FDA animal testing phaseout urges AI-based trial alternatives, organoids, other “NAMs”

Background

In recent years, the U.S. Food and Drug Administration (FDA) has resisted calls to phase out animal testing, with former FDA commissioner Robert Califf saying that animal testing can't easily be replaced, especially in public health emergencies. Former FDA Center for Biologics Evaluation and Research (CBER) director Peter Marks also stated that animal testing remains necessary in many cases.

On the industry side, however, we have observed efforts to reduce the burden of animal testing, especially related to evaluations of an irritation/intracutaneous reactivity endpoint. For example, in certain circumstances, for medical devices or components that contact intact skin surfaces – regardless of duration of contact – specific information may be provided in premarket submissions to support the established biocompatibility of these products instead of direct testing.

Congress has been active in encouraging the study and use of animal testing alternatives. For example, the Modernization of Cosmetics Regulation Act of 2022 (MOCRA) included a provision stating the “sense of the Congress” that “animal testing should not be used for the purposes of safety testing on cosmetic products and should be phased out with the exception of appropriate allowances.” That provision, however, created no new authority for FDA, and was not enforceable. Nevertheless, FDA has initiated research projects related to organ-chip and organoid technologies and has accepted an organ-chip technology into its Innovative Science and Technology Approaches for New Drugs (ISTAND) Pilot Program, which aims to assist industry in qualifying drug development tools.

Now, FDA has announced that its animal testing requirement “will be reduced, refined, or potentially replaced using a range of approaches, including AI-based computational models of toxicity and cell lines and organoid toxicity testing in a laboratory setting (so-called New Approach Methodologies or NAMs data).” FDA also plans to begin using pre-existing, real-world safety data (RWD) from other countries that have “comparable regulatory standards, where the drug has already been studied in humans” to make determinations as to the efficacy of NAMs in place of traditional animal studies.

“New approach methodologies”

Along with the announcement, FDA published a “roadmap” for reducing animal testing, which outlines the approach that the agency intends to deploy in preclinical safety studies with scientifically validated new approach methodologies (NAMs), including:

• In silico tools and computational modeling. FDA is encouraging the use of artificial intelligence (AI) and machine learning (ML) to "leverage existing data to predict safety, immunogenicity, and pharmacokinetics, reducing the need for new animal experiments.” FDA may review tools like Physiologically-Based Pharmacokinetic (PBPK) modeling to inform first-in-human dosing and justify waiving animal studies that would normally serve that purpose. AI/ML predictive models, along with in silico tools, can be leveraged to flag problematic sequences and binding, “de-risk” products, and predict toxicities by learning patterns from molecules that caused certain adverse events. Additionally, FDA asserted that Quantitative Systems Pharmacology (QSP) models could reduce reliance on animal testing by providing a virtual human on which to test “what-if” scenarios.
• Organoids and microphysiological systems (MPS) (often called “organs-on-chips,”). FDA is projecting that organoids/MPS, which model tissue architecture and simulate tissue functions, can evaluate target-specific and off-target effects in a controlled human microenvironment to assess the safety of monoclonal antibodies. FDA suggests that these technologies may also permit real-time monitoring of functional endpoints that parallel clinical safety markers, like immune-related and toxicological effects. Touting these technologies as predictive (or more predictive) than animal tests, FDA discusses how organoids/MPS can avoid species differences and can reveal effects that are more relevant to patients.
• Ex vivo human tissues. Advances in organ donation and tissue preservation allow scientists to test drugs on actual human tissues and complement engineered organoids, FDA’s roadmap says.
• High-throughput cell-based screening. Robotic high-content screening using panels of human cells (e.g., induced pluripotent stem cell-derived cells from diverse genetic backgrounds) can profile the effects of a product on many cell types, which “can reveal off-target cytotoxicity or functional changes in a broad, human-relevant manner.”
• Microdosing and imaging in human volunteers. In certain cases, microdosing studies in humans can yield early pharmacokinetic and distribution data via positron emission tomography (PET) imaging, the agency stated.
• Refined in vivo methods. FDA recommended using humanized transgenic mice to reduce animal numbers and pain as an interim step to reduce reliance on animal testing.

The agency said it aims to “accelerate the validation and adoption of these human-relevant methods, improving predictive accuracy while reducing animal use.” Not discussed in the announcement or the roadmap is the agency’s legal authority to rely on non-sponsor data to reach regulatory conclusions, particularly in the context of BLAs, where reliance on data the sponsor does not own, or for which it does not have a right of reference may, under current law, be limited to applications submitted under section 351(k) of the Public Health Service Act.

International data and global harmonization concerns

With this announcement, FDA appears ready to accept the use of pre-existing international human data to reduce the need for new animal testing in U.S. drug and biologic applications. When a compound has already been approved in a country with regulatory standards comparable to U.S. standards, FDA is encouraging manufacturers to gather and submit that data for consideration in their Investigational New Drug (IND) applications. It is unclear what jurisdictions will be considered comparable to FDA. Additionally, sponsor should note that FDA in its guidance on Acceptance of Foreign Clinical Studies Not Conducted Under an IND states that foreign clinical studies supporting an IND must meet requirements under 21 CFR 312.20. And, as noted above, not discussed in the materials published by FDA is the scope of the agency’s authority to rely on such data in the context of the approval of a marketing application, particularly a BLA, where the statutory authority for sponsors to rely on data they do not own or to which they do not have a right of reference may be subject to debate.

Recognizing the global nature of drug development, FDA states that it is taking active steps to influence international regulatory frameworks to accept New Approach Methodologies (NAMs). Through participation in international forums such as the International Council for Harmonisation (ICH), and collaborations with agencies like the European Medicines Agency (EMA) and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), FDA aims to align global regulatory expectations. Initiatives such as joint workshops, cross-border validation studies (e.g., of organ chips), and harmonized guidance updates are part of this effort.

While FDA states that it is actively exploring moving toward replacing animal studies with NAMs, sponsors must remain mindful that other jurisdictions may still require traditional animal testing. However, as the FDA works to build international consensus and drive a global shift in regulatory science, the long-term vision is a harmonized environment in which NAMs are widely accepted, reducing duplication of animal studies and facilitating more efficient, ethical global drug development.

Implementation timeline

FDA said implementation of the animal testing alternative regimen will begin immediately for investigational new drug (IND) applications “where inclusion of NAMs data is encouraged.” However, FDA’s roadmap clarifies that the new program will only begin with monoclonal antibodies (mAb) in preclinical safety testing, “and then will expand to include other biological molecules and eventually new chemical entities and medical countermeasures.” The use of NAMs to support a marketing application is not addressed in the materials circulated by FDA.

Meanwhile, FDA will launch a pilot program over the next year that will allow select developers of the therapeutics to use a testing strategy primarily based on NAMs. Companies that submit strong safety data without using animal testing may receive a streamlined review, FDA wrote. Sponsors will be encouraged to submit NAM data “in parallel with animal data to build a repository of experience” and fill gaps created by the lack of centralized access to comprehensive animal and human toxicity data. FDA plans to track and quantify its progress in changing toxicity testing by promoting NAMs on a bi-annual basis to the extent feasible.

In the long-term (“three to five years”), FDA said it “will aim to make animal studies the exception rather than the norm for pre-clinical safety/toxicity testing,” according to the roadmap. “By this stage, validated NAMs could cover all critical areas, and FDA requirements can shift to a NAM-based default.” The roadmap adds: “Ultimately, the vision is that no conventional animal testing will be required for mAb safety, and eventually all drugs/therapeutics. Instead, a comprehensive integrated NAM toolbox (human cell models plus computational models) will be the new standard.”

Next steps

In accord with FDA’s roadmap, the agency stated its intent to release guidance documents on how NAMs can be used in various development programs, which may include guidance on replacing specific animal studies, tissue chip stability, cell characterization, or computational model verification when used in regulatory submissions, and/or examples in guidance of how sponsors can incorporate NAM data alongside or in place of animal data in their IND or Biologics License Application (BLA) submissions.

FDA is also proposing to identify key safety and efficacy endpoints for drugs and biologics where NAMs could replace or augment animal testing, such as toxicity, pharmacokinetics, and immune responses. The agency plans to support the targeted development of NAM technologies through research collaborations and by creating comprehensive databases of toxicity data to improve model training. The roadmap also proposes the establishment of validation and qualification pathways for NAMs, including retrospective analyses, prospective validation trials, and reproducibility testing, to ensure that NAMs are reliable, standardized, and aligned with human clinical data. Additionally, the FDA suggests formalizing NAM acceptance through its Drug Development Tool (DDT) Qualification programs, enabling sponsors to use NAMs confidently in regulatory submissions.

FDA also said it will hold a public workshop later this year to “discuss the roadmap and gather stakeholder input”; no specific date is yet set for the workshop. FDA also discussed in the roadmap its plans for coordinating on the policy shift through the “Interagency Coordinating Committee on the Validation of Alternative Methods,” which also includes the National Institutes of Health, the National Toxicology Program and the Department of Veterans Affairs.

Feel free to reach out to any of the authors of this alert or the Hogan Lovells attorney with whom you regularly work with any questions.

Authored by Robert Church, Heidi Gertner, Dave Fox, Jason Conaty, and Ashley Grey.