Ligand-binding assays : development, validation, and implementation in the drug development arena

Abstract

Preface. Contributors. 1 Ligand-Binding Assays in Drug Development: Introduction and Historical Perspective (John W.A. Findlay and Masood N. Khan). 1.1 General. 1.2 Historical Review. 1.3 LBAs for Macromolecules. 1.4 Advantages and Limitations of LBAs. 1.5 Ligand-Binding Assay Bioanalytical Focus Group of AAPS. 1.6 Scope of the Present Volume. References. 2 Ligand-Binding Assays to Support Disposition Studies of Macromolecular Therapeutics (Marian M. Kelley, Marjorie A. Mohler, and John W.A. Findlay). 2.1 Introduction. 2.2 Differences Between Low Molecular Weight Molecules and Macromolecules. 2.3 LBA Assay Considerations Relative to Research and Development Stage. 2.4 Critical Future Challenges for Ligand-Binding Assays. 2.5 Conclusions. References. 3 Development of Ligand-Binding Assays for Drug Development Support (Masood N. Khan, Proveen D. Dass, John H. Leete, Richard F. Schuman, Michele Gunsior, and Chanchal Sadhu). 3.1 Introduction. 3.2 Inherent Complexities of Immunoassay Development. 3.3 Steps in the Development of a Validatable Immunoassay. 3.4 Development and Optimization of an Immunoassay. 3.5 Optimization of Commercial Kit-Based Assays. 3.6 Troubleshooting Immunoassays. 3.7. Conclusions. Acknowledgments. References. 4 Validation of Ligand-Binding Assays to Support Pharmacokinetic Assessments of Biotherapeutics (Binodh S. DeSilva and Ronald R. Bowsher). 4.1 Introduction. 4.2 Assay Development and Validation Paradigm. 4.3 Prestudy Validation Phase. 4.4 Analytical Performance Characteristics. 4.5 In-Study Validation Phase. 4.6 Partial Validations/Method Transfer/Cross-Validation. 4.7 Documentation. 4.8 Conclusions. References. 5 Statistical Considerations in the Validation of Ligand-Binding Assays (Bruno Boulanger, Viswanath Devanarayan, and Walthere Dewe). 5.1 Introduction. 5.2 Objectives of Assay Validation. 5.3 Validation Criteria. 5.4 Estimating Assay Performance Characteristics. 5.5 Decision Rules and Risk Assessment in Prestudy Validation. 5.6 Decision Rules During In-Study Phase and Associated Risks. 5.7 Reconciling Validation and Routine Decision Rules. 5.8 Conclusions. References. 6 Development and Validation of Ligand-Binding Assays for Biomarkers (Jean W. Lee, Yang Pan, Peter J. O Brien, and Ren Xu). 6.1 Introduction. 6.2 Preanalytical Considerations and Method Feasibility. 6.3 Method Development and Method Qualification for Exploratory Applications. 6.4 Method Development and Method Validation for Advanced Applications. 6.5 Partial Validation for Change Control. 6.6 Documentation, Record Keeping, and Reporting. 6.7 Regulatory Issues. 6.8 In-study Validation. 6.9 Conclusions. Acknowledgments. References. 7 The Use of Commercial Assay Kits for PK/PD Analysis in Drug Development (John L. Allinson and John D. Chappell). 7.1 Introduction. 7.2 Validation Definitions That May be Interpreted Inconsistently. 7.3 Validation Experiments. 7.4 Stability. 7.5 Reoptimizing Reagent Concentrations. 7.6 The Use of Commercial Kits for PK and TK Assays. 7.7 Matrix Problems. 7.8 Changing Method Protocol. 7.9 Conclusions. References. 8 Development and Validation of Immunogenicity Assays for Preclinical and Clinical Studies (Thomas H. Parish, Deborah Finco, and Viswanath Devanarayan). 8.1 Introduction. 8.2 Immunogenicity Risk-Based Strategy. 8.3 Regulatory Guidance. 8.4 Assay Design. 8.5 Optimization and Validation: Total Binding Antibody Assays. 8.6 Optimization and Validation: Neutralizing Antibody Assays. 8.7 Assays and Risk Assessment. 8.8 Application and Interpretation of Data. 8.9 Conclusions. 8.10 Appendix 8.A Illustration of Screening Cut Point Evaluation. References. 9 Macromolecular Reference Standards for Biotherapeutic Pharmacokinetic Analysis (Marie T. Rock and Stephen Keller). 9.1 Introduction. 9.2 United States Pharmacopeia. 9.3 Characterization of Non-USP Reference Standards. 9.4 The PK Assay. 9.5 Conclusions. References. 10 Strategies for Successful Transfer of Ligand-Binding Assays for Successful Validation and