Preclinical Safety Evaluation of Biopharmaceuticals: A Science-Based Approach to Facilitating Clinical Trials

ACKNOWLEDGMENTS.

CONTRIBUTORS.

PART I: BACKGROUND.

1. Biopharmaceuticals: Defi nition and Regulation (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 (Patricia D. Williams, PhD (Summit Drug Development Services)).

PART II: PRINCIPLES OF PRECLINICAL DEVELOPMENT.

3. The Principles of ICH S6 and the Case-by-Case Approach (Joy A. Cavagnaro, PhD, DABT, RAC (Access BIO)).

4. Implementation of ICH S6: EU Perspective (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 (Takahiro Nakazawa, PhD (Eli Lilly Japan)).

6. Implementation of ICH S6: US Perspective (Mary Ellen Cosenza, PhD, MS, DABT, RAC (Amgen)).

PART III: CURRENT PRACTICES IN PRECLINICAL DEVELOPMENT.

7. Comparison of Preclinical Development Programs for Small Molecules (Drugs/Pharmaceuticals) and Large Molecules (Biologics/Biopharmaceuticals): Studies, Timing, Materials, and Costs (Christopher Horvath, DVM, MS, DACVP (Archemix Corp.)).

8. Demonstration of Comparability of a Licensed Product after a Manufacturing Change (Richard M. Lewis, PhD (Access BIO)).

PART IV: SELECTION OF RELEVANT SPECIES.

9. Selection of Relevant Species (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 (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 (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 (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 (Johan te Koppele, PhD (TNO Quality of Life) and Renger Witkamp, PhD (Wageningen University, The Netherlands)).

PART V: SAFETY/TOXICITY ENDPOINTS.

14. Safety Pharmacology: Similarities and Differences between Small Molecules and Novel Biopharmaceuticals (Edward W. Bernton, MD (Pathway Pharmacology)).

15. Genetic Toxicity Testing of Biopharmaceuticals (David Jacobson-Kram, PhD, DABT, and Hanan Ghantous, PhD, DABT (FDA)).

16. General Toxicity Testing and Immunotoxicity Testing for Biopharmaceuticals (Jeanine L. Bussiere, PhD, DABT (Amgen)).

17. Reproductive Toxicity Testing for Biopharmaceuticals (Pauline L. Martin, PhD (Centocor Research and Development Inc.)).

18. Reproductive/Developmental Toxicity Assessment of Biopharmaceuticals in Nonhuman Primates (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 (Joy A. Cavagnaro, PhD, DABT, RAC (Access BIO)).

20. Immunogenicity of Therapeutic Proteins and the Assessment of Risk (Huub Schellekens, MD, PhD (Utrecht University), and Wim Jiskoot, PhD (Leiden University)).

21. Assessment of Autoimmunity and Hypersensitivity (Jacques Descotes, MD, PharmD, PhD, and Thierry Vial, MD (Poison Centere and Pharmacovigilance Unit, Lyon, France)).

PART VI: SPECIFIC CONSIDERATIONS BASED ON PRODUCT CLASS.

22. Current Practices in the Preclinical Safety Assessment of Peptides (Shawn M. Heidel, DVM, PhD, and Todd J. Page, PhD (Eli Lilly)).

23. Enzyme Replacement Therapies (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 (Arthur A. Levin, PhD, DABT (Biotech & Pharmaceutical Consulting), and Scott P. Henry, PhD, DABT (Isis)).

25. Preclinical Saxfety Evaluation of Biological Oncology Drugs (Theresa Reynolds, BA, DABT (Genentech)).

26. Preclinical Safety Evaluation of Monoclonal Antibodies (George Treacy, MS, and Pauline Martin, PhD (Centocor Research and Development)).

27. Immunomodulatory Biopharmaceuticals and Risk of Neoplasia (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 (Stanley A. Roberts, PhD, DABT, Gary Woodnutt, PhD, and Curt W. Bradshaw, PhD (CovX Research, LLC)).

29. Preclinical Safety Evaluation of Immunotoxins (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 (Richard M. Lewis, PhD (Access BIO)).

31. Preclinical Safety Evaluation of Viral Vaccines (A. Marguerite Dempster, PhD, DABT, and Richard Haworth, FRCPath, DPhil (GlaxoSmithKline)).

32. Preclinical Safety Evaluation of Biopharmaceuticals (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 (Joy A. Cavagnaro, PhD, DABT, RAC (Access BIO)).

34. Preclinical Safety Evaluation of Biopharmaceuticals: Combination Products (Biologic/Device) (Bruce Babbitt, PhD, and Barry Sall (Parexel Consulting)).

35. Tissue Engineered Products: Preclinical Development of Neo-Organs (Timothy A. Bertram, DVM, PhD, and Manuel Jayo, DVM, PhD (Tengion)).

PART VII: PRECLINICAL STUDY DESIGN, IMPLEMENTATION, AND ANALYSIS.

36. GLP Requirements and Current Practices (Tanya Scharton-Kersten (Novartis)).

37. Preclinical Safety Study Design Templates and Estimated Costs (Gary W. Wolfe, PhD, DABT (Summit Drug Development Services)).

38. Practical Considerations in the Design of Preclinical Safety Assessments for Biopharmaceuticals (Damon R. Demady, PhD (Knopp Neurosciences)).

39. Survey of Preclinical Toxicology Programs for Approved Biopharmaceuticals (Anita Marie O’Connor, PhD (Anita O’Connor Consulting, LLC)).

PART VIII: TRANSITIONING FROM PRECLINICAL DEVELOPMENT TO CLINICAL TRIALS.

40. Science and Judgment in Establishing a Safe Starting Dose for First-in-Human Trials of Biopharmaceuticals (Jennifer Visich, PhD (Genentech), and Rafael Ponce, PhD, DABT (Zymogenetics)).

PART IX: AFTERWORD.

A Retrospective (Anthony D. Dayan, LLB, MD, FRCP, FRCPath, FFOM, FFPM, FIBiol).

INDEX.