here is increasing global momentum to use nonanimal models (NAMs, also known as Novel Approach Methods) in pre-clinical drug development. Because they are attractive in principle and for practical and ethical reasons, the important questions and challenges they present must be addressed systematically and dispassionately. This worthwhile effort is now underway in earnest.

NAMs refers to the range of future technologies that will provide an alternative to traditional animal-based methods of safety and efficacy testing. One driver has been the reduction in experimental animal use such as under the EMA “Replacement, Reduction and Refinement” regulatory guidance and the US FDA Modernization Act 2.0, which allowed for alternatives to animal testing in FDA drug and biological regulatory submissions. An equally important factor is the recognition that pre-clinical animal trials can provide limited predictive value of safety and efficacy for many newer therapeutics, such as cell and gene therapies, therapeutics modulating the immune system, and protein or certain peptide therapeutics.

NAMs encompass a wide range of approaches including human cell-based assays, organoid systems, organ-on-a-chip models (i.e., microphysiological systems), computer in silico modeling, and use of artificial intelligence. While these approaches are evolving to be commonplace in some academic institutions, the challenge lies in moving a new therapeutic from the laboratory to the clinic—undertaking a first in human (FIH) clinical trial—which requires developers and those providing regulatory and ethical approval of the trial to be confident that the product is safe. Drug developers, ICH, and regulators alike have long-established requirements for animal-based pre-clinical studies for pharmacodynamics, safety pharmacology, pharmacokinetics and dose-finding, genotoxicity, and repeat dose toxicity assessments. Can these studies be reduced and replaced by NAMs while retaining confidence that a new product is safe for administration to humans? If NAMs are to replace or complement animal pre-clinical studies, it is critical for bodies that approve FIH clinical trials to have confidence in their relevance in predicting the safety (and potentially the efficacy) in humans.

In Australia, the Therapeutic Goods Administration (TGA) delegates ethical and scientific review of most clinical trials to Human Research Ethics Committees (HRECs) via the Clinical Trial Notification (CTN) Scheme. Unlike Institutional Review Boards (IRBs) in the US which focus primarily on ethical review, HRECs are responsible for ensuring both the ethical acceptability and the scientific integrity of human research. Thus, HRECs play a vital role in shaping trial approvals, oversight, and the adoption of NAMs. As Australia’s largest reviewer and approver of FIH clinical trials, Bellberry Ltd, along with the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT), and international collaborators, have launched a multiyear project to accelerate the adoption of NAMs in therapeutic development and integrate NAMs into regulatory, ethical, and research frameworks.

An invitation-only project workshop held in Melbourne on 30 November 2024 was the first of three, with follow-up workshops planned for 2025 and 2026. The project aims to deliver consensus guidance on NAM validation, evidence requirements, and their application in therapeutic development. Presentations from regulatory bodies, HRECs, technology developers, and industry representatives highlighted the current state, challenges, and future direction for NAMs.

At the workshop, participants selected from academia, industry, HRECs, and regulators called for better guidance for those reviewing clinical trial proposals, with the inclusion of data science, computational modeling, and in silico expertise being important additions to HRECs when considering FIH trial applications based on NAMs. Industry participants noted that sponsors expect methods to be “pre-validated” before investment. Technology developers face the challenge that while they can provide validation of a particular NAM platform, they cannot provide target-specific validation without close cooperation with commercial drug development programs. Even with such cooperation, the question of who should pay for such proof of principle is not clear. There is a need for clearer commercialization pathways for NAMs (outside those in-house NAMs utilized by industry), structured evidence packages, and early engagement with regulators.

While there is broad public support for reducing use of animals in research, it will also be critical to build public awareness of NAMs and for those participating in FIH clinical trials to be aware of, and comfortable with, their use in drug development. Consideration must be given to how to address participant information and consent processes for FIH studies that progress without traditional programs of animal testing.

There remain several barriers to the wider development and utilization of NAMs, which must be overcome:

• Our understanding of NAM potential is still developing. Development of suitable NAMs remains in its infancy in several areas, particularly for three-dimensional cellular NAMs that can reliably replicate the function of human organs. Development of NAMs that can represent individual human diseases also remains an emerging field, as does pre-clinical safety and efficacy evaluation of new therapeutics based on in silico approaches.
• Wider access to suitable NAMs. Many NAMs are developed for in-house screening of drug candidates by pharmaceutical and biotech companies or provided as a service by contract research organizations (CROs). This can hinder their ability to be validated by regulatory agencies or pharmacopeial bodies, which can limit wider acceptance and use.
• Clear and sustainable business models for NAM development are needed. Sponsors expect methods to be “pre-validated” before investment, and there is a need for clearer commercialization pathways, structured evidence packages, and early engagement by NAM developers with regulators.
• The development of sustainable business models would be assisted by the strategic identification of use cases most likely to support a translation pathway. This could include cases where repeated testing is required over time. Many FIH trials provide a “once and done” pathway for pre-clinical testing that does not lend itself to the requirement for platform validation. Examples could include investigational products that use a platform such as targeted oncology therapies or vaccines, or alternately, routine quality control analytical requirements.
• Regulatory conservatism. Many of the pre-clinical drug and biologic guidances from individual regulatory agencies and several ICH guidelines are focused on pre-clinical safety and efficacy testing using animals. While many regulatory agencies have indicated their future intention to accept NAMs, none have yet provided pragmatic guidance as to what validation will be required to consider a NAM as fully acceptable. Many international pharmacopeias also still specify the use of animals for several tests for products such as certain vaccines. Better guidance for those charged with making decisions on method acceptability for FIH trials is required. Regulatory and pharmacopeial guidance documents can take years to update, and changes are often only considered once the alternative technology is considered “mature.” Additionally, sponsors and CROs have invested significantly in pre-clinical development infrastructure based on animal testing and so may be reluctant to move away from this approach.

It should be emphasized that no one anticipates that the use of animals in pre-clinical testing will be abandoned. Rather, there will be a reduction in animal use, and combining animal pre-clinical toxicology and safety studies together with use of particular NAMs may provide results that are more relevant to the particular human disease under study.

Other innovations could include a centralized database to track NAMs in development, their validation status, and readiness for use. Such a tool would allow industry to identify models for specific development needs, streamline engagement, and support collaboration between academia and industry.

Education of drug developers, regulators, and members of IRBs/HRECs in the use and acceptability of NAMs will be required to support evidence-based decision-making, particularly as they relate to decisions on safety for FIH clinical trials. Educational institutions (e.g., universities) need to restructure current curricula to include content which informs the next generation of drug discovery and developers about the role and application of NAMs, through discovery, validation, and implementation pathways.

Committees may benefit from additional expertise, such as ad hoc inclusion of specialists in cell and tissue biology, cell culture, data science, and in silico computational modeling. Cross-membership between institutional animal and HRECs could also strengthen knowledge-sharing and smooth the transition from animal to nonanimal models. A “regulatory sandbox” or “safe harbor” approach could facilitate nonbinding collaboration to trial NAMs and develop use cases between regulators, industry, and technology developers.

Future workshops will explore these challenges with a broader range of stakeholders. The next event in late 2025 will pay particular attention to generating case study examples to demonstrate the challenges associated with translation and adoption, and to articulate early success stories that have achieved regulatory acceptability.

Workshops in 2026 will focus on developing a Decision Tree Framework for HRECs and regulators to guide evidence requirements for NAM-based regulatory submissions. Key therapeutic scenarios for the use of NAMS will be developed to support HRECs and regulators in their decision-making and clarify evidence requirements. These will promote the validation and application of NAMs across diverse therapeutic areas, for example for small molecules, monoclonal antibodies, cell and gene therapies, and antibody-drug conjugates.