Regulatory acceptance of new approach methodologies (NAMs) to reduce animal use testing

New approach methodologies (NAMs) refer to novel methods that are compliant with the so-called 3Rs principles for the ethical use of animals in medicine testing across the European Union (EU). '3Rs' stands for replacement, reduction and refinement of animal use. The European Medicines Agency (EMA) supports the regulatory acceptance of these new approach methodologies. This ensures NAMs are scientifically sound and can be used in regulatory decision-making.

This content applies to human and veterinary medicines.

New approach methodologies (NAMs) represent potential alternatives to animal testing in the non-clinical development phase of new medicines.

They may be incorporated in the assessment of the safety and efficacy of new medicines. This could replace or reduce animal use, in line with the 3Rs principles. 

Examples of NAMs include in vitro (cell-based) systems and computer modelling.

EMA fosters regulatory acceptance of NAMs - which ensures they are scientifically sound and useful in regulatory decision-making. 

EMA interacts with NAMs developers at different stages of medicine development.

For more information on ethical use of animals in medicine testing, see:

• Ethical use of animals in medicine testing

Regulatory acceptance of new approach methodologies: how to interact with EMA

EMA works with new approach methodology (NAM) developers to facilitate the regulatory acceptance of these methodologies. 

There are several types of regulatory interactions that EMA makes available to developers.

Select the expandable panels below for information on scope and outcome of regulatory interactions between EMA and NAM developers:

Briefing meetings within EMA's Innovation Task Force (ITF)

EMA holds briefing meetings with new approach methodology (NAM) developers.

Scope

These meetings host informal discussions on NAM development and readiness for regulatory acceptance. 

They take place within EMA's Innovation Task Force (ITF). This provides developers with a forum for early dialogue with EMA on innovative medicines and novel methodologies.

Experts from the European medicines regulatory network also participate in these discussions.

Applications are free of charge.

Outcome

EMA shares confidential meeting minutes with participating developers.

For more information on EMA's Innovation Task Force (ITF), see:

• Supporting innovation

Scientific advice

EMA enables new approach methodology (NAM) developers to ask its Scientific Advice Working Party specific scientific and regulatory questions.

These questions can refer to the development and use of NAMs.

Scope

The scope is to consider including NAM data in a future clinical trial application or in marketing authorisation application (MAA) for a particular medicine.

Outcome

EMA's CHMP or CVMP issues a confidential final advice letter containing answers to the specific questions that developers raised.

For more information on requesting scientific advice from EMA, see:

• Requesting scientific advice or protocol assistance from EMA
• Scientific advice for veterinary medicines

Qualification

New approach methodology (NAM) developers can apply for CHMP qualification. 

Scope

They can do so if they have generated sufficient and robust data.This is needed to demonstrate the utility and regulatory relevance of a NAM for a specific context of use. 

A context of use describes the circumstances under which the NAM is applied in the assessment of human or veterinary medicines.

A qualification team composed of EMA and experts from the European medicines regulatory network then assesses the data submitted to support the use of the NAM within medicine development.

For NAMs to be qualified in veterinary medicines development, the qualification procedure is carried out within the request for general scientific advice for veterinary medicines.

Outcome 

EMA's CHMP can issue qualification advice on protocols and methods with the aim of moving towards a positive qualification opinion.

Based on CHMP's advice, EMA may propose a letter of support even when it cannot yet qualify a NAM. 

This letter signals that EMA considers the preliminary data received to be promising. It can also raise awareness of the method proposed. Moreover, it can indicate EMA expectation to receive data that can further support a positive qualification opinion.

The CHMP can also issue a qualification opinion on the acceptability of a NAM within a specific context of use in drug development.

Before adopting a qualification opinion, the CHMP makes its evaluation open for public consultation by the scientific community.

To ensure public awareness, EMA publishes all qualification opinions.

Voluntary submission of data

Scope

Under the voluntary submission of data procedure, new approach methodology (NAM) developers can submit data obtained by using a NAM.

EMA does not use data generated with the NAM as part of its regulatory decision-making process, for instance within a MAA procedure. However, EMA evaluates these data independently. 

This is for the purpose of NAM evaluation for possible future regulatory acceptance. It also aims to help EMA develop a better understanding of the potential added value of NAMs.

The voluntary submission of data procedure is also known as the safe harbour approach. This is because there is no ‘penalty’ in a regulatory sense for submitting the data (even if it does not concur with animal data).  

Outcome 

This procedure can allow the generation, compilation and review of data to help define and / or fine-tune a context of use for a NAM. 

This also helps evaluate the readiness and limitations for regulatory acceptance of the NAM within a specific context of use.

In addition, it allows regulators to gain confidence in NAM data. 

Moreover, this approach may help EMA draft qualification criteria for NAMs based on a context-of-use.

Achieving regulatory acceptance of new approach methodologies: what to consider

EMA makes considerations for regulatory acceptance available to developers of new approach methodologies (NAMs). This helps them prepare for their interactions with EMA.

Principles for regulatory acceptance of 3Rs testing approaches

A guideline on the principles for regulatory acceptance of 3Rs testing approaches is available. 

These principles include: 

• Availability of a defined test methodology (protocol, endpoints)
• Description of the proposed NAM context of use
• Establishment of the relevance within that particular context of use
• Demonstration of NAM reliability and robustness 

For more information, see:

• Ethical use of animals in medicine testing: Scientific guidelines
• Regulatory acceptance of 3R (replacement, reduction, refinement) testing approaches - Scientific guideline

Context of use

Context of use describes the circumstances under which the NAM is applied in the development and assessment of human or veterinary medicinal products.

Developers should give careful and detailed consideration to the intended context of use. This will allow EMA to provide focused advice at an early stage. 

In qualification procedure applications, developers need to explicitly define the intended context of use.  

Developers should consider how NAM data will be used in the context of regulatory decision making. The NAM can replace an existing regulatory requirement or it can contribute to a 'weight of evidence' approach. 

The latter option refers to an assessment based on all the available data generated to date on a product. This includes the pharmacology, pharmacokinetic and other available in vitro and in vivo data.   

Regulatory readiness 

When preparing for regulatory interaction with EMA, developers may consider critically appraising and indicating the level of readiness of their proposed NAM for regulatory purposes.

For example, developers may consider seeking advice for:

• a NAM still under development intended for regulatory use;
• the suitability for regulatory use of a NAM with a proposed context of use and for which early technical and biological characterisation is available;
• or a NAM for which qualification data are available that can be submitted for consideration.

Requirements for regulatory acceptance

Requirements for models used in primary pharmacology and proof-of-concept studies are not strictly defined. 

Requirements for NAMs are much more stringent when it comes to methods used to demonstrate safety. This is also the case with animal data. 

Where the requirements are less well defined, regulatory acceptance of NAMs used in this context could happen within a marketing authorisation application. The NAM may not necessarily need to be formally qualified in a separate procedure. This is assessed on a case-by-case basis. Developers should initiate discussions with EMA at an early stage.

This is in line with the ICH M3(R2) guideline on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals.

For more information, see:

• ICH M3 (R2) non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals - Scientific guideline