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Application of new approach methodologies for nonclinical safety assessment of drug candidates

Nature Reviews Drug Discovery volume 24, pages 705–725 (2025)Cite this article

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Abstract

The development of new approach methodologies (NAMs) and advances with in vitro testing systems have prompted revisions in regulatory guidelines and inspired dedicated in vitro/ex vivo studies for nonclinical safety assessment. This Review by a safety reflection initiative subgroup of the European Federation of Pharmaceutical Industries and Associations (EFPIA)/Preclinical Development Expert Group (PDEG) summarizes the current state and potential application of in vitro studies using human-derived material for safety assessment in drug development. It focuses on case studies from recent projects in which animal models alone proved to be limited or inadequate for safety testing. It further highlights four categories of drug candidates for which alternative in vitro approaches are applicable and discusses progress in using in vitro testing solutions for safety assessment in these categories. Finally, the article highlights new risk assessment strategies, initiatives and consortia promoting the advancement of NAMs. This collective work is meant to encourage the use of NAMs for more human-relevant safety assessment, which should ultimately result in reduced animal testing for drug development.

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Fig. 1: Categories of drug candidates for safety assessment based on their pharmacological target.
Fig. 2: Example from category 1: animal species lack the target.
Fig. 3: Example from category 2: cross-species target issues.
Fig. 4: Example from category 3: non-mammalian targets.

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Acknowledgements

The authors thank the European Federation of Pharmaceutical Industries and Associations (EFPIA)/Preclinical Development Expert Group (PDEG), especially P. Brinck, B. Haenen and E. Vock for initiating the establishment of this safety reflection working group.

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Authors and Affiliations

  1. Global Nonclinical Safety & DMPK, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany

    Mario Beilmann

  2. Sanofi US, Cambridge, MA, USA

    Karissa Adkins

  3. Non-Clinical Safety Research, H. Lundbeck A/S, Valby, Denmark

    Harrie C. M. Boonen

  4. Chemical and Preclinical Safety, Merck Healthcare KGaA, Darmstadt, Germany

    Philip Hewitt

  5. Vividion Therapeutics, San Diego, CA, USA

    Wenyue Hu

  6. Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland

    Robert Mader & Remi Villenave

  7. Nonclinical Safety Projects, GSK, Stevenage, UK

    Susanne Moore

  8. Drug Safety R&D, Pfizer Inc., Groton, CT, USA

    Payal Rana

  9. Research & Development, Pharmaceuticals, Preclinical Development, Bayer AG, Berlin, Germany

    Thomas Steger-Hartmann

  10. Preclinical Safety, AbbVie, Chicago, IL, USA

    Terry van Vleet

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Correspondence to Mario Beilmann.

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Competing interests

M.B., K.A., H.C.M.B., P.H., W.H., R.M., S.M., P.R., T.S.-H., R.V., T.v.V. are employees of pharmaceutical companies. R.V. holds equity in Emulate. The authors declare no further competing interests.

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Nature Reviews Drug Discovery thanks Anna-Karin Sjögren, Szczepan Baran and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

3RsC: https://3rc.org/

ASPIS cluster: https://aspis-cluster.eu/

Biotechnology Innovation Organization: https://www.bio.org/

CleanCut: https://nc3rs.org.uk/crackit/cleancut

CrossDART: https://nc3rs.org.uk/crackit/crossdart

FDA news release in April 2025: https://www.fda.gov/news-events/press-announcements/fda-announces-plan-phase-out-animal-testing-requirement-monoclonal-antibodies-and-other-drugs

In vitro TDAR: https://nc3rs.org.uk/crackit/vitro-tdar

IQ Consortium: https://iqconsortium.org/

IQ MPS Afffiliate: https://www.iqmps.org/

NC3Rs: https://nc3rs.org.uk/

ONTOX: https://ontox-project.eu/

PrecisionTox: https://precisiontox.org/

Retinal 3D: https://nc3rs.org.uk/crackit/retinal-3d

Risk-Hunt3R: https://www.risk-hunt3r.eu/

SensOoChip: https://nc3rs.org.uk/crackit/sensoochip

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Beilmann, M., Adkins, K., Boonen, H.C.M. et al. Application of new approach methodologies for nonclinical safety assessment of drug candidates. Nat Rev Drug Discov 24, 705–725 (2025). https://doi.org/10.1038/s41573-025-01182-9

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