Preclinical Safety Evaluation of Biopharmaceuticals

"The goal is to provide a comprehensive reference book for the preclinicaldiscovery and development scientist whose responsibilities span target identification, lead candidate selection, pharmacokinetics, pharmacology, and toxicology, and for regulatory scientists whose responsibilities include the evaluation of novel therapies." —From the Afterword by Anthony D. Dayan Proper preclinical safety evaluation can improve the predictive value, lessen the time and cost of launching new biopharmaceuticals, and speed potentially lifesaving drugs to market. This guide covers topics ranging from lead candidate selection to establishing proof of concept and toxicity testing to the selection of the first human doses. With chapters contributed by experts in their specific areas, Preclinical Safety Evaluation of Biopharmaceuticals: A Science-Based Approach to Facilitating Clinical Trials: Includes an overview of biopharmaceuticals with information on regulation and methods of production Discusses the principles of ICH S6 and their implementation in the U.S., Europe, and Japan Covers current practices in preclinical development and includes a comparison of safety assessments for small molecules with those for biopharmaceuticals Addresses all aspects of the preclinical evaluation process, including: the selection of relevant species; safety/toxicity endpoints; specific considerations based upon class; and practical considerations in the design, implementation, and analysis of biopharmaceuticals Covers transitioning from preclinical development to clinical trials This is a hands-on, straightforward reference for professionals involved in preclinical drug development, including scientists, toxicologists, project managers, consultants, and regulatory personnel.

Foreword xi Joy A. Cavagnaro, PhD, DABT, RAC, and Anthony D. Dayan, LLB, MD, FRCP, FRCPath, FFOM, FFPM, FIBiol Acknowledgments xix Contributors xxi  Part I Background 1 1. Biopharmaceuticals: Definition and Regulation 3 Lincoln Tsang, PhD, FRSC, FIBiol, FRPharmS (Arnold and Porter, London, UK), and Nathan Cortez (Southern Methodist University) 2. Methods of Production of Biopharmaceutical Products and Assessment of Environmental Impact 21 Patricia D. Williams, PhD (Summit Drug Development Services) Part II Principles of Preclinical Development 43 3. The Principles of ICH S6 and the Case-by-Case Approach 45 Joy A. Cavagnaro, PhD, DABT, RAC (Access BIO) 4. Implementation of ICH S6: EU Perspective 67 Peter R. Ryle, PhD, DipRCPath (Tox), FRCPath (PR BioServices), and David J. Snodin, PhD, FRSC, MChemA, MSc (Parexel Consulting) 5. Implementation of ICH S6: Japanese Perspective 93 Takahiro Nakazawa, PhD (Eli Lilly Japan) 6. Implementation of ICH S6: US Perspective 111 Mary Ellen Cosenza, PhD, MS, DABT, RAC (Amgen) Part III Current Practices in Preclinical Development 123 7. Comparison of Preclinical Development Programs for Small Molecules (Drugs/Pharmaceuticals) and Large Molecules (Biologics/Biopharmaceuticals): Studies, Timing, Materials, and Costs 125 Christopher Horvath, DVM, MS, DACVP (Archemix Corp.) 8. Demonstration of Comparability of a Licensed Product after a Manufacturing Change 161 Richard M. Lewis, PhD (Access BIO) Part IV Selection of Relevant Species 179 9. Selection of Relevant Species 181 Meena Subramanyam, PhD, Nicola Rinaldi, PhD, Elisabeth Mertsching, PhD, and David Hutto, PhD, DVM (Biogen Idec) 10. Tissue Cross-Reactivity Studies for Monoclonal Antibodies: Predictive Value and Use for Selection of Relevant Animal Species for Toxicity Testing 207 William C. Hall, VMD, PhD, DACVP (Hall Consulting Inc.), Shari A. Price-Schiavi, PhD, DABT (Charles River Laboratories—PAI), Joan Wicks, DVM, PhD, DACVP (Charles River Laboratories—PAI), and Jennifer L. Rojko, DVM, PhD, DACVP (Charles River Laboratories—PAI) 11. Physiologic IgG Biodistribution, Transport, and Clearance: Implications for Monoclonal Antibody Products 241 Jennifer L. Rojko, DVM, PhD, DACVP, and Shari Price-Schiavi, PhD, DABT (Charles River Laboratories—PAI) 12. The Role of Pharmacokinetics and Pharmacodynamics in Selecting a Relevant Species 277 Martin D. Green, PhD (FDA), and Melanie Hartsough, PhD (Biologics Consulting Group, Inc.) 13. Use of Animal Models of Disease in the Preclinical Safety Evaluation of Biopharmaceuticals 293 Johan te Koppele, PhD (TNO Quality of Life) and Renger Witkamp, PhD (Wageningen University, The Netherlands) Part V Safety/toxicity Endpoints 309 14. Safety Pharmacology: Similarities and Differences between Small Molecules and Novel Biopharmaceuticals 311 Edward W. Bernton, MD (Pathway Pharmacology) 15. Genetic Toxicology Testing of Biopharmaceuticals 337 David Jacobson-Kram, PhD, DABT, and Hanan Ghantous, PhD, Dabt (fda) 16. General Toxicity Testing and Immunotoxicity Testing for Biopharmaceuticals 343 Jeanine L. Bussiere, PhD, DABT (Amgen) 17. Reproductive Toxicity Testing for Biopharmaceuticals 357 Pauline L. Martin, PhD (Centocor Research and Development Inc.) 18. Reproductive/Developmental Toxicity Assessment of Biopharmaceuticals in Nonhuman Primates 379 Gerhard F. Weinbauer, PhD, Werner Frings, PhD, Antje Fuchs, PhD, Michael Niehaus, PhD, and Ingrid Osterburg (Covance, Germany) 19. Preclinical Evaluation of Cancer Hazard and Risk of Biopharmaceuticals 399 Joy A. Cavagnaro, PhD, DABT, RAC (Access BIO) 20. Immunogenicity of Therapeutic Proteins and the Assessment of Risk 475 Huub Schellekens, MD, PhD (Utrecht University), and Wim Jiskoot, PhD (Leiden University) 21. Assessment of Autoimmunity and Hypersensitivity 487 Jacques Descotes, md, PharmD, PhD, and Thierry Vial, md (Poison Centere and Pharmacovigilance Unit, Lyon, France) Part VI Specific Considerations Based on Product Class 499 22. Current Practices in the Preclinical Safety Assessment of Peptides 501 Shawn M. Heidel, DVM, PhD, and Todd J. Page, PhD (Eli Lilly) 23. Enzyme Replacement Therapies 517 Laura Andrews, PhD, DABT (Genzyme), and Michael O’Callaghan, DVM, PhD, MRCVS (Genzyme) 24. Toxicology of Oligonucleotide Therapeutics and Understanding the Relevance of the Toxicities 537 Arthur A. Levin, PhD, DABT (Biotech & Pharmaceutical Consulting), and Scott P. Henry, PhD, DABT (Isis) 25. Preclinical Safety Evaluation of Biological Oncology Drugs 575 Theresa Reynolds, BA, DABT (Genentech) 26. Preclinical Safety Evaluation of Monoclonal Antibodies 587 George Treacy, MS, and Pauline Martin, PhD (Centocor Research and Development) 27. Immunomodulatory Biopharmaceuticals and Risk of Neoplasia 601 Peter J. Bugelski, PhD, FRCPath, Clifford Sachs, PhD, DABT, Joel Cornacoff, DVM, PhD, DABT, Pauline Martin, PhD, and George Treacy, MS (Centocor Research and Development) 28. Strategy Considerations for Developing the Preclinical Safety Testing Programs for Protein Scaffold Therapeutics 633 Stanley A. Roberts, PhD, DABT, Gary Woodnutt, PhD, and Curt W. Bradshaw, PhD (CovX Research, LLC) 29. Preclinical Safety Evaluation of Immunotoxins 649 Jennifer G. Brown, PhD, Joycelyn Entwistle, PhD, Nick Glover, PhD, and Glen C. MacDonald, PhD (Viventia Biotech, Inc) 30. Preclinical Safety Evaluation of Blood Products 669 Richard M. Lewis, PhD (Access BIO) 31. Preclinical Safety Evaluation of Viral Vaccines 683 A. Marguerite Dempster, PhD, DABT, and Richard Haworth, FRCPath, DPhil (GlaxoSmithKline) 32. Preclinical Safety Evaluation of Biopharmaceuticals 713 Mercedes A. Serabian, MS, DABT, and Ying Huang, PhD (FDA) 33. Considerations in Design of Preclinical Safety Evaluation Programs to Support Human Cell-Based Therapies 749 Joy A. Cavagnaro, PhD, DABT, RAC (Access BIO) 34. Preclinical Safety Evaluation of Biopharmaceuticals: Combination Products (Biologic/Device) 783 Bruce Babbitt, PhD, and Barry Sall (Parexel Consulting) 35. Tissue Engineered Products: Preclinical Development of Neo-Organs 799 Timothy A. Bertram, DVM, PhD, and Manuel Jayo, DVM, PhD (Tengion) Part VII Preclinical Study Design, Implementation, and Analysis 827 36. GLP Requirements and Current Practices 829 Tanya Scharton-Kersten (Novartis) 37. Preclinical Safety Study Design Templates and Estimated Costs 851 Gary W. Wolfe, PhD, DABT (Summit Drug Development Services) 38. Practical Considerations in the Design of Preclinical Safety Assessments for Biopharmaceuticals 913 Damon R. Demady, PhD (Knopp Neurosciences) 39. Survey of Preclinical Toxicology Programs for Approved Biopharmaceuticals 931 Anita Marie O’Connor, PhD (Anita O’Connor Consulting, LLC) Part VIII Transitioning From Preclinical Development to Clinical Trials 969 40. Science and Judgment in Establishing a Safe Starting Dose for First-in-Human Trials of Biopharmaceuticals 971 Jennifer Visich, PhD (Genentech), and Rafael Ponce, PhD, DABT (Zymogenetics) Part IX Afterword 985 A Retrospective 987 Anthony D. Dayan, LLB, MD, FRCP, FRCPath, FFOM, FFPM, FIBiol Index 999