Biomarkers in Drug Discovery and Development

RAMIN RAHBARI, MS, MBA, is an expert in biomarkers at Innovative Scientific Management and has previously held similar consulting and research positions at IBM, Cognizant and Pfizer. JONATHAN VAN NIEWAAL, MBA, is Technology Principal at Innovative Scientific Management and has held software development and technology delivery roles in the healthcare, financial services, and technology industries. MICHAEL R. BLEAVINS, PHD, DABT, is the founder of White Crow Innovation, LLC, a Michigan-based drug development consulting company, and cofounder of Michigan Technology and Research Institute.

List of Contributors vii Preface xiii Part I Biomarkers and Their Role in Drug Development 1 1 Biomarkers are Not New 3 Ian Dews 2 Biomarkers: Facing the Challenges at the Crossroads of Research and Health Care 15 Gregory J. Downing 3 Enabling Go/No Go Decisions 31 J. Fred Pritchard and M. Lynn Pritchard 4 Developing a Clinical Biomarker Method with External Resources: A Case Study 43 Ross A. Fredenburg Part II Identifying New Biomarkers: Technology Approaches 51 5 Imaging as a Localized Biomarker: Opportunities and Challenges 53 Jonathan B. Moody, Philip S. Murphy, and Edward P. Ficaro 6 Imaging for Early Clinical Drug Development: Integrating Imaging Science with Drug Research 89 Philip S. Murphy, Mats Bergstrom, Jonathan B. Moody, and Edward P. Ficaro 7 Circulating MicroRNAs as Biomarkers in Cardiovascular and Pulmonary Vascular Disease: Promises and Challenges 113 Miranda K. Culley and Stephen Y. Chan Part III Characterization, Validation, and Utilization 139 8 Characterization and Validation of Biomarkers in Drug Development: Regulatory Perspective 141 Federico Goodsaid 9 Fit-for-Purpose Method Validation and Assays for Biomarker Characterization to Support Drug Development 149 Jean W. Lee, Yuling Wu, and Jin Wang 10 Applying Statistics Appropriately for Your Biomarker Application 177 Mary Zacour Part IV Biomarkers in Discovery and Preclinical Safety 219 11 Qualification of Safety Biomarkers for Application to Early Drug Development 221 William B. Mattes and Frank D. Sistare 12 A Pathologists View of Drug and Biomarker Development 233 Robert W. Dunstan 13 Development of Serum Calcium and Phosphorus as Safety Biomarkers for Drug-Induced Systemic Mineralization: Case Study with the MEK Inhibitor PD0325901 255 Alan P. Brown 14 New Markers of Kidney Injury 281 Sven A. Beushausen Part V Translating from Preclinical to Clinical and Back 307 15 Biomarkers from Bench to Bedside and Back Back-Translation of Clinical Studies to Preclinical Models 309 Damian O'Connell, David Adler, Frank Kramer, and Matthias Ocker 16 Translational Medicine A Paradigm Shift in Modern Drug Discovery and Development: The Role of Biomarkers 333 Giora Z. Feuerstein, Salvatore Alesci, Frank L.Walsh, J. Lynn Rutkowski, and Robert R. Ruffolo Jr. 17 Clinical Validation and Biomarker Translation 347 Ji-Young V. Kim, Raymond T. Ng, Robert Balshaw, Paul Keown, Robert McMaster, Bruce McManus, Karen Lam, and Scott J. Tebbutt 18 Predicting and Assessing an Inflammatory Disease and Its Complications: Example from Rheumatoid Arthritis 365 Christina Trollmo and Lars Klareskog 19 Validating In Vitro Toxicity Biomarkers Against Clinical Endpoints 379 Calvert Louden and Ruth A. Roberts Part VI Biomarkers in Clinical Trials 389 20 Opportunities and Pitfalls Associated with Early Utilization of Biomarkers: A Case Study in Anticoagulant Development 391 Kay A. Criswell 21 Integrating Molecular Testing into Clinical Applications 409 Anthony A. Killeen Part VII Big Data, Data Mining, and Biomarkers 421 22 IT Supporting Biomarker-Enabled Drug Development 423 Michael Hehenberger 23 Identifying Biomarker Profiles Through the Epidemiologic Analysis of Big Health Care Data Implications for Clinical Management and Clinical Trial Design: A Case Study in Anemia of Chronic Kidney Disease 447 Gregory P. Fusco 24 Computational Biology Approaches to Support Biomarker Discovery and Development 469 Bin Li, Hyunjin Shin, William L. Trepicchio, and Andrew Dorner Part VIII Lessons Learned: Practical Aspects of Biomarker Implementation 485 25 Biomarkers in Pharmaceutical Development: The Essential Role of Project Management and Teamwork 487 Lena King, Mall Jurima-Romet, and Nita Ichhpurani 26 Novel and Traditional Nonclinical Biomarker Utilization in the Estimation of Pharmaceutical Therapeutic Indices 505 Bruce D. Car, Brian Gemzik, and William R. Foster Part IX Where are We Heading and What Do We Re