Written by: Madhu Nag, PhD, Chief Scientific Officer at InSphero
A Turning Point for Smarter, More Human-Relevant Safety Science
The recent draft guidance from U.S. Food and Drug Administration outlining pathways to reduce non-human primate (NHP) use in monoclonal antibody development marks an important moment for our industry. It reflects what many of us working at the intersection of translational science, safety pharmacology, and regulatory science have long recognized: that advances in human-relevant in vitro models, when rigorously validated and appropriately contextualized, can now meaningfully inform critical development decisions, including when and how NHP studies are conducted.
Importantly, this guidance does not frame NHP reduction as an ethical aspiration alone, but as a scientific and strategic opportunity; one that depends on the development and availability of predictive, mechanistically informative, and reproducible alternative systems. This is an important distinction. The path forward is not about eliminating complexity, but about placing the right model, with the right biology, in the right context of use.
Standardized 3D InSight™ Cynomolgus Monkey Liver Microtissues enable reliable, high-throughput identification of potential liver toxicities prior to preclinical in vivo studies, and help verify whether toxicities observed in NHP models are likely to translate to humans
At InSphero, we view this guidance as both a validation of long-standing scientific investment and a call to action. Our 3D InSight™ Microtissue Platform, spanning human, non-human primate, and additional species (rat, mouse and dog) were designed from the outset to support cross-species translatability, mechanistic interpretation, and quantitative exposure–response analysis. This multi-species capability is especially critical for biologics, where target expression, pathway engagement, Fc receptor biology, and immune modulation often differ meaningfully and critically between human and traditional toxicology species.
From a practical standpoint, our advanced 3D InSight™ Microtissues offer three concrete advantages in the context of the FDA’s draft guidance.
Earlier human relevance
Human primary liver immune-competent microtissues allow developers to interrogate on-target and off-target liabilities in a physiologically structured human cellular environment, before committing to long and resource-intensive NHP studies. This supports better-informed first-in-human strategies and a more rational selection of in vivo models when and where they remain necessary.
Mechanistic de-risking: not just hazard flags
Unlike traditional 2D monolayer systems, structured 3D tissues enable temporal, multi-parametric readouts, including functional recovery, stress adaptation, inflammatory signaling, and tissue remodeling. For monoclonal antibodies and related modalities, this is essential for distinguishing pharmacology-driven biology from true safety liabilities, a distinction that often drives over-conservative animal study designs.
Intelligent reduction; not blind replacement of NHP use
Importantly, the FDA guidance still acknowledges that NHP studies may be required in certain mechanistic or target-specific circumstances. This is where paired human NHP 3D tissue testing becomes a powerful translational bridge, allowing teams to directly assess species concordance at the tissue level before escalating to whole-animal studies. In many cases, this enables more focused, shorter, and better-powered in vivo programs, rather than default six-month studies.
What will determine the real impact of this draft guidance is not aspiration, but execution: clear contexts of use, analytical validation, biological benchmarking, and regulatory confidence built on transparent performance data. These principles are fully aligned with how we and many collaborators across pharma, academia, and regulatory bodies are already advancing New Approach Methodologies (NAMs).
The FDA’s message is clear: the future of biologics safety assessment will be hybrid, data-rich, mechanistically anchored, and increasingly human-centric. The companies that succeed will be those that use advanced in vitro systems not as stand-alone replacements, but as decision-enabling engines that sharpen when, where, and how animal studies are truly needed.
For those of us building these platforms, the responsibility is equally clear: to deliver rigorous science, reproducible performance, and regulatory-ready evidence packages that make guidance like this not only aspirational, but operational.
