Key Takeaways
- Animal welfare emerges as a priority for new FDA Commissioner Martin Makary, whose first major announcement is a new approach to encouraging development of alternative methods for preclinical studies.
- A pilot program allowing select monoclonal antibody developers to use non-animal-based testing strategies is expected in the coming year.
- As part of a “unified federal strategy,” the new approach will be coordinated by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), which could impact the FDA’s leadership role in the field.
Newly installed US FDA Commissioner Martin Makary opened his tenure with a “new approach” to animal testing that leapfrogged existing agency initiatives to understand so-called “new alternative methods” or “new approach methodologies” (NAMs) that do not require animals.
In what the FDA’s 10 April announcement characterized as a “groundbreaking step,” animal testing requirements will be “reduced, refined or potentially replaced” using NAMs data, a goal often known as the 3Rs by the international movement to develop more humane preclinical development.
“Implementation of the regimen will begin immediately for investigational new drug (IND) applications, where inclusion of NAMs data is encouraged,” the agency said.
The program will begin with preclinical testing of monoclonal antibodies, but is intended to expand to other biologics and eventually new chemical entities and medical countermeasures, according to an accompanying roadmap document.
“To make determinations of efficacy, the agency will also begin [to] use pre-existing, real-world safety data from other countries, with comparable regulatory standards, where the drug has already been studied in humans,” the announcement said.
The FDA had been grappling with incorporating NAMs into regulatory frameworks for years, focusing on development and qualification within a specific context of use. A Predictive Toxicology Roadmap was published in 2017. The Office of the Chief Scientist now coordinates the FDA’s New Alternative Methods Program, created in the agency’s fiscal year 2023 budget.
The FDA Science Board’s NAM subcommittee released a major report in October 2024 that indicated “very modest success in adoption of new NAMs” and urged the creation of a new central office in the FDA commissioner’s office to provide a “one-stop shop” for NAMs advice, precedent and qualification programs. The central office also would coordinate with international regulators, an key role given the more extensive adoption of NAMs overseas, especially in the European Union.
“It is important to recognize that considerably more research and development is needed for tools that might replace, reduce, or refine the large battery of animal studies that support a multitude of toxicity, safety, and effectiveness assessments,” the FDA’s NAM Program website states. “In the near term, the current state of the science related to alternative methods may provide tools that complement traditional methods and, in some cases, possibly eliminate specific tests.”
The FDA’s new approach includes many of the same goals as the NAM Program, but with fewer caveats. The announcement points to familiar examples of NAM technologies, like “organoid” or organ-on-a-chip systems, with an optimistic description of their benefits.
“Software models could simulate how a monoclonal antibody distributes through the human body and reliably predict side effects based on this distribution as well as the drug’s molecular composition,” the agency said. Organ-on-a-chip technology “can reveal toxic effects that could easily go undetected in animals, providing a more direct window into human responses.”
The new roadmap also makes the bold statement that “a majority of drug development failures are due to lack of efficacy or unexpected safety issues that were not evident in animal tests,” citing a narrative review by authors from activist groups including Animal Research Institute and Cruelty Free International.
The National Association for Biomedical Research, a nonprofit focused on humane use of animals in biomedical research, pushed back on the optimistic projections, stating “there is currently no full replacement for animal models in biomedical research and drug development.”
Artificial intelligence, one of the technologies touted in the roadmap, “is incredible and promises to speed up many aspects of research,” NABR President Matthew Bailey said in a statement. “However, one of the problems with AI is that it largely depends on pulling from existing data … The unknown variables could present the biggest risk to patients.”
‘Unified Federal Strategy’
The new approach sees the FDA as a component of the larger Health and Human Services Department. Where the Science Board report urged centralizing the FDA’s NAM activities, the new approach roadmap makes the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) the coordination site.
“In essence, ICCVAM provides the mechanism for a unified federal strategy,” the roadmap states. The ICCVAM “provides a ready-made platform for partnership with other federal entities.”
The permanent committee of the National Institute for Environmental Health Sciences was established in 2000 and includes representatives from 18 federal regulatory and research agencies who consider toxicological and safety testing information.
The FDA’s representatives to ICCVAM currently include:
- CDER Office of New Drugs Associate Director for Pharmacology and Toxicology Paul Brown
- CDER OND Associate Director for NAM Nakissa Sadrieh
- CBER Office of Therapeutic Products Division of Pharmacology/Toxicology 1’s Allen Wensky
- CBER Consumer Safety Office Leslie Wagner
- FDA National Center for Toxicological Research Division of Systems Biology Deputy Director Jessica Oliphant
- FDA NCTR Division of Genetic and Molecular Toxicology Supervisory Research Microbiologist Mugimane Manjanatha
- FDA Office of the Chief Scientist Senior Science Advisor Chad Nelson
- FDA Office of the Chief Scientist Office of Regulatory Science and Innovation toxicologist Tracy Chen
From Promise To Practice
A public workshop is expected later this year to discuss the roadmap and gather stakeholder input.
“Over the coming year, the FDA aims to launch a pilot program allowing select monoclonal antibody developers to use a primarily non-animal-based testing strategy, under close FDA consultation,” the FDA announcement states. “Findings from an accompanying pilot study will inform broader policy changes and guidance updates expected to roll out in phases.”
The roadmap outlines an investigation of the use of international human drug toxicity data in US IND applications over the next three years.
“By default, it will not be necessary to submit additional human data to the FDA if the product has been approved in a different country with similar regulatory standards unless the data are felt to be insufficient by FDA reviewers,” the roadmap states.
Sponsors will be encouraged to submit NAM data “in parallel with animal data to build a repository of experience.”
The roadmap also calls for creation of an “open-access repository with a comprehensive collection of international drug toxicity data from animals and humans.”
“In the long-term (three to five years), FDA will aim to make animal studies the exception rather than the norm for pre-clinical safety/toxicity testing,” the roadmap states. “By this stage, validated NAMs could cover all critical areas, and FDA requirements can shift to a NAM-based default.”
“Ultimately, the vision is that no conventional animal testing will be required for mAb safety, and eventually all drugs/therapeutics,” the roadmap states. “Instead, a comprehensive integrated NAM toolbox (human cell models plus computational models) will be the new standard.”
