Last Updated: October 2, 2026, 3 pm UTC
Drug developers have long relied on animal studies to generate critical nonclinical evidence before testing a therapy in humans. But as our understanding of human biology and our ability to model it become more sophisticated, the role of animal testing is evolving.
New Approach Methodologies (NAMs) and Model-Informed Drug Development (MIDD) are at the center of this evolution. Rather than relying on a single animal study to answer a development question, these approaches can bring together evidence from in silico, in chemico, in vitro, ex vivo, and in vivo methods to build a more comprehensive picture of how a therapy may behave in humans.
The goal is not to simply replace animal studies one-for-one, but to use multiple complementary approaches to generate a stronger weight-of-evidence (WoE). This article explores how NAMs and MIDD work together, how regulators recommend their use, and where these methods are already being applied in drug development.
NAMs and MIDD: A Complementary Approach
NAMs encompass a broad range of methods designed to improve the predictive relevance of nonclinical testing for humans, including in vitro models, human ex vivo tissue, organoids, microphysiological systems, and computational models.
MIDD uses modeling and simulation to integrate different sources of information, including nonclinical and clinical data and prior knowledge, to inform drug development decisions.
The real opportunity lies in bringing these approaches together. NAMs can generate human-relevant biological data, while MIDD can help integrate that information and translate it into predictions that support development decisions.
This combination can help answer questions that traditional animal studies may not fully address. Animal models are complex biological systems, but they do not always provide a quantitative match for what will happen in humans. NAM and MIDD approaches are not currently a universal replacement for animal or human studies, but their value lies in improving the relevance and quality of the evidence and, where scientifically justified, reducing or refining animal testing.
Regulators are Embracing a Weight-of-Evidence Framework
The principles of the “Three Rs,” replacement, reduction, and refinement, have been part of the scientific and regulatory conversation for decades. As time and technology allow, the regulatory environment evolves in alignment with the Three Rs. As such, recent regulatory guidance has increasingly emphasized alternative approaches and the use of a WoE framework.
The International Council for Harmonization (ICH) has supported this evolution through guidance addressing areas such as general nonclinical development, oncology, biotechnology-derived pharmaceuticals, photosafety, reproductive and developmental toxicity, pediatric pharmaceuticals, genotoxicity, and carcinogenicity. For example, in 2022, ICH S1B(R1) incorporated a WoE assessment that could support waiving a two-year rat carcinogenicity study [1].
The FDA has similarly provided flexibility around nonclinical requirements, including for drug combinations and products administered through alternative routes. Its 2026 guidance on NAMs provides additional recommendations around validation and their use in drug development [2].
The evolving regulatory landscape and continued release of guidance on NAMs and MIDD signal growing regulatory momentum and a clear commitment to embracing new approaches to drug development.
Context of Use is Critical
Regulators often stress that as NAMs and MIDD become more sophisticated, simply selecting an alternative method is not enough. One of the most important considerations is defining the context of use (COU).
The COU describes what a particular NAM is intended to do and what specific drug development or regulatory decision it is intended to support. That question should be defined before determining whether a particular model or method is appropriate.
For example, a NAM might be used to support dosage selection, determine the extent of patient monitoring needed in a clinical trial, investigate the human relevance of an adverse event, justify why a particular animal species may not add meaningful information, or contribute to a broader WoE assessment.
This becomes especially important for computational models. As in silico approaches become more advanced, regulators need to understand not only the model’s output, but also the assumptions underlying it, its technical characteristics, limitations, and intended application.
ICH M15, issued in 2026, represents an important step in this area by providing harmonized principles around the format, structure, and technical content of MIDD submissions [3]. Establishing a consistent framework can make it easier for regulators to evaluate modeling approaches and understand whether a model is appropriate for the question being asked.
For sponsors, this means a NAM strategy should begin with the scientific and regulatory question, not with the technology itself, and getting regulatory buy-in early on is critically important.
MIDD is Already Making a Difference
While the broader vision for NAMs and MIDD is still developing, MIDD approaches are already being applied in drug development.
For ibrutinib (Imbruvica), physiologically based pharmacokinetic (PBPK) modeling and pharmacometrics were used. PBPK models can help predict how a drug moves through the body and make more effective use of existing data, and in this case, reduced the need for additional drug-drug interaction (DDI) and pediatric studies [4].
Oseltamivir (Tamiflu) provides another example. A physiologically based biopharmaceutic model supported virtual bioequivalence assessments, demonstrating how modeling can potentially reduce the need for experimental formulation-bridging studies [5].
More sophisticated approaches are also being used for complex biological questions. For mosunetuzumab, a bispecific antibody targeting CD20 on B cells and CD3 on T cells, quantitative systems pharmacology (QSP) modeling was used to predict cytokine release syndrome risk and support first-in-human dose selection. The model provided mechanistic evidence that complemented traditional nonclinical studies and informed progression into the clinic [6].
Looking Ahead
The movement toward NAMs and MIDD is not about eliminating every animal study overnight. Instead, it represents a shift toward a more risk-based, question-driven approach to nonclinical development.
Successful implementation requires cross-functional collaboration among toxicology, clinical pharmacology, pharmacometrics, regulatory, and other disciplines. Sponsors should define the COU, understand a model’s validation and limitations, and build a WoE package that demonstrates its relevance to the development question. Early regulatory engagement can also help sponsors discuss and refine their proposed strategies and will be critical to successful implementation.
Ultimately, NAMs and MIDD offer the potential to make nonclinical development more human-relevant while reducing reliance on animal testing where scientifically justified. The future is unlikely to be defined by a single technology replacing animal studies. Instead, it will be shaped by better questions, better models, and better integration of evidence, helping drug developers make more informed decisions as they move therapies toward patients.
When strategically planned and used together, NAMs and MIDD can help improve the relevance and quality of data and, where scientifically justified, reduce or refine animal testing. Connect with our team to explore how these approaches can be applied to support your drug development program.
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REFERENCES:
- U.S. Food and Drug Administration. “S1B(R1) Addendum to S1B Testing for Carcinogenicity of Pharmaceuticals.” FDA, 11 July 2022, . Accessed 2 Sept. 2026.
- U.S. Food and Drug Administration. “General Considerations for the Use of New Approach Methodologies in Drug Development.” FDA, Mar. 2026, . Accessed 2 Sept. 2026.
- U.S. Food and Drug Administration. “M15 General Principles for Model-Informed Drug Development.” FDA, June 2026, . Accessed 2 Sept. 2026.
- Ouellet, D. (2018). MIDD applied post-approval: Examples with ibrutinib, a BTK inhibitor [FDA workshop presentation]. U.S. Food and Drug Administration. https://www.fda.gov/media/112937/download
- Miao, L., Mousa, Y. M., Zhao, L., Raines, K., Seo, P., & Wu, F. (2020). Using a physiologically based pharmacokinetic absorption model to establish dissolution bioequivalence safe space for oseltamivir in adult and pediatric populations. The AAPS Journal, 22(5), Article 107. https://doi.org/10.1208/s12248-020-00493-6
- Bai, J. P. F., Liu, G., Zhao, M., Wang, J., Xiong, Y., Truong, T., Earp, J. C., Yang, Y., Liu, J., Zhu, H., & Burckart, G. J. (2024). Landscape of regulatory quantitative systems pharmacology submissions to the U.S. Food and Drug Administration: An update report. CPT: Pharmacometrics & Systems Pharmacology.
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