New approach methodologies have moved from the margins of preclinical science to the centre of regulatory policy. Since publishing its Roadmap to Reducing Animal Testing in Preclinical Safety Studies in April 2025, the United States Food and Drug Administration has issued draft guidance on validating alternative methods and accepted the first letter of intent for a computational tool into its drug development tool qualification pathway. The United Kingdom has committed roughly £75 million and a set of dated deadlines. Understanding what these methods are, and what regulators will currently accept from them, has become a practical requirement for anyone assembling a nonclinical safety package.
What new approach methodologies are
New approach methodologies, commonly shortened to NAMs, are testing approaches used to assess the safety, efficacy or quality of medicines without relying on conventional animal studies. The FDA set out the range in draft guidance issued on 18 March 2026, General Considerations for the Use of New Approach Methodologies in Drug Development. Examples include complex and two-dimensional in vitro studies, alongside three-dimensional models such as organoids, spheroids and organs on chips. The list also covers chemical reactivity studies and in silico modelling. It extends to work in what the FDA calls phylogenetically lower animals, such as zebrafish and Caenorhabditis elegans.
That final category is a useful corrective to a common misreading. NAMs are frequently described as non-animal methods, yet the regulatory definition is broader. It covers approaches that reduce or refine animal use as well as those that replace it outright. That is consistent with the 3Rs framework of replacement, reduction and refinement, which has governed laboratory animal science for decades.
The predictivity problem driving the shift
The scientific case for these methods rests on a persistent failure rate. The FDA has stated that, historically, more than 90 per cent of drugs that clear animal studies do not go on to receive agency approval, often because safety or efficacy problems surface only once a compound reaches humans. Every one of those failures carries a cost in time, capital and patient exposure.
Some of the most quantified supporting evidence comes from liver models. A study published in Communications Medicine in December 2022 assessed 870 human Liver-Chips against a blinded set of 27 hepatotoxic and non-toxic drugs nominated by the Innovation and Quality consortium. The chips did not wrongly flag any of the non-toxic compounds, giving a specificity of 100 per cent. Sensitivity was 80 per cent on the initial analysis, and rose to 87 per cent across the 18 drugs tested in two hepatocyte donors once the results were corrected for plasma protein binding. The authors estimated that broad adoption could deliver more than $3 billion a year in additional small molecule research productivity.
That figure warrants one qualification. The study was conducted by Emulate, the company that manufactures the Liver-Chip and the economic model that produced the $3 billion estimate, so it is not an independent assessment of a commercial platform. The authors state that the performance data were verified by two external toxicologists, and the drug set was specified by a third party rather than chosen by the manufacturer, both of which strengthen the result. Readers assembling a business case should weigh it accordingly.
The arithmetic in biologics is more direct. The FDA has noted that a typical nonclinical programme for a monoclonal antibody can involve more than 100 non-human primates, at a cost of roughly $50,000 per animal. Reducing that requirement is the clearest near-term commercial argument for alternative methods.
How the FDA is validating alternative methods
The March 2026 draft guidance established four core validation principles. Sponsors must define the context of use, meaning the specific regulatory purpose a method serves. They must demonstrate human biological relevance, showing how the method assesses toxicity. They must provide technical characterisation, establishing that the method is robust, reliable and reproducible. Finally, they must show the method is fit for purpose, meaning it genuinely assists regulatory decision-making.
One point in the guidance is easily missed and commercially significant. Full formal validation is not a precondition for a method to be considered in a submission. A fit-for-purpose method that is not fully validated may still address a specific toxicological question when it is assessed within the broader weight of evidence for a product. CDER has already accepted methods on that basis, including in vitro assays for skin sensitisation and for eye and skin irritation.
Tracy Beth Høeg, then Acting Director of the Center for Drug Evaluation and Research, said at the time that it was time for the agency to move away from a default of using animals to predict human responses. The aim, she said, was to obtain those data instead from “human-centric models” that predict human drug reactions more reliably, efficiently and ethically before clinical trials begin.
The guidance is deliberately general. It does not address individual methodologies or drug discovery applications, and the agency has encouraged sponsors to consult the relevant review division on organ-, endpoint- and indication-specific questions. Nor has it been received without objection. The Physicians Committee for Responsible Medicine welcomed the draft but, in comments filed in June 2026, urged the FDA to revise it, arguing that the emphasis on validation risked leaving developers defaulting to animal studies rather than moving away from them. Vanda Pharmaceuticals, which has litigated against FDA animal study requirements, criticised the draft on release as falling short of practical reform.
Qualification moves from principle to practice
The mechanism for turning a promising assay into a regulatory instrument is the Innovative Science and Technology Approaches for New Drugs programme, known as ISTAND, which became a permanent qualification pathway on 31 July 2025. On 3 June 2026, the Center for Drug Evaluation and Research accepted the first letter of intent for an in silico drug development tool. The tool is an artificial intelligence-driven digital liver model, designed to predict drug-induced liver injury in small molecule candidates.
The model compares the chemical structures of new candidates against reference drugs with known liver injury risk. If qualified, the FDA says it would complement existing preclinical data and support decisions taken before a phase I trial begins, rather than replace those data. The agency did not name the developer. Absentia Labs, a Boston company founded in 2024, identified itself as the sponsor in a statement issued on 7 July 2026.
Jeffrey Siegel, Director of the Office of Drug Evaluation Sciences in CDER’s Office of New Drugs, said the model “shows promise in assessing the risk of hepatotoxicity” during the preclinical phases of development.
Acceptance is the first of three stages. A qualification plan follows, then a full qualification package, and only after that may sponsors rely on the tool within its specified context of use. That sequence explains why regulatory adoption runs several years behind the announcements.
Monoclonal antibodies as the entry point
The FDA roadmap begins with monoclonal antibodies, a class where the agency says animal models have proved particularly unreliable. Draft guidance issued on 2 December 2025, Monoclonal Antibodies: Streamlined Nonclinical Safety Studies, identified product types for which six-month toxicity testing in non-human primates may be reduced or eliminated. Studies longer than three months in non-rodent species would generally not be warranted, provided three-month data are supplemented by a weight-of-evidence risk assessment.
The scope is narrower than the headlines suggested, in two respects. It applies to monospecific antibodies, meaning those recognising a single molecular target, and not to multispecific antibodies, antibody-drug conjugates or antibody constructs. It also excludes indications reviewed by the FDA’s Office of Oncologic Diseases, which were addressed separately in draft guidance on streamlined nonclinical safety studies for oncology biologics and conjugated products, released on 29 May 2026.
Marty Makary, then FDA Commissioner, said the agency was “delivering on our roadmap commitment to eliminate animal testing requirements” in drug evaluation. The sequencing matters for planning purposes. Small molecules and new chemical entities sit further back in the roadmap than biologics, so the practical timeline differs sharply by modality.
The UK strategy attaches dates to the transition
The United Kingdom published Replacing animals in science: A strategy to support the development, validation and uptake of alternative methods on 11 November 2025. It was produced by the Department for Science, Innovation and Technology with the Home Office and Defra, and presented to Parliament by command of His Majesty. It is among the more specific documents of its kind internationally because it attaches deadlines, sorted into three “baskets” according to how mature the replacement technology is.
In the first basket, regulatory animal testing to assess whether new treatments cause skin and eye irritation or skin sensitisation is to end by the close of 2026. By the end of 2027, potency testing of botulinum toxin in mice is to stop, and adventitious agent testing of human medicines is to rely only on DNA-based laboratory methods. In the second basket, dedicated pharmacokinetic studies in dogs and non-human primates are to fall by at least 35 per cent by 2030.
Funding announced alongside the strategy totals roughly £75 million. The strategy itself is backed by £60 million, split between a preclinical translational models hub and a UK Centre for the Validation of Alternative Methods, the latter intended to shorten the path to regulatory acceptance. A separate £15.9 million from the Medical Research Council, Innovate UK and Wellcome funds five teams working on human in vitro models covering the liver, brain, cancer, pain and the vascular system. The government describes the plan as one of the most detailed of its kind in the world. LSDN has examined how far the technology actually supports those targets in its analysis, NAMs and Animal Testing: Separating Progress From Hype.
Lord Vallance, then Science Minister, described the strategy as a roadmap that would allow government, business and animal welfare groups to work together to “find alternatives to animal testing faster”. Delivery was to be overseen by a cross-governmental ministerial group chaired by the Science Minister, with a public dashboard of key performance indicators tracking progress from 2026. Lord Vallance resigned in July 2026, and the Department for Science, Innovation and Technology was dissolved on 21 July 2026, its science and innovation functions moving to the renamed Department for Business, Innovation, Science and Trade. Current ownership of that oversight function is unconfirmed.
The industry response was supportive but qualified. Richard Torbett, Chief Executive of the Association of the British Pharmaceutical Industry, welcomed the strategy. He noted that “the science does not yet exist to fully eliminate animal testing”, and pointed to the progress the sector had already made on reduction, replacement and refinement.
Europe and the harmonisation question
The European Medicines Agency sets out its position on the ethical use of animals in medicine testing through its 3Rs Working Party, which advises the agency’s scientific committees on animal use in regulatory testing. A separate guideline sets out the principles of regulatory acceptance for 3Rs testing approaches. Directive 2010/63/EU already requires non-animal methods wherever a scientifically satisfactory alternative exists.
The agency established a Non-Clinical and New Approach Methodologies European Specialised Expert Community in 2023, now numbering more than 100 experts. It consulted until 31 January 2026 on a draft reflection paper covering non-human primate use in the safety testing of human medicines.
Harmonisation remains the practical constraint. A method qualified for a defined purpose with one regulator does not transfer automatically to another. Sponsors filing across several regions are therefore bound in practice by the most conservative agency in their strategy. The FDA roadmap identifies revision of International Council for Harmonisation guidance, and ICH S6 in particular, as a longer-term objective, with an eventual ICH guideline dedicated to alternative methods as the stated ambition.
What these methods cannot yet replace
The remaining gap is integrated toxicology. A general toxicity study asks an open-ended question across every organ system, at multiple doses and over time, and is designed to detect effects nobody thought to look for. Organ chips and computational models, the most mature of the alternatives, answer targeted questions well. Reconstructing a whole-body safety picture from a set of targeted answers is a scientific problem rather than an administrative one, and it is the principal reason animal toxicology persists.
Wendy Jarrett, then Chief Executive of Understanding Animal Research, the membership body for UK organisations that conduct animal research, welcomed the UK strategy. She also observed that animals would be needed “for many years to come” to study disease and to assess how candidate medicines behave in whole living organisms.
What to watch next
The FDA reported in April 2026 that it had met its first-year roadmap goals. It cited updated guidance supporting a transition away from horseshoe crab-derived endotoxin testing, which it estimates could spare more than one million animals a year. It also pointed to a searchable database of acceptable alternative methods, a permanent tool qualification pathway and a formal partnership with the National Institutes of Health.
Momentum now depends in part on people who are no longer in post. The FDA has had five directors of its drug evaluation centre in little more than a year, and both the Commissioner who launched the roadmap and the acting centre director who issued the validation guidance left the agency in May 2026. In the United Kingdom, the minister who chaired the delivery group resigned in July. Neither programme has been reversed, but neither now sits with the officials who set it in motion.
The first hard read on UK delivery arrived in July 2026. Home Office statistics published on 9 July recorded 2,537,507 scientific procedures on living animals in Great Britain during 2025, a fall of 3.8 per cent, while procedures involving specially protected species rose by 7 per cent. The same release recorded 31 regulatory skin sensitisation procedures on mice, all to satisfy requirements derived from EU legislation, with none carried out to meet UK requirements alone. Cruelty Free International, reviewing the strategy’s first eight months in a report titled From Promise to Proof, judged progress minimal and fragmented. It considered the UKCVAM funding on track, but found little publicly available evidence of movement on training for early career researchers or on scrutiny of animal use in funding applications.
Three markers will indicate whether momentum holds. The first is publication of the UK key performance indicators against the November 2025 deadlines. The second is whether the digital liver model progresses beyond its letter of intent to a qualification plan. The third is whether the monoclonal antibody and validation guidance documents are finalised in substantially their draft form. Each will say more about the future of new approach methodologies in preclinical safety testing than any further statement of ambition.
