Biomarkers in drug discovery and development: a handbook of practice, application, and strategy

Cover......Page 1
Title Page......Page 3
Copyright......Page 4
Contents......Page 5
List of Contributors......Page 9
Preface......Page 15
Part I Biomarkers and Their Role in Drug Development......Page 19
  Uroscopy......Page 21
  Blood Pressure......Page 23
  Imaging......Page 24
  Electrocardiography......Page 27
  Hematology......Page 28
  Blood and Urine Chemistry......Page 29
  Fashionable “Omics”......Page 31
  The Future......Page 32
  Introduction......Page 33
  Brief History of Biomarker Research, 1998–2008: The First Decade......Page 34
  Science and Technology Advances in Biomarker Research......Page 37
  Policies and Partnerships......Page 40
  Challenges and Setbacks......Page 42
  Looking Forward......Page 43
  References......Page 45
  Understanding Risk......Page 49
  Decision Gates......Page 50
  Role of Biomarkers in Decision‐Making......Page 54
  Efficacy Biomarkers......Page 56
  Biomarkers and Patient Selection......Page 57
  Future Roles of Biomarkers in Decision‐Making......Page 58
  References......Page 59
 Chapter 4 Developing a Clinical Biomarker Method with External Resources: A Case Study......Page 61
  References......Page 67
Part II Identifying New Biomarkers: Technology Approaches......Page 69
  Introduction......Page 71
  Anatomy of an Imaging Biomarker......Page 78
  Quantitative Imaging Biomarkers Alliance (QIBA)......Page 91
  References......Page 97
  Introduction......Page 107
  An Overview of Early Clinical Development......Page 108
  How Imaging Can Inform Early Development?......Page 109
    Tissue Drug Penetration......Page 110
    Positron Emission Tomography as a Method to Study Drug Exposure......Page 111
    Radiolabeling for PET Studies......Page 112
    Generic Labeling of Protein Pharmaceuticals......Page 114
    Preclinical Qualifications of a Labeled Drug......Page 115
    Target Expression......Page 116
    Target Interaction......Page 117
   Pillar 3 – Expression of Pharmacology......Page 118
    Further Examples of Pharmacodynamics Imaging......Page 119
    Preparing Imaging Methods for Application as Pharmacodynamic Endpoints......Page 120
  Guiding an Imaging Solution Toward Application......Page 122
  Conclusions and Future Directions......Page 124
  References......Page 125
  MicroRNA Biogenesis......Page 131
  Detection of Extracellular miRNAs......Page 132
   Sampling......Page 135
   RNA Extraction......Page 136
   RT‐qPCR......Page 137
   Microarray......Page 138
   RNA Sequencing......Page 139
  Utility of c‐miRNAs as Biomarkers in Cardiovascular Disease......Page 140
  Challenges of Using c‐miRNAs as Biomarkers......Page 146
  Conclusions and Future Perspectives......Page 148
  References......Page 149
Part III Characterization, Validation, and Utilization......Page 157
  Introduction......Page 159
  Regulatory Paths in Biomarker Evaluation and Qualification......Page 160
  Evidentiary Recommendations......Page 162
  Harmonization......Page 163
  References......Page 164
  Introduction......Page 167
  General Processes......Page 169
   Population Range and Assay Range......Page 171
   Sample Integrity: Sample Collection at the Clinic......Page 172
    What Will Be Measured?......Page 173
    Reference Standard and Alternative Matrix for Standard Preparation......Page 174
    Selection of Critical Reagents in Ligand‐Binding Assays......Page 175
    Critical Reagents Characterization, Consistency, Stability, and Documentation......Page 176
    Accuracy and Precision......Page 178
    Sensitivity......Page 179
    Specificity......Page 180
    Standard Operating Procedure......Page 182
    Acceptance Criteria......Page 183
    Controls in Clinical Studies......Page 184
    Confirming Selectivity in Patient Populations......Page 185
    Specificity and Sensitivity of Novel Biomarker on Drug Effect......Page 187
    Documentation......Page 188
  Conclusions and Perspectives......Page 189
  References......Page 191
  Introduction......Page 195
   Is That Significance Significant? (and Conversely, the Significant Insignificance)......Page 197
   Air the Error......Page 198
    Continuous Data Quantifications......Page 199
    Noncontinuous Data......Page 201
   What to Do?......Page 202
   Guilty by Association (and Other Misuses of Correlation Analysis)......Page 205
   Checking the Dessert Menu First......Page 206
   Taking Care of Business......Page 210
   The Odd Risk......Page 214
  Practi(sti)cal Magic: Which Witch is Which?......Page 215
    Independence......Page 216
    Normally Distributed Data......Page 217
    Equivalent Variances Between Groups......Page 218
   Simple Regression and Correlation Analysis......Page 219
   t‐Test vs. ANOVA......Page 220
   Paired vs. Unpaired......Page 221
   BLQ Data......Page 222
   Genetic Association Studies......Page 223
   Microarray or Other “Omics”‐Type Data......Page 226
   Bayesian Information Integration for Personalized Medicine......Page 228
   Don't......Page 231
  References......Page 232
Part IV iomarkers in Discovery and Preclinical Safety......Page 237
  Historical Background to Preclinical Safety Assessment......Page 239
  Limitations Faced in Preclinical Safety Assessment......Page 240
   Liver Injury......Page 241
   Drug‐Induced Skeletal Myopathy......Page 242
  Why Qualify Biomarkers?......Page 243
  Collaboration in Biomarker Qualification......Page 246
  References......Page 247
 Chapter 12 A Pathologist's View of Drug and Biomarker Development......Page 251
   Suggestion 1: Gene Expression Studies Analysis Should Be Correlated with Spatial and Temporal Aspects of the Disease......Page 260
   Suggestion 2: Think Carefully About the Value Gained by Compromising Morphology for RNA Quality......Page 261
   Suggestion 3: Anatomic Pathology Methods Need to Become Standardized......Page 262
   Suggestion 4: Anatomic Pathology Needs to Change from a Descriptive to a Quantitative Discipline......Page 264
  References......Page 269
  Introduction......Page 273
  Toxicology Studies......Page 275
  Discussion......Page 285
  Clinical Doses and Responses......Page 289
  Conclusions......Page 292
  References......Page 293
  Introduction......Page 299
  New Preclinical Biomarkers of Nephrotoxiciy......Page 300
   2‐Microglobulin......Page 303
   Clusterin......Page 304
   Cystatin‐C......Page 306
   Glutathione S‐Transferases......Page 307
   Kidney Injury Molecule 1......Page 308
   Microalbumin......Page 310
   Osteopontin......Page 311
   Neutrophil Gelatinase–Associated Lipocalin......Page 312
   Renal Papillary Antigen 1......Page 313
  Summary......Page 314
  References......Page 316
Part V Translating from Preclinical to Clinical and Back......Page 325
  Introduction......Page 327
  Current Immuno‐Oncology Approaches – One Size Fits All? The Case of PD‐L1......Page 330
  Cardiovascular Diseases – Heart Failure......Page 333
  Role of Biomarkers in Heart Failure Drug Development......Page 334
  The Role of Medical Devices as Tools to Back‐Translate the Human Situation into Preclinical Disease Models......Page 336
  Metabolic Liver Diseases......Page 338
  Discussion......Page 340
  References......Page 342
  Drug Targets: Historical Perspectives......Page 351
  Biomarkers: Utilitarian Classification......Page 352
  Principles of Target Selection......Page 357
   Class B: Target Present Physiologically in a Nonactive Form but Is Activated and Contributes to the Disease......Page 358
   Class C: Target Functions Physiologically but in an Augmented, Uncontrolled Fashion That Contributes to the Disease......Page 359
   Class D: Target Maintains Physiological Functions in Normal and Disease States......Page 360
  Summary......Page 361
  References......Page 362
  Introduction......Page 365
   Biomarker Discovery to Clinical Use......Page 366
   Biomarker Validation and Qualification: Current Practice......Page 367
   Biomarker Validation and Qualification: Regulatory Development and Case Studies......Page 368
   Pathways for Regulatory Approval of Diagnostics......Page 370
   Biomarker Validation and Qualification: Challenges......Page 372
   Technical Factors......Page 373
   Technological Advancements and Emergence of “Omics”......Page 374
   Evidentiary Standards......Page 376
  Conclusion......Page 378
  References......Page 379
  Introduction......Page 383
  Rheumatoid Arthritis Disease Process......Page 384
   Genes......Page 385
   Environment......Page 387
   Citrulline Immunity......Page 388
  Better Diagnosis by Means of Biomarkers and Genetics......Page 389
   Extra‐articular Disease Manifestations......Page 391
   Cardiovascular Disease in RA......Page 392
   Cartilage and Bone Destruction......Page 393
  Concluding Remarks......Page 394
  Reference......Page 395
   Biomarkers in Drug Development......Page 397
   Toxicity Biomarkers In Vitro......Page 398
   Characteristics of Biomarkers......Page 399
   Biomarkers of Safety......Page 400
   Endocrine and Exocrine Pancreatic Toxicity......Page 401
   Liver Toxicity......Page 402
   Phospholipidosis......Page 404
  Conclusions......Page 405
  Reference......Page 406
Part VI Biomarkers in Clinical Trials......Page 407
  Introduction......Page 409
   Dose Selection for Ex vivo Experiments......Page 414
   Effect on Absolute Prothrombin Time......Page 415
   Effect on PT/Control Ratio and INR......Page 416
  Pursuing Biomarkers Beyond PT, INR, and aPTT......Page 420
  Conclusions......Page 423
  References......Page 424
  Clinical Laboratory Regulation......Page 427
   Proficiency Testing......Page 429
   Analytic Testing......Page 431
   Personnel Qualifications......Page 432
  Genetic Testing and Patient Privacy......Page 433
  Molecular Testing from Research to Clinical Application......Page 434
  Reimbursement for Molecular Testing......Page 436
  References......Page 437
Part VII Big Data, Data Mining, and Biomarkers......Page 439
  A Paradigm Shift in Bio‐pharmaceutical RD......Page 441
   Processes, Workflows, IT Standards, and Architectures......Page 442
   Clinical Biomarkers and Associated Data Types......Page 447
  Data Integration and Management......Page 448
  Imaging Biomarker Data, Regulatory Compliance, and SOA......Page 452
  Biomarkers and Cognitive Computing......Page 453
   Beilstein/Reaxys:......Page 454
   Thomson‐Reuters Derwent World Patent and World Drug Index......Page 455
   OMIM......Page 456
   UniProt: ExPASy, PIR, Swiss‐Prot, TrEMBL, and GOA......Page 457
   Mouse Genome Informatics (MGI)......Page 458
   The Cancer Genome Atlas (TCGA)......Page 459
   BioCarta......Page 460
   InterPro......Page 461
  Conclusions......Page 462
  References......Page 463
  Introduction......Page 465
  Considerations on Epidemiologic Design and the Analysis of Big Health Care Data......Page 467
  Clinical Background of Anemia of CKD and Study Premises......Page 469
  Study Concept, Biological Rationale, and Study Design......Page 470
  The Biomarker Profile: Implications for Clinical Management......Page 477
  The Biomarker Profile: Implications for Clinical Trial Design......Page 478
  References......Page 479
  Introduction......Page 487
  Mapping Pathways of Diseases and Drugs Through Text Mining......Page 488
  Identification of Biomarkers for Patient Stratification Through Predictive Modeling......Page 491
  Building Translational Research Platforms Integrating Clinical, Phenotypic, and Genomic Data to Support Predictive Modeling......Page 494
  A Case Study Identifying Cell Line–Derived Translational Biomarkers for Predicting the Treatment Outcome to Erlotinib or Sorafenib, and Selecting Drug‐Sensitive Cancer Indications......Page 495
  Conclusions......Page 497
  References......Page 498
Part VIII Lessons Learned: Practical Aspects of Biomarker Implementation......Page 503
  Introduction: Pharmaceutical Project Teams......Page 505
  Team Dynamics: Pharmaceutical Project Teams......Page 509
  Consequences of Biomarkers in Pharmaceutical Development Strategies......Page 510
  Project Management......Page 511
  Challenges Associated with Different Types of Biomarkers......Page 514
   Efficacy Biomarkers......Page 515
   Patient Stratification Biomarkers......Page 516
   Safety Biomarkers......Page 517
  Management of Logistics, Processes, and Expectations......Page 518
  References......Page 521
  Introduction......Page 523
  In Vitro Therapeutic Indices......Page 524
   Muraglitazar‐Induced Urinary Bladder Transitional Cell Carcinoma......Page 527
  Novel Transcriptomic Biomarkers......Page 528
  Conclusions......Page 529
  References......Page 530
Part IX Where Are We Heading and What Do We Really Need?......Page 533
  Introduction......Page 535
  Biomarkers, Ethics, and Investigative Research......Page 537
  Population Biobanks and the Challenge of Harmonization......Page 539
  Informed Consent: Centrality and Inadequacy of the Ideal......Page 543
  Other Areas that Warrant Consideration: Commercialization of Biobanks......Page 546
  Science, Ethics, and the Changing Role of the Public......Page 547
  Public Consultation and Deliberative Democracy......Page 548
  Conclusions......Page 549
  References......Page 550
  Introduction......Page 555
  Unicorn Biomarkers......Page 557
  Horse Biomarkers......Page 558
  Mule Biomarkers......Page 560
  Conclusions......Page 562
  References......Page 563
  Introduction......Page 571
  Yesterday's Imaging Biomarkers: Prototypes for Tomorrow......Page 572
   Recent Evolution......Page 574
   Latest Trends Evidenced in Peer‐Reviewed Literature......Page 575
   Current Clinical Prevalence......Page 576
   Learnings Driving Today's Needs......Page 577
   18F‐FDG PET Imaging of Tissue Metabolism......Page 579
   18F PET Tracer Imaging in Alzheimer's Disease: Amyloid‐ and Tau......Page 580
   Magnetic Resonance Spectroscopy......Page 581
   What Do We Need?......Page 582
   Imaging Agents: Precision Tools for Precision Medicine......Page 584
   Immuno‐oncology Imaging Agents......Page 585
   Therapeutic Cell Imaging......Page 587
   Resting State fMRI......Page 588
   New Modalities and Hardware......Page 589
   Artificial Intelligence......Page 590
   Facilitation and Outlook......Page 591
  Summary......Page 592
  References......Page 593
Index......Page 603
EULA......Page 611