The Utility of an Intra-Agency NAM Office

By Breanne Kincaid | January 10th, 2025

Recently, the US Food and Drug Administration (FDA) Science Board subcommittee on New Alternative Methods released a report highlighting potential approaches to drive the integration of New Approach Methodologies (NAMs) for regulatory decision-making.

Historically, FDA has relied on data from standardized animal studies to understand the toxicity of foods, cosmetics, and pharmaceuticals. However, these studies can take years to complete, are costly to undertake, and in certain contexts, aren’t sufficiently predictive of human biology.

NAMs are emerging technologies in toxicology that include in vitro tests, computational modeling, biomarkers, and modified in vivo assays. Their cost effectiveness, scalability, and utilization of cells or data from the species of interest (humans) hold promise for driving faster and more accurate human risk assessments while reducing current reliance on animal testing. As such, FDA and other regulatory authorities have indicated favorability toward integrating NAMs into their regulatory schemes.

One of the subcommittee’s recommendations was for the creation of a centralized office within FDA to coordinate and drive NAM integration into the agency’s regulatory scheme. Some may interpret the creation of such an office as duplicative of efforts currently undertaken by the federal government’s Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM). However, important distinctions exist between the two bodies and both are needed.

The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) is an advisory body that promotes the development, validation and regulatory acceptance of alternative testing methods across fifteen federal agencies with responsibilities over chemical safety, public health, and environmental protection – including FDA. ICCVAM has made progress publishing frameworks and facilitating collaboration on NAMs, but the committee lacks direct regulatory authority and cannot require agencies to utilize or accept NAM data submitted to for regulatory decision-making. While ICCVAM’s role in coordinating alternative method adoption is valuable, its multi-agency scope can dilute the specificity of its efforts, leading to general recommendations that may not align with the FDA’s specific regulatory mandates.

For example, under FDA regulation 21 CFR 170.39, if a food contact material such as packaging contain a carcinogenic impurity, the compound must be tested in a two-year rodent feeding study to confirm that its TD50 value—the dose that causes cancer in 50% of test animals—exceeds 6.25 mg/kg body weight per day. Here, a higher TD50 value indicates lower risk[PL1] . A NAM intended to replace this test must address this specific context of use. It must provide a dose response assessment that can be extrapolated to humans over a prolonged time period in order to adequately identify the cancer hazard.

Since cancer can be caused through many different processes, including mutagenicity (causing DNA mutations), clastogenicity (causing chromosomal breakage), aneugenicity (causing a change in chromosome number), or non-genotoxic mechanisms such as cell proliferation or chronic inflammation, it’s important that a NAM or approved battery of NAMs intended to replace the two-year rodent bioassay can adequately capture this biology. In vitro tests like the Ames test, micronucleus assay, and in vitro chromosomal aberration assay help identify genotoxic carcinogens, but currently lack the full biological complexity to answer the specific long-term carcinogenicity question that FDA requires to confidently determine a TD50 equivalent value.

This is a potential scope limitation that a centralized agency office would be well-poised to tackle.

The FDA’s NAM office would operate within the legal authorities granted to the FDA by the Federal Food, Drug, and Cosmetic Act (FDCA) and other statutes. This internal office could integrate NAMs directly into FDA-specific regulatory processes, tailoring their application to the agency’s unique needs and statutory mandates. The FDA office can also provide targeted resources for industry stakeholders, including detailed guidance and pathways for submitting NAM-derived data, enhancing the practical utility of these methods. These avenues would enable the FDA to streamline the implementation of NAMs for context-specific uses that are directly relevant to regulatory decision-making.

In summary, the FDA’s NAM office represents a strategic evolution in integrating innovative methodologies into regulatory science. While it complements ICCVAM’s mission, its intra-agency focus and regulatory authority position it to drive faster, more context-specific advancements in risk assessment. Creating and empowering this office would be  a promising step toward a future where safety evaluations are scientifically robust,use far fewer animals and tailored to protect public health effectively.

The views expressed do not necessarily reflect the official policy or position of Johns Hopkins University or Johns Hopkins Bloomberg School of Public Health.