for a number of years. Where it can be shown that deviating from expectations for in vivo studies in current International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines seems to pose no risk to human health of the specific clinical use proposed, the MHRA is open to considering proposals that omit animal studies, if alternative methods address safety.
At this time, the MHRA will continue to accept applications that include animal studies in line with international guidelines in place at the time the studies in animals were done: our position is that refusing such applications because they include animal studies is not in the best interests of UK patients. A period can be envisaged in which one developer might apply animal studies and another developer might apply only non-animal based methods, yet each approach could be acceptable.
General considerations
There is a time lag, and this can be typically more than 10 years, between conduct of animal studies to support early clinical testing of a new medicinal product and a company making a Marketing Authorisation application. Noting this, applications submitted to the MHRA will likely contain results of animal studies for the foreseeable future.
For a Clinical Trial Authorisation application, developers need to establish a scientific justification as to why the proposed therapeutic intervention could be of benefit to an identifiable group of patients. This justification should include specific aspects such as dose / exposure, route of administration and quantitative data on why the disease might be influenced beneficially by the drug.
Safety of the proposed trial must also be established, which includes consideration of quantitative aspects (for example, dose, exposure and duration of use).
In a Marketing Authorisation application, the developer should include all study reports that support each aspect including the rationale for how the drug works and why its use, as outlined in the draft Summary of Product Characteristics, is expected to be safe.
The MHRA does not expect that specific non-animal methods can be used to replace specific animal studies, indicated in current guidance, on a 1:1 basis. For instance, it is not expected that a specific study design not using animals will replace the current approaches for repeat dose general toxicity studies in two species of animal, or that a specific (set of) alternative methods will directly replace a reproductive toxicity study in pregnant animals. Alternative assays should provide data on which to make a decision and the MHRA review will focus on whether the data package, overall (with or without data from animal studies), supports safe and scientifically justified use of the product as outlined (in either a clinical trial protocol or a Summary of Product Characteristics).
In making an application to the MHRA, developers are encouraged to submit data generated from non-animal methods (including for example, in silico methods, microphysiological systems, complex in vitro models) with information on their robustness and relevance to humans: this can be in parallel with conventional animal studies. The MHRA will assess data from such experiments in the context of each application it receives: regulatory decisions will be made based on all information presented.
Product-specific considerations
For certain drug substances that are not pharmacologically active in animals, the MHRA does not support testing in animals (including with surrogate molecules). For this group of drugs, non-animal-based methods suffice to support expectations for efficacy and safety in clinical development.
For generic and biosimilar products, the MHRA does not support testing in animals.
For products with a pharmacological profile that is well-recognised in regulatory terms (for example, same pharmacological target as an approved drug, or use of the same product in the same way in prior clinical trials), the MHRA considers it may be acceptable to permit UK clinical trials without animal studies. In such cases, the developer should, in its application, discuss international guidelines and areas of lack of compliance and justify an approach that it has alternative data that meet expectations expressed in the General Considerations section of this document.
For products with a novel pharmacological action, the MHRA expects to see relevant animal studies to support human use which address the General Considerations above, aligning with international guidelines. However, for biological products, general toxicity testing in one species only, if pharmacologically relevant, is acceptable to the MHRA.
There is a small number of products that cannot be tested in clinical trials for efficacy: for example vaccines for, or treatments against, smallpox or, possibly, emerging pandemic infectious diseases. Such products have, in the past, been licensed based on animal immunogenicity and animal challenge studies with data on clinical immunogenicity and safety: this remains acceptable to the MHRA.
MHRA review of Module 4 in isolation
By the end of 2026, the MHRA will establish a mechanism by which companies with a product that has been developed without any animal studies can have Module 4 of their Marketing Authorisation application reviewed by the MHRA in advance of a future full application.
Certain requirements must be met for this which are:
- at least one clinical trial must be completed and reported for access to this scheme;
- companies should expect to submit their intended final Module 4, the latest edition of the Investigator Brochure and the final report of at least one clinical trial for review; in Module 2, a draft overview and draft summaries (sections 2.4 and 2.6) should also be provided.
The MHRA will give a non-binding written opinion, accepting the adequacy of the data, or if not, explaining perceived deficiencies.
At the time of a later Marketing Authorisation application, the company should expect to submit:
- the same Module 4 with the MHRA written opinion.
If appropriate,
- a revised Module 4 (and hence revised Modules 2.4 and 2.6) with any studies additional to those on which the opinion was based can be submitted instead.
The MHRA will undertake a further review with a focus to either endorse or, if necessary, reject the application, with reasons given. Consultation with the Commission on Human Medicines at this stage.
This review of Module 4, containing no animal studies, aims to de-risk development strategies that exclude animals. There will be a fee set at a level to recover administrative costs and discourage unsuitable applications. This relates only to Marketing Authorisation applications and has no impact on Clinical Trial Authorisation applications.
Applicability of Good Laboratory Practice
Studies seeking to characterise the safety of a drug are expected to be in compliance with Good Laboratory Practice (GLP). The MHRA expects that safety studies comply with the Organisation for Economic Coordination and Development (OECD) GLP programme, allowing mutual acceptability of data between adherent countries.
A move away from use of animals does not reduce this expectation - where safety studies can be conducted in compliance with OECD GLP, this is expected. Nevertheless, the MHRA does accept that in some instances, compliance with GLP may not be claimed for a particular study within a dossier; where this is so, a discussion should be presented in the dossier to support this.
If non-OECD GLP studies are presented as pivotal safety studies, the MHRA position remains that it could reject an application due to lack of OECD GLP compliance.
Examples
The following examples illustrate, at a high level, the approach the MHRA may take when considering applications that include, or omit, animal studies. These examples are intended to demonstrate general regulatory principles rather than define prescriptive requirements. Each application is assessed on a case-by-case basis, taking into account the totality of the evidence presented and the proposed clinical use.
In drug development, non-clinical data generated to support a clinical trial are generally expected to be sufficient to support later clinical use of a similar nature, including in subsequent trials or use on grant of a marketing authorisation. Accordingly, the principles described below may be relevant to both Clinical Trial Authorisation and Marketing Authorisation applications.
Developers remain encouraged to seek product-specific scientific advice from the MHRA where there is uncertainty regarding the appropriate non-clinical evidence package.
Scenario 1
Novel systemically administered small molecules
General considerations
For novel small-molecule medicinal products intended for systemic administration, particularly those with limited prior human experience, the generation of an appropriate non-clinical evidence base remains an important consideration in supporting initial clinical use. This is often particularly relevant where the pharmacological target, mechanism of action, or broader safety profile is not yet well characterised.
Historically, in vivo studies have contributed substantially to the development of this evidence base, helping to explore systemic tolerability, potential target-organ effects, exposure–response relationships, and areas of uncertainty that may not have been fully addressed through other approaches. At the same time, advances in non-animal methodologies — including increasingly sophisticated in vitro and in silico tools — are expanding the range of scientifically credible options available to address these questions.
In line with these developments, the MHRA supports the use of scientifically robust non-animal approaches where they are capable of addressing the relevant safety questions. The choice of non-clinical methods should be proportionate, risk-based, and grounded in sound scientific justification. For novel systemically administered small molecules, the overall evidence package — whether derived from animal studies, non-animal methodologies, or an integrated combination of approaches — should provide sufficient assurance of safety in relation to the proposed clinical population and context of use.
Where applicants propose to rely primarily on non-animal data, a clear and well-reasoned justification would be expected, demonstrating how the selected methods adequately characterise potential risks and manage residual uncertainty.
Scenario 2
Vaccines and other biological products with platform or component similarity
General considerations
For vaccines and certain other biological medicinal products, animal studies have traditionally formed part of the evidence base supporting progression to human use. However, where there is substantial prior experience with a closely related product, platform, or component, it may be appropriate to leverage prior knowledge rather than repeat studies with each new construct.
In such circumstances, the MHRA may consider the use of data generated with a highly similar product to support aspects of non-clinical safety, provided that similarity is adequately justified and relevant to the question being addressed. This may include consideration of shared manufacturing approaches, physicochemical characteristics, or known drivers of toxicity.
Where reliance is placed on data from related products, applicants are expected to clearly justify the relevance of those data to the proposed product and clinical use. The overall assessment will focus on whether the totality of the evidence sufficiently supports the safety of the product as proposed, rather than on the presence or absence of studies conducted with the exact clinical material.
Scenario 3
Monoclonal antibodies and other modalities with limited animal relevance
General considerations
For some monoclonal antibodies and similar modalities, animal studies may provide limited or no meaningful information for human risk assessment. This may be the case where there is no pharmacologically relevant animal species, and where alternative approaches are more appropriate for characterising safety.
In such situations, the MHRA may consider applications that do not include animal studies, provided that residual risk is adequately addressed through a combination of human-relevant non-clinical data, existing knowledge of the target biology and modality, and appropriate clinical risk-mitigation measures.
Factors that may support this approach include a well-characterised mechanism of action, prior human experience with the same or a closely related product, and robust analytical and functional characterisation demonstrating consistency with established expectations. The adequacy of the overall evidence package, rather than the absence of a specific study type, will be the focus of the regulatory assessment.
Scenario 4
Advanced Therapy Medicinal Products where animal testing is not expected
General considerations
For certain advanced therapy medicinal products, including those based on human-specific cells or genetic modification, animal models may not be scientifically relevant or predictive of human safety. In these cases, the MHRA accepts that in vivo animal studies may not contribute meaningfully to the assessment of risk.
Where animal studies are omitted, applicants are expected to present a comprehensive, human-relevant non-clinical evidence package that addresses key safety considerations using alternative approaches. This may include in vitro or ex vivo studies, detailed product characterisation, and a robust manufacturing and control strategy.
In the absence of animal data, particular emphasis is placed on the design of the clinical development programme, including conservative dosing strategies, enhanced safety monitoring, and clearly defined risk-mitigation measures. Where the overall approach is scientifically justified and proportionate to the risks identified, the absence of animal studies would not, in itself, be expected to preclude authorisation.