FDA Endorses Human-Relevant Nonclinical Models: A Welcome Shift for Monoclonal Antibody Development
by Johannes Stanta, PhD – Global Scientific Director, Sabina Paglialunga, PhD – Senior Scientific Director, and Aernout Van Haarst, PhD – Senior Scientific Director
The FDA’s recent decision to support non-animal methods for the safety evaluation of monoclonal antibodies (mAbs) is a significant—and long overdue—step forward in modernizing drug development. While the scientific community has long embraced the 3Rs framework (Refine, Reduce, Replace), regulatory acceptance has historically lagged behind. This has limited the practical application of advanced non-animal technologies beyond academic discovery and internal candidate selection.
Until now, animal testing has remained a regulatory default—often considered mandatory—with little room for alternative strategies. Good Laboratory Practice (GLP) enforcement has added further rigidity, making it challenging to integrate more flexible, human-relevant tools into regulated programs.
A Question of Translation, Not Tradition
The limitations of animal models are well established. Across therapeutic areas, particularly in immunology and oncology, the predictive value of animal studies for human outcomes is poor. In the context of mAbs, these limitations are especially pronounced. Safety signals often arise from excessive pharmacologic action or immune activation, rather than classical dose-dependent, off-target toxicity. These mechanisms are difficult—if not impossible—to model in animals, where interspecies differences in immune architecture obscure translatability.
This regulatory shift now enables the broader use of validated New Approach Methodologies (NAMs)—including organoid models, immune microphysiological systems, and in silico tools—as part of safety packages for investigational new drug (IND) applications. Notably, the FDA will also begin accepting real-world human safety data from other regulatory jurisdictions, providing an opportunity to reduce duplicative and ethically questionable animal studies.
Opportunities and Challenges for the Field
This shift raises important questions for the drug development ecosystem:
- Can NAMs provide sufficient data to inform a safe starting dose for a first-in-human study? The current mAb paradigm relies on minimal anticipated biological effect level (MABEL) or physiologically active dose (PAD) to establish a first starting dose. While the MABEL approach can be fulfilled without animal testing as it often includes in vitro receptor occupancy assessments, the PAD approach tends to comprise of animal models, which may require rethinking or development of newer methodologies to substantiate a non-animal model.
- How do we build confidence in the performance of NAMs? While early data on systems like liver chips and cytokine release assays are promising, widespread adoption will require validation, reproducibility, and clearly defined regulatory contexts of use.
- Are current laboratory infrastructures ready to support the complexity of these models? Organoids and microphysiological systems demand expertise in cell biology, tissue engineering, and real-time functional readouts. Integrating such technologies into a GLP-aligned environment is a non-trivial task, especially as these concepts have often been deployed in non-GLP discovery or academic settings.
- What frameworks are needed to standardize these methods across sponsors and regulators? Without harmonized protocols, the interpretation of NAM-based safety data risks inconsistency, delaying regulatory confidence.
- How will bioanalytical and pharmacokinetic modeling capabilities evolve to complement these in vitro systems? Tools like physiology-based pharmacokinetic (PBPK) modeling, quantitative systems pharmacology (QSP), and immunogenicity prediction will need to be deeply integrated into the workflow and accelerated using machine learning approaches to continuously improve outcomes and applicability.
- What type of research organizations will be best equipped to navigate this transition? It is reasonable to envision that GLP-accredited laboratories combining molecular and cellular assay expertise, regulatory bioanalysis and tight integration with clinical trial units may be best positioned to bridge nonclinical insights and clinical execution.
A Critical Inflection Point
The field has been scientifically prepared for this transition for years. Now, with regulatory momentum finally aligning, the challenge is operational. The focus must turn to building capacity, ensuring reproducibility, and developing harmonized protocols while educating regulators to work with these tools effectively.
This move by the FDA is not just a policy update—it is a call to action. If implemented thoughtfully, it will accelerate development timelines, reduce costs, uphold ethical standards, and, most importantly, improve the relevance of preclinical data to human biology.
The burden now shifts to the industry to answer:
Are we ready to let go of legacy models and build a nonclinical paradigm that truly reflects human physiology?