Regulatory Toxicology and Pharmacology 113 (2020) 104624 Contents lists available at ScienceDirect Regulatory Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/yrtph Opportunities for use of one species for longer-term toxicology testing during drug development: A cross-industry evaluation T ∗ Helen Priora, , Paul Baldrickb, Sonja Bekenc, Helen Boolerd, Nancy Bowere, Paul Brookerf, Paul Browng, Brian Burlinsonh, Leigh Ann Burns-Naasi, Warren Caseyj, Melissa Chapmank, David Clarkel, Lolke de Haanm, Olaf Doehrn, Noel Downeso, Meghan Flahertyp, Nichola Gellatlya, Sophia Gry Moesgaardq, Jennifer Harrisr, Mark Holbrooks, Julia Huit, David Jonesu, Keith Jonesv, Hilla Kedarw, Andreas Mahlx, Alli Mannineny, Aidan McGuirez, Elisabeth Mortimer-Cassenaa, Marjorie Perazaab, Michael K. Pugsleyac, Jacques Richardad, Ruth Robertsae, Wendy Roosenaf, Andreas Rothfussag, Ankie Schoenmakersah, Fiona Sewella, Richard Weaverai, Lucinda Weiraj, Alison Wolfreysak, Ian Kimberal a National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), Gibbs Building, 215 Euston Road, London, NW1 2BE, UK b Covance Laboratories Ltd, Otley Road, Harrogate, HG3 1PY, UK c Federal Agency for Medicines and Health Products (FAMHP), Victor Hortaplace 40/40, Brussels, 1060, Belgium d Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA e Eisai Inc, 155 Tice Blvd, Woodcliff Lake, NJ, 07677, USA f Board member, NC3Rs, Gibbs Building, 215 Euston Road, London, NW1 2BE, UK g Food and Drug Administration (FDA), 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA h Covance, Huntingdon, Cambridgeshire, PE28 4HS, UK i Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA, 94404, USA j National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC, 27709, USA k Oncology Safety, Clinical Pharmacology and Safety Sciences,R&D, AstraZeneca, Cambridge, UK l Lilly Research Laboratories, Indianapolis, IN, 46285, USA m Biologics and Advanced Therapeutics Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK n Bayer Pharma AG, Müllerstrasse 170, 13353, Berlin, Germany o Sequani Limited, Bromyard Rd, Ledbury, Herefordshire, HR8 1LH, UK p Takeda Pharmaceuticals, 300 Massachusetts Ave, Cambridge, MA, 02139, USA q Novo Nordisk A/S, Novo Nordisk Park, Maaloev, Denmark r Association of British Pharmaceutical Industry (ABPI), 105 Victoria Street, London, SW1E 6QT, UK s VAST Pharma Solutions Ltd, Harrogate, UK t Celgene, 86 Morris Avenue, Summit, NJ, 07901, USA u Medicines Healthcare products Regulatory Agency (MHRA) 10 South Colonnade, Canary Wharf, London, E14 4PU, UK v CFMD Ltd, Peterborough, UK w Teva Pharmaceuticals, Netanya Area, Israel x Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland y Prekliniska Byran Sweden AB, Stockholm, Sweden z Charles River Laboratories, Preclinical Services, Tranent, Edinburgh, EH33 2NE, UK aa Regulatory Safety Centre of Excellence, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK ab Pfizer Drug Safety Research and Development, 300 Technology Square, Cambridge, MA, 02139, USA ac Cytokinetics, South San Francisco, CA, 94080, USA ad Sanofi, 371 Rue du Professeur Blayac, Montpellier, 34000, France ae ApconiX, Alderley Park, Alderley Edge, Cheshire, SK10 4TG, UK af Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium ag Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, CH - 4070, Basel, Switzerland ah Charles River Laboratories, Den Bosch B.V, the Netherlands ai Institut de Recherches Internationales Servier, Biopharmacy, 92284, Suresnes, Cedex, France Abbreviations: ADC, Antibody-drug conjugate; ABPI, Association of the British Pharmaceutical Industry; CRO, contract research organisation; EU, European Union; FIH, first-in-human; GLP, Good Laboratory Practice; ICH, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; IND, Investigational New Drug; mAbs, monoclonal antibodies; NC3Rs, National Centre for the Replacement, Refinement and Reduction of Animals in Research; NHP, non-human primate ∗ Corresponding author. Gibbs Building, 215 Euston Rd, London, NW1 2BE, UK. E-mail address: [email protected] (H. Prior). https://doi.org/10.1016/j.yrtph.2020.104624 Available online 29 February 2020 0273-2300/ © 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/). H. Prior, et al. Regulatory Toxicology and Pharmacology 113 (2020) 104624 aj GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 0DP, UK ak UCB Biopharma, Bath Rd, Slough, SL1 3WE, UK al University of Manchester, Faculty of Biology, Medicine and Health, Oxford Rd, Manchester, M13 9PL, UK ARTICLE INFO ABSTRACT Keywords: An international expert working group representing 37 organisations (pharmaceutical/biotechnology compa- 3Rs nies, contract research organisations, academic institutions and regulatory bodies) collaborated in a data sharing Biologics exercise to evaluate the utility of two species within regulatory general toxicology studies. Anonymised data on Drug development 172 drug candidates (92 small molecules, 46 monoclonal antibodies, 15 recombinant proteins, 13 synthetic ICHS6(R1) peptides and 6 antibody-drug conjugates) were submitted by 18 organisations. The use of one or two species Nonclinical across molecule types, the frequency for reduction to a single species within the package of general toxicology Non-rodent fi Rodent studies, and a comparison of target organ toxicities identi ed in each species in both short and longer-term Small molecules studies were determined. Reduction to a single species for longer-term toxicity studies, as used for the devel- Species selection opment of biologicals (ICHS6(R1) guideline) was only applied for 8/133 drug candidates, but might have been Toxicology possible for more, regardless of drug modality, as similar target organ toxicity profiles were identified in the short-term studies. However, definition and harmonisation around the criteria for similarity of toxicity profiles is needed to enable wider consideration of these principles. Analysis of a more robust dataset would be required to provide clear, evidence-based recommendations for expansion of these principles to small molecules or other modalities where two species toxicity testing is currently recommended. 1. Introduction different approaches to safety assessment can enhance predictivity, as well as reduce animal use through efficiency improvements or The biopharmaceutical industry recognises the importance of an streamlined processes. This may include a requirement for fewer stu- ongoing review of the regulatory recommendations for the nonclinical dies, fewer animals per study or shortened timelines to reach decision- safety assessment of new investigative drugs. There is a responsibility to making milestones. Arguably, such reviews are conducted most effec- ensure human safety and that individual nonclinical studies and overall tively when pharmaceutical companies work together to share data and safety strategies reflect advances in the scientific field, such as em- experience, in concert with regulatory authorities, for example as ploying new technologies (e.g., in silico and in vitro approaches), and the contributors to working parties and industry consortia. Recently, con- growing application of mechanistic toxicology to understand molecular sortia have reviewed topics such as nonclinical to clinical data trans- pathways underlying toxic effects. This can also lead to opportunities to lation (Monticello et al., 2017), the effectiveness of nonclinical strate- replace, refine and reduce (the 3Rs) the use of laboratory animals when gies in support of safe clinical trials (Butler et al., 2017), in silico appropriate. Review of best practices and identification of new and/or prediction of toxicities (Briggs et al., 2015) and the most appropriate Table 1 Relevant extracts from ICH general guidance regarding the species required for general toxicology studies. ICHM3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals 5. Repeated dose toxicity studies. In principle, the duration of the animal toxicity studies conducted in two mammalian species (one non-rodent) should be equal to or exceed the duration of the human clinical trials up to the maximum recommended duration of the repeated-dose toxicity studies. Recommended Non-clinical Studies to Support Exploratory Clinical Trials. Approaches 1 and 2 describe requirements for a toxicity study in one species, usually rodent ICHS6(R1): Pre-clinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals 3.3 Animal Species/Model Selection. Safety evaluation programs should include the use of relevant species. A relevant species is one in which the test material is pharmacologically active due to the expression of the receptor or an epitope (in the case of monoclonal antibodies). Safety evaluation programs should normally include two relevant species. However, in certain justified cases one relevant species may suffice (e.g., when only one relevant species can be identified or where the biological activity of the biopharmaceutical is well understood). In addition, even where two species may be necessary to characterise toxicity