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 Pathologist's 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 PD[...]
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 [...], 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, Mallé 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 Really Need? 515

27 Ethics of Biomarkers: The Borders of Investigative Research, Informed Consent, and Patient Protection 517
Sara Assadian, Michael Burgess, Breanne Crouch, Karen Lam, and Bruce McManus

28 Anti-Unicorn Principle: Appropriate Biomarkers Don't Need to Be Rare or Hard to Find 537
Michael R. Bleavins and Ramin Rahbari

29 Translational Biomarker Imaging: Applications, Trends, and Successes Today and Tomorrow 553
Patrick McConville and Deanne Lister

Index 585