There is a great deal of confusion over where we are with non-animal technologies, what the terms mean and who the main investors are. UAR has created a factsheet and the key takeaways are explained here.
What are New Approach Methodologies?
‘New approach methodologies’, often abbreviated to NAMs, are methods for testing the safety of new medicines, chemicals or medical treatments that completely or partially replace the use of animals.
The term New Approach Methodology is specific to safety testing but is sometimes confused with the similar-sounding terms ‘non-animal methods’ or ‘non-animal technologies’, which refer to the broader movement to replace the use of animals in science.
Why is safety testing of new medicines important?
Testing the safety of a new medicine prior to its use in human clinical trials is a regulatory requirement by medicines regulators, such as the UK Medicines and Healthcare products Regulatory Agency (MHRA).
In most countries, including the UK, the use of animals for some of these safety tests is required. This is because the effectiveness of the animal model in protecting humans from adverse effects has been demonstrated by data collected over more than 100 years of applied science. Alternative methods can be highly effective at modelling individual parts of the puzzle but can rarely – so far – replicate the complexity of a whole organism. The whole-body effects of a new medicine or chemical can be extremely complex and difficult to predict. That is why all the world’s medical regulators still consider some animal use to be essential in ensuring the safety of new medicines.
This is also why we talk about ‘phasing-in’ new technologies, rather than ‘phasing-out’ the animal model. Animals give many data points – such as how the drug travels around a live body, how it’s metabolised, which tissues it’s absorbed into, its effects on a dozen organs and whether it modifies animal behaviour – that can all be collected in one study. Technologies such as a liver-on-a-chip are incredibly useful tools, but don’t model that range of effects. Phasing-in NAMs can lead to a reduction in animal use, for instance if it spots compounds that will later prove dangerous, but animal models will not be phased out until the complete suite of effects can be modelled by other means. Particularly difficult things to model include effects on fertility, the effects of chronic exposures and instances where the body’s metabolism changes how the compound behaves. Some sunscreens that are safe in non-animal tests, for instance, become toxic after they are metabolised by sea creatures.
The development and approval of new medicines is a global process. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) brings together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of medicinal drug registration. The goal is to “achieve greater harmonisation worldwide to ensure that safe, effective and high-quality medicines are developed and registered in the most resource-efficient manner”1. The ICH guidelines detail the animal models that are considered acceptable for use in pre-clinical toxicology studies. The guidelines allow for flexible, combinatory approaches to pre-clinical toxicology and the use of non-animal alternatives where these exist. They are updated on a rolling basis.
It should be noted that any alternative methods are required to be accepted by all ICH regulatory authorities. At the point of writing this document, there are no ICH agreed in vitro alternatives for general safety assessment of potential new medicines.
UK investment in NAMs
The UK’s National Centre for the 3Rs (NC3Rs) invests millions of pounds each year into finding replacements for animal use, helping to reduce the number of animals used and refining the ways that animals are used in research. Since it was established in 2004, the NC3Rs has spent £77 million in research and awarded £27 million in contracts, making it the world’s leading investor in the development of non-animal technologies, including NAMs. It also has the trust of industry partners, facilitating collaborative initiatives that would be harder without an “honest broker”. Several of the NC3Rs’ CRACK IT challenges have been sponsored by industry partners.The Association for the British Pharmaceutical Industry (ABPI) has also partnered with the NC3Rs to fund research into replacing animals in research. Finally, the NC3Rs is embedded within regulators and academia who cooperate to remove or improve animal use where possible.
Many UK pharmaceutical companies , contract research organisations, universities and life sciences entrepreneurs have their own ongoing research programmes aimed at replacing the use of animals in research. Some examples are given below, such is the level of investment that contract research organisations, which undertake regulatory animal testing, are today the largest funders of non-animal technology in the world.
The international context
Most new medicines are developed for a global market, so any safety tests need to be acceptable to all the licensing bodies around the world. Decisions on phasing-in NAMs therefore need to be international.
The European Pharmaceutical Industry, including UK-based companies, places a strong emphasis on the need to phase in new approaches to the use of animals in research, and has collated many examples of good practice. In the US, the FDA has updated its position on phasing in new approaches and has a page on its website dedicated to its work to advance alternative methods in this area as well as a page on where we are in the meantime.
The European Commission has a strong focus on NAMs development and validation, and the European Medicines Agency (EMA) has a long-term strategic goal to “move 3R-methods from discovery toxicology towards regulatory use and promote acceptance of animal-free innovations or new approach methodologies (NAMs)”. The EMA also has plans to develop specific guidance on regulatory acceptance criteria for developers of microphysiological systems (also known as “organs on chips”) for specific contexts of use. There is a particular focus on the more developed systems that could be prioritised for regulators, such as liver-on-chip technology for predicting drug-induced liver injury and heart-on-chip technology for exploring safety pharmacology endpoints.
Several international collaborations, other than the pharma-focussed ICH, also exist and can specify testing protocols for things such as medical devices and chemicals. These include the International Organization for Standardization (ISO), and the Organisation for Economic Co-operation and Development (OECD). Like the ICH, these operate a cascade system, starting from simple in vitro tests and requiring animal use only if necessary to answer more complex questions.
Why are animals still used for toxicity testing?
The simple answer is that the current generation of new approach methodologies are not yet mature, accurate and reliable enough to replace animal models in every context. Animal tests are being replaced for the assessment of skin sensitisation, skin irritation andcorrosion and eye irritation, but animals can not yet be replaced when it comes to assessing the toxicology of potential new medicines. Animal studies are therefore still used to determine patient safety before a medicine is given to humans for the first time.
This is not to say that existing NAMs could not be used more widely in regulatory testing, but this will entail international cooperation and commitment to phasing in their use. In 2023 the NC3Rs and Unilever convened a workshop to discuss a vision for the UK to lead the way in the wider use of NAMs in the safety testing of chemicals, including pharmaceuticals, for human use. There is also work at the UK government level to encourage the development, validation and adoption of NAMs. It is widely recognised that there is a “validation gap” where promising approaches have not been formally put to the test. Many will undoubtedly fail validation, whereas others seem likely to become standard parts of the testing toolkit.
The most likely scenario is that NAMs will replace animals in some scenarios, but not others. As with any tool, whether they can be used depends on exactly what you arere trying to do. An example would be contact lenses, which have different testing requirements depending on whether they are the disposable daily sort or the kindyou wear for a month.
Risks associated with new approach methodologies
The UK bioscience sector strongly supports the development and application of new approach methodologies, and whenever they are shown to be as accurate as animal models for specific areas of safety testing regulators should be supported and encouraged to accept their use. However, an understandable anxiety to remove all animal suffering from the drug development process should not blind us to the obstacles that safety testing presents. Wishful thinking has no place in science. Arbitrary timelines or targets for phasing in new approach methodologies that do not respect the reality of their specific usefulness or accuracy would endanger the safety, wellbeing and even lives of patients.
Examples of UAR member organisations’ ongoing work to phase in new approach methodologies
Charles River Laboratories has invested in in vitro oncology models, in silico approaches and non-animal products such as Endosafe® Trillium® recombinant technology which replaces the use of horseshoe crab blood in testing for endotoxins, . It has committed some $300 million to developing new NAMs in the next five years, building upon a previous investment of $200million since 2020.
Labcorp has an ongoing collaboration with Mimetas, a global leader in disease modelling using Micro Physiological System (organ-on-a-chip) technology. The overall long-term aim of this collaboration is to generate human blood vessels on a chip which could be used to understand the toxicity of novel therapeutics without the need to dose compounds into the blood vessels of animals. Labcorp’s in-kind contribution to imSAVAR’s immunotoxicology project will help to develop better models for immunotherapies.
In 2016, Labcorp also announced a collaboration with Emulate. The companies are working together to identify and qualify specific applications in which Emulate’s organs-on-chips platform can help improve the existing drug development process. The first application is focused on the kidney chip and is examining how the organ chips can assist in drug-transporter interaction assessments, a component of preclinical testing that will benefit from appropriate modelling using in vitro human systems.
Sanofi has committed to a 50% reduction in its use of live animals in research between 2020 and 2030. It aims to achieve this by challenging every proposed use of an animal model and working with regulators to foster acceptance of novel technologies, models and approaches. Communication will also be key as the company works to foster synergies and embed new methodologies across sites and with third parties.
Inotiv is committed to the 3Rs, is actively engaged in reducing animal usage, and is dedicated to increasing translation to the clinic during the discovery and development of new therapeutics. Inotiv has established:
- in silico approaches to safety assessment that can also be leveraged for target discovery
- human-derived, in vitro test systems for cancer-related mutagenicity
- human-derived, in vitro approaches to immune responses and liver activity.
Current efforts and active collaborations are focused on maintaining and validating in vitro capabilities in human, multicellular systems related to the brain, gastrointestinal, cardiovascular, respiratory, and renal systems. Furthermore, none of these human test systems involve the use of embryonic stem cells.
How do animal activist charities contribute to NAMs?
The annual funding for replacement technologies from animal welfare groups is extremely marginal. The total investment from activist charities would amount to about two-days spending from the combined efforts of the life sciences sector.
Last edited: 11 December 2024 13:19
