Nonclinical Development of Novel Biologics, Biosimilars, Vaccines and Specialty Biologics

Dedication

Preface

Contributors

Acknowledgments

Section I: Development of Biopharmaceuticals Defined as Novel Biologics

Chapter 1. Overview of Biopharmaceuticals and Comparison with Small-molecule Drug Development

Introduction

History and Evolution of Biopharmaceuticals

Development of Diverse Biopharmaceutical Modalities

Comparison of Small-Molecule Drugs to Biopharmaceuticals

Summary

References

Chapter 2. Regulatory Guidelines and their Application in the Nonclinical Evaluation of Biological Medicines

Introduction

Species Selection

Study Design Considerations for Repeat-Dose Studies

Immunogenicity

Reproductive and Developmental Toxicity

Genotoxicity and Carcinogenicity

Special Considerations for Anticancer Drugs

First-in-Human (Fih) Clinical Trial

Summary

References

Chapter 3. Early De-risking Strategy for Novel Biotherapeutics

Introduction

Establishing A Safety Profile for Biotherapeutics

General Safety Considerations Related to Biotherapeutics

Progress in Evaluation of Immunotoxicity

Can We Better Address Potential Off-Target Toxicity?

Summary

References

Chapter 4. Novel Biopharmaceuticals: Pharmacokinetics, Pharmacodynamics, and Bioanalytics

Introduction

Absorption, Distribution and Elimination of Biopharmaceuticals

Disposition of Modified Molecules

“Metabolism” and Biodistribution for Biopharmaceuticals

Immunogenicity and impacts on PK and biodistribution

Pharmacokinetics and Pharmacodynamics

Preclinical to Clinical Translation

Bioanalytics

Drug Assays

Biomarkers: Target Engagement Assays

Immunogenicity Assessment: ADA Assays

Summary

References

Section II: Development of Biosimilars

Chapter 5. Overview of Biosimilar Therapeutics

Introduction

The Concept of Biosimilars

General Considerations for Development of Biosimilars

Biosimilar Candidates Based on Modality and Therapeutic Class

Summary

References

Chapter 6. Regulatory Standards for the Approval of Biosimilar Products: A Global Review

Introduction

European Union—Pioneer for the First Regulatory Pathway for Biosimilar Products

The World Health Organization Guidance on Biosimilars

Regulatory Pathway for Biosimilar Products in the United States

Biosimilar Pathways in Other Regions

Summary

References

Chapter 7. Early Characterization of Biosimilar Therapeutics

Introduction

Recombinant Insulins

Recombinant Human Growth Hormone

Recombinant Erythropoietins

Recombinant Granulocyte Colony-Stimulating Factor

Recombinant Interferons

Low Molecular Weight Heparins

Monoclonal Antibodies

Other Classes

Summary

References

Section III: Vaccines

Chapter 8. Introduction to Vaccines and Adjuvants

Introduction

The History of Vaccines

The Impact of Vaccines on Human Health

Advancements in Vaccines Technologies

Advancements in Adjuvant Technologies

Approved Infectious Disease Vaccines and Diseases for Which Preventive Vaccines are Still Needed

Therapeutic Vaccines

Product Complexity From A Quality Perspective

Nonclinical Testing

Clinical Testing

Vaccine Development Using the Animal Rule

The Anti-Vaccines Movement and Misperceptions About Vaccines and Their Safety

Summary

References

Chapter 9. Global Regulatory Guidelines for Vaccines

Introduction

Toxicity Assessment

Additional Toxicity Assessments

Special Considerations

Formulation/Delivery Devices

Alternate Routes of Administration

Special Considerations for Particular Types of Vaccines

Summary

References

Chapter 10. Special Considerations for the Nonclinical Safety Assessment of Vaccines

Introduction

De-risking Strategies for Vaccines

Pharmacokinetics and Pharmacodynamics Assessments

Differences in the Nonclinical Safety Assessment of Vaccines and Biopharmaceutical Drugs

Summary

References

Section IV: Specialty Biologics and Indications

Chapter 11. Turning the Corner with Viral-based Gene Therapy—Development of the Rogue Biopharmaceutical

Introduction

A History and Primer of Gene Therapy

The Process of Getting Genes into Cells

Health Authority Regulation of Gene Therapy Products

Nonclinical Safety Studies and Regulatory Guidance

Summary

References

Chapter 12. Blood Products

Introduction

Plasma-Derived Blood Products

Blood Products Derived from Recombinant Technologies

Summary

References

Chapter 13. Biological Therapies for Cancer

Introduction

Global Regulatory Guidances

General Principles of Toxicology Assessments

Nonclinical Studies and Principles of Study Design

Specialty Toxicology Assessments

Pharmacokinetics, Immunogenicity, and Pharmacodynamics

Nonclinical Development of Marketed Biologics

Recombinant Analogs of Endogeneous Human Proteins (Interferons, Cytokines, Enzymes)

Summary

References

Chapter 14. Nonclinical Development of Multi-targeting Biopharmaceuticals

Introduction

Scientific Rationale for Multi-Targeting Biopharmaceuticals (MTBs)

Evolution of Technology Platforms

General Challenges and Considerations

Summary of Challenges

T Cell–Dependent Bispecific Antibody (TDB) Biotherapeutics

Dual-Targeting Antibodies

Summary

References

Chapter 15. Considerations in the Development of Pluripotent Stem Cell-based Therapies

Introduction

Early Decisions

NONclinical Development

Translating Preclinical Data to Clinical Application

Global Regulatory Guidance

Summary

References

Color Plates

Index