When and Why to Use Nonhuman Primates (NHPs) — and How New Approach Methodologies (NAMs) Are Changing the Landscape

Advancing regenerative medicine therapies from discovery to clinical application often stalls in the “valley of death” - the critical gap where preclinical evidence fails to translate effectively into human outcomes. Nonhuman primate (NHP) studies have long provided essential translational insights in the development of advanced regenerative medicines. However, with increasing ‘fit for purpose’ New Approach Methodologies (NAMs), such as organ-on-chip systems, humanized models, and AI-driven simulations, the landscape is evolving rapidly. NAMs can complement and reduce animal use in many programs, while NHP models remain uniquely valuable in select, high-complexity cases where no other system can replicate human biology.

The Regulatory Perspective¹

NHP studies are not a “default” step for IND submissions in regenerative medicine, but when used selectively, and integrated with complimentary modeling, they provide a decisive, scientifically grounded bridge from promising preclinical results to safe, first-in-human trials.

• No universal requirement: The FDA, EMA, and ICH all emphasize that NHPs should only be used when no other relevant species can address the scientific questions.
• Model selection must be justified²: The chosen test system, whether animal or NAM, must be ‘valid’ – that is, biologically relevant, sensitive to product-specific risks, and technically appropriate for the intended delivery route.

• NAMs are officially recognized³: The FDA’s Advancing New Alternative Methods (NAMs) program supports integrating validated in vitro and computational models into regulatory submissions.

   

1. Summarizes current scientific and regulatory perspectives as of 2025. It is intended for informational purposes only and does not constitute formal regulatory advice.
2. Jeffers, M.S., Xi, C.E., Bapuji, R. et al. Synthesizing regulatory guidance for demonstrating preclinical efficacy and translating promising cell therapies to early phase clinical trials: a scoping review. BMC Med 22, 487 (2024). doi.org/10.1186/s12916-024-03690-8
3. Yao J, Peretz J, Bebenek I, Avila A, Alapatt T, Lee B, Patel D, Brown P, Davis-Bruno K. FDA/CDER/OND Experience With New Approach Methodologies (NAMs). Int J Toxicol. 2025 Nov 13:10915818251384270. doi: 10.1177/10915818251384270. Epub ahead of print. PMID: 41231273; PMCID: PMC12666506. journals.sagepub.com/doi/10.1177/10915818251384270
4. Tieghi, Ricardo Scheufen, et al. “The promise of animal testing alternatives at the U.S. Food and Drug Administration and National Institutes of Health.” NEJM AI, vol. 3, no. 1, 24 Dec. 2025, doi.org/10.1056/aipc2500587. 

Model Selection Strategy

1. Define the translational questions. Determine which endpoints require in vivo context and which can be resolved with NAMs.
2. Engage regulators early. The FDA’s Office of Tissues and Advanced Therapies (OTAT) encourages discussion of integrated IND strategies.
3. Combine evidence streams. Use NAMs for mechanistic and predictive insights, and animals for systemic validation, building a totality-of-evidence package.
4. Document your rationale. Transparently explain why a given model (or NAM) was chosen and how it supports safety, efficacy, and clinical translation.

How NAMs Are Transforming Preclinical Development

NAMs provide powerful human-relevant tools that complement or, in some cases, replace animal studies. Their adoption is accelerating across regenerative medicine, where complexity and translational risk are high.

NAM Advantages

• Human relevance: Directly models patient biology, not animal surrogates
• Early insight: Identifies toxicity or efficacy issues earlier in development
• Ethical and scalable: Reduces reliance on scarce or high-cost animal models

When NHPs Are Most Relevant

NHP studies remain uniquely valuable for select regenerative therapies. NHPs share near-human genetics, immunology, and physiology:

• Capture human-like immune tolerance, vector immunogenicity, and cell–host interactions.
• Reflect complex systems, especially immune, neural, and cardiovascular, that are difficult to model otherwise.
• Provide developmental parallels.

Systemic and Long-Term Safety Assessment: NHPs allow long-term observation of biodistribution, persistence, and immune response in a whole organism, something no current NAM can replicate.

Procedural and Surgical Fidelity: For therapies requiring implantation, catheter delivery, or microsurgery, primate anatomy and scale are essential for validating both the procedure and local tissue response.

Confidence to move to first-in-human trials: Investigators and regulators view well-designed NHP studies as high-value evidence, especially for novel delivery routes, systemic exposures, or uncertain immune risks. They often provide the decisive data enabling a safe first-in-human trial.

Scarcity as a Strategic Filter: Because NHP studies are resource-intensive and available at only a limited number of qualified facilities, they naturally focus on the most promising, late-stage candidates, ensuring that this unique resource is used for high-impact, high-readiness therapies.

When NHPs Are Not Typically Needed

• Localized or autologous therapies with minimal systemic exposure
• Products with pharmacologic activity in rodents or large non-primate species
• Device-based scaffolds or biomaterials where mechanical performance, not immune compatibility, is the key variable

In these cases, rodent and swine models, and increasingly, NAMs, typically can adequately address safety and performance questions.

Integration with NAMs

The strongest programs often use a NAM-plus-NHP hybrid strategy:

• NAMs optimize construct design and predict risks early.
• NHPs confirm systemic safety and procedural validity.
  Together, they accelerate translation with fewer animals and stronger human relevance.

Balancing Innovation and Translation

Both approaches are complementary, not competitive. Together, NAMs and NHP studies create a safe, efficient, and scientifically grounded translational pathway - bridging the gap between discovery and the clinic for regenerative medicine therapies.