From Option to Obligation: The Legal Imperative for NAMs
By Jo Anderson | August 7th, 2025
The Current Legal and Regulatory Framework: NAMs as an "Option"
Under the EPA’s definition, New Approach Methodologies (NAMs) are technologies, methods, or computational techniques that provide information on chemical hazard and risk assessment without using intact vertebrate animals. Examples include in vitro tests, in chemico assays, and in silico algorithms. Once merely regarded as alternatives to animal testing, NAMs have now emerged as a driving force in regulatory science. Legal mandates, ethical concerns, and scientific progress account for the increasing push for NAMs to become the new standard for regulatory decisions. The Toxic Substances Control Act (TSCA), as amended by the Frank R. Lautenberg Chemical Safety for the 21st Century Act, explicitly instructs the Environmental Protection Agency (EPA) to reduce and replace vertebrate animal testing “to the extent practicable and scientifically justified.” It also encourages the development and rapid adoption of New Approach Methodologies (NAMs) to support this transition. Most environmental laws have broad discretion in their wording, with many statutes neither specifying the types of testing required nor requiring the use of animal models. This legal flexibility helps facilitate the consideration and use of NAMs. To support this effort, the EPA keeps a list of NAMs that are deemed scientifically reliable and relevant, including tools such as quantitative structure-activity relationships (QSARs), read-across methods, and other computational techniques.
Legal and Regulatory Hurdles to Full Standard Adoption
Still, some regulations explicitly require animal testing, especially in pharmaceutical drug approval processes and certain EPA programs. For instance, laws and regulations related to New Drug Applications (NDAs) and Investigational New Drug (IND) applications often mandate animal pharmacology and toxicology data. Although phrases like "pertinent animal data may also be used" suggest some flexibility, the actual effect is that animal studies remain. The FDA often depends on these studies for critical decisions, such as drug approvals and clinical holds. However, this sometimes requires long-term toxicity studies in non-rodent species to assess human risk. While many environmental laws are written broadly, some existing regulations explicitly require testing on animals. As a result, replacing these methods with NAMs often involves formal rulemaking—a process that consumes time and resources, making it difficult to keep pace with scientific advancements. Judicial deference to conventional animal testing requirements also complicates the process. In cases like Vanda Pharmaceuticals Inc. v. FDA, courts have upheld the FDA’s authority to require animal studies for drug approvals and clinical holds, viewing animal data as central to existing regulations and laws. Legal challenges to the FDA’s practices mainly focus on procedural issues rather than supporting NAMs, and courts have generally avoided reinterpreting the core role of animal studies, as seen when they refused to consider Vanda’s late argument under the FDA Modernization Act 2.0. Courts have in the past deferred to the FDA’s scientific judgment in these cases, supporting a regulatory framework that still defaults to, or explicitly requires, the use of traditional animal data for specific safety assessments, even as NAMs continue to develop.
Why the Shift to NAMs as a Standard is Necessary and Underway
A combination of ethical, scientific, and practical reasons drives the shift toward NAMs. Ethically, there is a strong and admirable commitment to reducing, refining, and ultimately replacing vertebrate animal testing with more humane research methods. Scientifically, NAMs often yield high-quality, reproducible data that are more directly relevant to human health, largely because they focus on mechanisms of action (MOA)—the sequence of molecular events by which a substance causes a biological effect. For example, a chemical might bind to a receptor, alter gene expression, or inhibit an enzyme. EPA programs like ToxCast use high-throughput NAMs to generate MOA-based data, which inform Adverse Outcome Pathways (AOPs) linking early molecular events to potential harm. This enables regulatory decisions, such as prioritization and risk assessment, to be based on scientifically grounded and human-relevant evidence. By integrating MOA-based evidence, the EPA increases the scientific rigor and human relevance of its decisions, while advancing its statutory goal of reducing and replacing vertebrate animal testing under the Toxic Substances Control Act (TSCA).
From a practical standpoint, NAMs enhance efficiency and cost-effectiveness by streamlining testing processes, minimizing unnecessary expenses, and fostering a more flexible, transparent, and sustainable approach to toxicology. Additionally, NAMs are actively being developed to address critical information gaps that traditional methods have struggled to cover, particularly in complex areas, such as developmental, reproductive, and immunotoxicity. International organizations like the Organisation for Economic Co-operation and Development (OECD) are working to standardize and validate NAMs through detailed guidance on models and reporting frameworks, thereby building scientific confidence and supporting broader regulatory acceptance worldwide.
The Path Forward: Solidifying NAMs as the Standard
To fully establish NAMs as the regulatory standard, several strategic actions are necessary. Legislative and regulatory updates must go beyond general encouragement and permit the use of NAMs as primary testing methods when scientifically justified. Continued scientific research and validation are also essential, especially in developing NAMs that address currently uncovered toxicity endpoints, such as target organs, cardiovascular toxicity, neurotoxicity, and systemic toxicity. Building confidence in these methods requires rigorous case studies, peer-reviewed research, and comprehensive training initiatives. Standardization and harmonization efforts, including the development of international frameworks like the OECD Omics Reporting Framework, are crucial for ensuring consistent data generation, analysis, and regulatory interpretation. Strategically, NAMs must be integrated across various decision-making contexts, including dose-response assessment, chemical prioritization, assessment of chemical mixtures, and read-across methodologies. Additionally, existing tools that the EPA has, such as ExpoCast and ToxCast, should be leveraged. Lastly, stakeholder engagement through open communication, public webinars, and collaboration with academia, industry, and international bodies will be vital in overcoming implementation barriers and promoting the widespread adoption of NAMs.
Conclusion: A Future Rooted in Modern Science
Although significant progress has been made, fully harnessing the potential of NAMs requires coordinated legislative and regulatory efforts. Transitioning NAMs from optional alternatives to regulatory standards is a complex process influenced by legal, scientific, and ethical considerations. These efforts must be backed by ongoing scientific validation and strategic implementation to establish NAMs as the primary and preferred testing methods. Making NAM-based testing a regulatory requirement will also stimulate investment in research, validation, and infrastructure, thus accelerating the development and refinement of NAM technologies. This approach will enhance protection for human health and the environment while substantially reducing reliance on animal testing.
The views expressed do not necessarily reflect the official policy or position of Johns Hopkins University or Johns Hopkins Bloomberg School of Public Health.
