The safety, efficacy and regulatory triangle in drug development: Impact for animal models and the use of animals

Peter J.K. Van Meer, Melanie L. Graham, Henk Jan Schuurman

Research output: Contribution to journalReview articlepeer-review

30 Scopus citations

Abstract

Abstract Nonclinical studies in animals are conducted to demonstrate proof-of-concept, mechanism of action and safety of new drugs. For a large part, in particular safety assessment, studies are done in compliance with international regulatory guidance. However, animal models supporting the initiation of clinical trials have their limitations, related to uncertainty regarding the predictive value for a clinical condition. The 3Rs principles (refinement, reduction and replacement) are better applied nowadays, with a more comprehensive application with respect to the original definition. This regards also regulatory guidance, so that opportunities exist to revise or reduce regulatory guidance with the perspective that the optimal balance between scientifically relevant data and animal wellbeing or a reduction in animal use can be achieved. In this manuscript we review the connections in the triangle between nonclinical efficacy/safety studies and regulatory aspects, with focus on in vivo testing of drugs. These connections differ for different drugs (chemistry-based low molecular weight compounds, recombinant proteins, cell therapy or gene therapy products). Regarding animal models and their translational value we focus on regulatory aspects and indications where scientific outcomes warrant changes, reduction or replacement, like for, e.g., biosimilar evaluation and safety testing of monoclonal antibodies. On the other hand, we present applications where translational value has been clearly demonstrated, e.g., immunosuppressives in transplantation. Especially for drugs of more recent date like recombinant proteins, cell therapy products and gene therapy products, a regulatory approach that allows the possibility to conduct combined efficacy/safety testing in validated animal models should strengthen scientific outcomes and improve translational value, while reducing the numbers of animals necessary.

Original languageEnglish (US)
Article number69841
Pages (from-to)3-13
Number of pages11
JournalEuropean Journal of Pharmacology
Volume759
DOIs
StatePublished - Jul 15 2015

Bibliographical note

Publisher Copyright:
© 2015 Elsevier B.V.

Keywords

  • Animal models
  • Drug development
  • Nonhuman primates
  • Recombinant proteins
  • Rodents
  • Translational value

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