Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

Towards in vitro models for reducing or replacing the use of animals in drug testing

Pharmaceutical companies continue to advocate for the use of in vitro models towards the reduction of animal use in drug discovery and development while acknowledging that further advancements are needed to heighten the models’ current state of readiness.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Types of in vitro NAM.

References

  1. Avila, A. M. et al. Regul. Toxicol. Pharmacol. 139, 105345 (2023).

    Article  CAS  PubMed  Google Scholar 

  2. ICH Guideline M3(R2) on Non-clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorisation for Pharmaceuticals: Step 5 (European Medicines Agency, 2013).

  3. Strategic Plan to Promote the Development and Implementation of Alternative Test Methods Within the TSCA Program (US Environmental Protection Agency, 2018).

  4. A Strategic Roadmap for Establishing New Approaches to Evaluate the Safety of Chemicals and Medical Products in the United States (ICCVAM, 2018).

  5. Avila, A. M. et al. Regul. Toxicol. Pharmacol. 114, 104662 (2020).

    Article  CAS  PubMed  Google Scholar 

  6. OECD Test Guidelines for Chemicals (OECD, accessed 24 October 2023); https://go.nature.com/3T4GMeV

  7. ICH Guideline M7(R2) on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk: Step 5 (European Medicines Agency, 2023).

  8. Butler, L. D. et al. Regul. Toxicol. Pharmacol. 87 (Suppl. 3), S1–S15 (2017).

  9. Valentin, J. P. & Leishman, D. Regul. Toxicol. Pharmacol. 139, 105368 (2023).

    Article  CAS  PubMed  Google Scholar 

  10. Schmeisser, S. et al. Environ. Int. 178, 108082 (2023).

    Article  CAS  PubMed  Google Scholar 

  11. Parish, S. T. et al. Regul. Toxicol. Pharmacol. 112, 104592 (2020).

    Article  PubMed  Google Scholar 

  12. Fabre, K. et al. Lab Chip 20, 1049–1057 (2020).

    Article  PubMed  Google Scholar 

  13. Vogt, N. Nat. Methods 18, 27 (2021).

    Article  CAS  PubMed  Google Scholar 

  14. Ingber, D. E. Nat. Rev. Genet. 23, 467–491 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Low, L. A., Mummery, C., Berridge, B. R., Austin, C. P. & Tagle, D. A. Nat. Rev. Drug Discov. 20, 345–361 (2021).

    Article  CAS  PubMed  Google Scholar 

  16. Rumsey, J. W. et al. Adv. Ther. 5, 2200030 (2022).

    Article  CAS  Google Scholar 

  17. Clapp, N., Amour, A., Rowan, W. C. & Candarlioglu, P. L. Biochem. Soc. Trans. 49, 1881–1890 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Baran, S. W. et al. ALTEX 39, 297–314 (2022).

    PubMed  Google Scholar 

  19. Kopec, A. K. et al. J. Toxicol. Sci. 46, 99–114 (2021).

    Article  CAS  PubMed  Google Scholar 

  20. Cairns, J. et al. Front. Pharmacol. https://doi.org/10.3389/fphar.2023.1142581 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Marx, U. et al. ALTEX 37, 365–394 (2020).

    PubMed  PubMed Central  Google Scholar 

  22. Vulto, P. & Joore, J. Nat. Rev. Drug Discov. 20, 961–962 (2021).

    Article  CAS  PubMed  Google Scholar 

  23. Ewart, L. et al. Commun. Med. 2, 154 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Proctor, W. R. et al. Arch. Toxicol. 91, 2849–2863 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schaller, T. H. et al. J. Immunother. Cancer 8, e000213 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ji, Y. et al. Clin. Transl. Sci. 15, 2218–2229 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dudal, S. et al. J. Immunother. 39, 279–289 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Muller, P. Y., Milton, M., Lloyd, P., Sims, J. & Brennan, F. R. Curr. Opin. Biotechnol. 20, 722–729 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Van Vleet, T. R., Liguori, M. J., Lynch, J. J. III, Rao, M. & Warder, S. SLAS Discov. 24, 1–24 (2019).

    Article  PubMed  Google Scholar 

  30. Obach, R. S. Curr. Top. Med. Chem. 11, 334–339 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Wang, J. & Urban, L. Drug Discov. World 73–86 (2004).

  32. OTP INTERACT Meeting (FDA, 14 June 2023); https://go.nature.com/47S08bq

  33. PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2023 Through 2027 (FDA, 2022); https://go.nature.com/413kiwP

  34. Innovative Science and Technology Approaches for New Drugs (ISTAND) Pilot Program (FDA, 6 April 2023); https://go.nature.com/418CsNq

  35. Horner, S. et al. Regul. Toxicol. Pharmacol. 65, 334–343 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Phillips, J. A. et al. Lab Chip 20, 468–476 (2020).

    Article  CAS  PubMed  Google Scholar 

  37. Novak, R. et al. Nat. Biomed. Eng. 4, 407–420 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Oleaga, C. et al. Sci. Rep. 6, 20030 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Edington, C. D. et al. Sci. Rep. 8, 4530 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Ronaldson-Bouchard, K. et al. Nat. Biomed. Eng. 6, 351–371 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Homan, K. A. Adv. Biol. 7, e2200334 (2023).

    Article  Google Scholar 

  42. Ainslie, G. R. et al. Lab Chip 19, 3152–3161 (2019).

    Article  CAS  PubMed  Google Scholar 

  43. Baudy, A. R. et al. Lab Chip 20, 215–225 (2020).

    Article  CAS  PubMed  Google Scholar 

  44. Fowler, S. et al. Lab Chip 20, 446–467 (2020).

    Article  CAS  PubMed  Google Scholar 

  45. Hardwick, R. N. et al. Lab Chip 20, 199–214 (2020).

    Article  CAS  PubMed  Google Scholar 

  46. Irrechukwu, O. et al. ALTEX 40, 485–518 (2023).

    PubMed  Google Scholar 

  47. Peters, M. F. et al. Lab Chip 20, 1177–1190 (2020).

    Article  CAS  PubMed  Google Scholar 

  48. Peterson, N. C., Mahalingaiah, P. K., Fullerton, A. & Di Piazza, M. Lab Chip 20, 697–708 (2020).

    Article  CAS  PubMed  Google Scholar 

  49. Pointon, A. et al. Lab Chip 21, 458–472 (2021).

    Article  CAS  PubMed  Google Scholar 

  50. Ramsden, D. et al. ALTEX 39, 273–296 (2022).

    PubMed  Google Scholar 

  51. Wang, X. et al. ALTEX 40, 314–336 (2022).

    PubMed  Google Scholar 

  52. Bloomingdale, P. et al. Curr. Opin. Toxicol. 4, 79–87 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Rusyn, I. et al. Toxicol. Sci. 188, 143–152 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Graham, J. C. et al. Cutan. Ocul. Toxicol. 37, 380–390 (2018).

    Article  CAS  PubMed  Google Scholar 

  55. Linsenmeier, R. A. & Saterbak, A. Ann. Biomed. Eng 48, 1590–1615 (2020).

    Article  PubMed  Google Scholar 

  56. Ewart, L. et al. Exp. Biol. Med. 242, 1579–1585 (2017).

    Article  CAS  Google Scholar 

  57. Gaskin, S. P., Griffin, A., Hauser, J. R., Katz, G. M. & Klein, R. L. in Wiley International Encyclopedia of Marketing (eds Sheth, J. N. & Malhotra, N. K.) 1–6 (John Wiley & Sons, 2010); https://doi.org/10.1002/9781444316568.wiem05020

  58. Tomlinson, L. et al. Adv. Biol. https://doi.org/10.1002/adbi.202300131 (2023).

    Article  Google Scholar 

  59. Ewart, L. & Roth, A. Nat. Rev. Drug Discov. 20, 327–328 (2021).

    Article  CAS  PubMed  Google Scholar 

  60. Hartung, T. et al. ALTEX 36, 3–17 (2019).

    Article  PubMed  Google Scholar 

  61. Salian-Mehta, S. et al. Toxicol. Res. Appl. https://doi.org/10.1177/2397847321999760 (2021).

    Article  Google Scholar 

  62. Medina, L. V., Coenen, J. & Kastello, M. D. J. Am. Assoc. Lab Anim. Sci. 54, 115–118 (2015).

    PubMed  PubMed Central  Google Scholar 

  63. Mangipudy, R., Burkhardt, J. & Kadambi, V. J. Regul. Toxicol. Pharmacol. 70, 439–441 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. Monticello, T. M. et al. Toxicol. Appl. Pharmacol. 334, 100–109 (2017).

    Article  CAS  PubMed  Google Scholar 

  65. Graham, J. C. et al. Regul. Toxicol. Pharmacol. 126, 105023 (2021).

    Article  PubMed  Google Scholar 

  66. Mitra, M. S. et al. Regul. Toxicol. Pharmacol. 122, 104895 (2021).

    Article  PubMed  Google Scholar 

  67. Lombardo, F. et al. J. Med. Chem. 60, 9097–9113 (2017).

    Article  CAS  PubMed  Google Scholar 

  68. Einholf, H. J. et al. Enabling the Virtual Human Through Physiologically-based Pharmacokinetic Modeling Pharmaceutical Technology Regulatory Sourcebook eBook 24–27 (pharmtech.com, 2021).

  69. Riedmaier, A. E. et al. AAPS J. 22, 123 (2020).

    Article  CAS  PubMed  Google Scholar 

  70. Jones, H. M. et al. Clin. Pharmacokinet. 50, 331–347 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. Price, E. et al. J. Med. Chem. 64, 9389–9403 (2021).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This Comment was developed with the support of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org). IQ is a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators and the broader research and development community. Within IQ, we recognize J. Brady, R. Abrahamson, R. Evers (Janssen) and T. Chan (Boehringer-Ingelheim) for their careful review of this manuscript.

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed to the writing of the manuscript. K.A.H., D.M.S. and A.K.K. organized the manuscript, and facilitated inclusive discussions among all authors.

Corresponding authors

Correspondence to David M. Stresser or Kimberly A. Homan.

Ethics declarations

Competing interests

All authors are employed by pharmaceutical companies, as per their affiliations. R.V holds equity in Emulate Inc.

Peer review

Peer review information

Nature Biomedical Engineering thanks Adrian Roth, Danilo Tagle and Y. Shrike Zhang for their contribution to the peer review of this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stresser, D.M., Kopec, A.K., Hewitt, P. et al. Towards in vitro models for reducing or replacing the use of animals in drug testing. Nat. Biomed. Eng (2023). https://doi.org/10.1038/s41551-023-01154-7

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/s41551-023-01154-7

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research