In a landmark decision signaling a paradigm shift in pharmaceutical safety assessment, the U.S. Food and Drug Administration (FDA) announced on April 10, 2025, a plan to phase out the requirement for animal testing in the development of monoclonal antibody therapies and other drugs. This “groundbreaking step” aims to advance public health by transitioning to “more effective, human-relevant methods.” The FDA anticipates this new approach will enhance drug safety predictions, accelerate the evaluation process, reduce animal experimentation, and potentially lower research and development (R&D) costs and drug prices.
At the core of this transformation lies the increasing adoption of New Approach Methodologies (NAMs). The FDA broadly describes NAMs as more effective and human-relevant methods to replace animal testing, encouraging the use of computer modeling and AI to predict a drug’s behavior. Expanding on this, the ALTEX article defines NAMs as methods based on human biology that can offer more relevant information for safety assessment by utilizing cells or tissues of the target species. Similarly, the European Medicines Agency (EMA) characterizes NAMs in the context of medicines development as 3Rs-compliant testing approaches, aligning with the principles of Replacement, Reduction, and Refinement of animal models.
Rather than a finite number of categories, NAMs encompass a spectrum of innovative tools and techniques. These include in silico (computational modeling), in vitro (laboratory-based using cells and tissues), ex vivo (studies on tissues outside a living organism), and in chemico (using chemical and physical methods) approaches. The FDA highlights examples such as AI-based computational models of toxicity and cell lines and organoid toxicity testing in a laboratory setting. The EMA’s horizon scanning report further illustrates the breadth of NAM R&D, identifying clusters ranging from complex in vitro models (tissue engineering, organoids) to molecular docking in silico models. This underscores that NAMs represent a diverse and evolving field.
Despite the promising potential of NAMs, their widespread integration into regulatory practice faces significant challenges and issues. These hurdles span technical and scientific barriers, such as the need for further development and validation of NAMs for complex systemic toxicities. There are also perceived scientific and technical issues stemming from a lack of familiarity and confidence with these new methodologies. Regulatory barriers are prominent, including existing legislative frameworks that may implicitly favor animal data and a perceived expectation from regulatory bodies to receive animal testing results. This can create a “chicken and egg” scenario where limited NAM submissions hinder regulatory understanding and acceptance. Economic barriers involve uncertainties surrounding the return on investment in NAMs and the necessary transition for contract research organizations (CROs). Moreover, cultural and societal obstacles, including inertia and comfort with traditional animal methods, and skepticism about regulatory acceptance, contribute to slower adoption. A crucial challenge also lies in defining a specific context of use for NAMs for regulatory purposes, moving away from broad claims of applicability. The EMA’s “Guideline on the principles of regulatory acceptance of 3Rs (replacement, reduction, refinement) testing approaches” aims to address some of these regulatory considerations.
The implementation of NAMs is expected to be a gradual process. The FDA’s announcement marks an immediate encouragement for the inclusion of NAMs data in investigational new drug (IND) applications. The agency plans to launch a pilot program for select monoclonal antibody developers utilizing primarily non-animal testing strategies, with the outcomes informing broader policy changes and updated guidance. Similarly, the EMA has a long-term strategic goal to promote the acceptance of animal-free innovations or NAMs. We can anticipate increased collaboration between developers, regulators, and other stakeholders to build confidence and establish clear frameworks for NAM qualification and regulatory acceptance. The development and publication of case studies demonstrating the successful application of NAMs will be vital in building an evidence base and fostering wider adoption across different regulatory frameworks. While animal models may still hold a role in specific, complex scenarios, the momentum is clearly shifting towards a future where human-relevant NAMs play an increasingly central role in ensuring the safety and efficacy of new medicines, aligning with both scientific advancements and ethical considerations.