Clinical and Translational Science (eBook)

Front Cover 1
Clinical and Translational Science 4
Copyright Page 5
Contents 8
List of contributors 10
Foreword 14
Acknowledgments 16
Introduction to Clinical Research 18
HISTORICAL BACKGROUND 18
ORGANIZATION OF THIS BOOK 20
REFERENCES 21
Part I: Fundamental Principles 22
Chapter 1 Patient-Oriented Research: Clinical Pathophysiology and Clinical Therapeutics 24
INTRODUCTION 24
TYPES OF PATIENT-ORIENTED RESEARCH 24
THE ROLE OF PATIENT-ORIENTED RESEARCH IN TRANSLATIONAL RESEARCH 27
SEQUENCE OF INVESTIGATION 27
CONCLUSIONS 31
REFERENCES 32
Chapter 2 Clinical Trials 34
INTRODUCTION 34
HISTORY 34
PHASES OF EVALUATION OF THERAPIES 34
CRITICAL GENERAL CONCEPTS 35
EXPRESSING CLINICAL TRIAL RESULTS 36
CONCEPTS UNDERLYING TRIAL DESIGN 38
GENERAL DESIGN CONSIDERATIONS 41
LEGAL AND ETHICAL ISSUES 43
HYPOTHESIS FORMULATION 47
PUBLICATION BIAS 48
STATISTICAL CONSIDERATIONS 48
META-ANALYSIS AND SYSTEMATIC OVERVIEWS 49
UNDERSTANDING COVARIATES AND SUBGROUPS 50
THERAPEUTIC TRUISMS 51
STUDY ORGANIZATION 51
INTEGRATION INTO PRACTICE 54
THE FUTURE 55
ACKNOWLEDGMENT 55
REFERENCES 56
Part II: Approaches 60
Chapter 3 Experimental Design 62
INTRODUCTION 62
HYPOTHESIS DEVELOPMENT 62
STUDY DESIGN OPTIONS 63
CONTROL OF BIAS 64
SAMPLE SIZE 66
ENDPOINTS 68
DATA MANAGEMENT 71
STATISTICAL ANALYSIS 75
CONCLUSION 77
REFERENCES 77
Chapter 4 Introduction to Biostatistics Ideas 80
BIOSTATISTICS: WHAT IS IT? 80
EVIDENCE: HOW MANY HEADS ON THIS COIN? 80
POPULATIONS AND DISTRIBUTIONS 81
SAMPLES 81
CLINICAL MEASURES OF INTEREST: WHAT DO WE WANT TO KNOW? 81
DATA AS SAMPLES: DISPLAY, LOOK AND THINK 83
THE MOST IMPORTANT PROBABILITY MODEL IN MEDICINE 83
THE CIRCLE OF INFERENCE 85
CENTRAL LIMIT THEOREM (CLT) 85
ESTIMATING THE TRUE POPULATION VALUE 86
TESTING PRE-SPECIFIED HYPOTHESES 87
THE MIGHTY P 87
REGRESSION ANALYSIS 88
THE MAIN POINTS ONCE AGAIN 88
REFERENCES 89
Chapter 5 Measurement of Biological Materials 90
INTRODUCTION 90
IMMUNOASSAYS AND IMMUNOCHEMISTRY 90
RADIOIMMUNOASSAYS 91
CHROMATOGRAPHY 93
MASS SPECTROMETRY (MS) 96
GENOMICS (GENE EXPRESSION MICROARRAYS) 99
PROTEOMICS 101
METABOLOMICS 103
REFERENCES 106
Chapter 6 Imaging Tools in Human Research 108
INTRODUCTION 108
IMAGING TECHNOLOGIES: A BRIEF OVERVIEW 108
IMAGING TECHNOLOGIES: HUMANS AND SMALL ANIMALS 111
SUMMARY 123
ACKNOWLEDGMENTS 123
REFERENCE 123
Chapter 7 Imaging Tools in Cardiovascular Research 126
INTRODUCTION 126
IMAGING AND RISK STRATIFICATION 126
PRESSURE WAVEFORM ANALYSIS AND ARTERIAL STIFFNESS 129
ARTERIAL IMAGING 135
ULTRASOUND IMAGING OF THE HEART 138
SUMMARY 139
REFERENCES 141
Chapter 8 Nanotechnology in Clinical and Translational Research 144
INTRODUCTION AND HISTORICAL PERSPECTIVE 144
NANOTECHNOLOGY IN BASIC RESEARCH APPLICATIONS SUPPORTING CLINICAL TRANSLATION 145
CLINICAL APPLICATIONS OF NANOTECHNOLOGY FOR RESEARCH 145
CONCLUSION AND FUTURE DIRECTIONS IN NANOMEDICINE 154
REFERENCES 154
Chapter 9 The Use of Questionnaires and Surveys 158
INTRODUCTION 158
THE PRACTICE OF QUESTIONNAIRE AND SURVEY MEASUREMENT 158
REFERENCES 173
Chapter 10 Information Technology 176
INTRODUCTION 176
CLINICAL DATA REPOSITORIES (CDRs) 176
PRINCIPLES OF DATA WAREHOUSING 177
INFORMATION TECHNOLOGY SUPPORT OF PARTICIPANT RECRUITMENT 182
PRINCIPLES OF DATA COLLECTION 183
DATA STANDARDS 184
CLINICAL TRIAL MANAGEMENT SYSTEMS 185
PUBLICLY AVAILABLE DATABASES 186
THE GROWING IMPACT OF THE WEB 187
SUMMARY 187
REFERENCES 187
Part III: Infrastructure 190
Chapter 11 Clinical and Translational Science Infrastructure 192
INTRODUCTION 192
BACKGROUND 192
REINVENTING THE CLINICAL RESEARCH INFRASTRUCTURE 193
CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTES 194
STRUCTURAL COMPONENTS OF A CLINICAL AND TRANSLATIONAL SCIENCE AWARD 195
CTSA SCIENTIFIC REVIEW 198
COLLECTIVE INITIATIVES OF THE CTSA CONSORTIUM 200
CONCLUSION 201
REFERENCES 202
Chapter 12 Industry-Sponsored Clinical Research in Academia 204
INTRODUCTION 204
THE PUBLIC PERSPECTIVE 204
THE AHC PERSPECTIVE 205
THE INDUSTRY PERSPECTIVE 205
THE INVESTIGATORS’ PERSPECTIVE 206
MATCHING INDUSTRY NEEDS AND AHC INTERESTS 206
ACADEMIC CLINICAL TRIALS CENTERS AS A SOLUTION 207
FINANCING CTCs 207
IT SOLUTIONS TO IMPROVE PATIENT ENROLLMENT 208
CONCLUDING REMARKS 208
ACKNOWLEDGMENT 209
REFERENCES 209
Part IV: Education, Training and Career Choices 210
Chapter 13 Training Basic, Clinical and Translational Investigators 212
INTRODUCTION 212
OVERVIEW 212
DIDACTIC CURRICULUM 213
DEGREE-GRANTING PROGRAMS IN CLINICAL OR TRANSLATIONAL RESEARCH 218
THE MENTORED RESEARCH EXPERIENCE 219
CAREER DEVELOPMENT RESOURCES 219
FUNDING FOR TRAINING CLINICAL AND TRANSLATIONAL INVESTIGATORS 219
REFERENCES 220
Chapter 14 A Stepwise Approach to a Career in Translational Research 222
DEFINITIONAL ISSUES 222
HISTORICAL PERSPECTIVE 222
STEP 1: THE STARTING POINT 223
STEP 2: THE NEED FOR NORMATIVE DATA AND CONTROL POPULATIONS 224
STEP 3: ENGAGEMENT OF RELEVANT BASIC RESEARCHERS AND TECHNOLOGIES 224
STEP 4: IDENTIFYING TRACTABLE PROBLEMS 224
STEP 5: IDENTIFYING APPROPRIATE MENTORS ACROSS A CAREER 225
STEP 6: OBTAINING SUCCESSFUL INDEPENDENT FUNDING 225
STEP 7: THE PERILS OF SENIOR LEADERSHIP 226
SUMMARY 226
REFERENCES 226
Chapter 15 Physician Careers in Industry 228
INTRODUCTION 228
PHASE 1 STUDIES 228
PHASE 2 STUDIES 229
PHASE 3 STUDIES 229
PHASE 4 STUDIES 229
CAREERS IN THE PHARMACEUTICAL INDUSTRY 229
CONCLUSION 236
REFERENCES 236
Part V: Funding 238
Chapter 16 Governmental Support of Research 240
OVERVIEW 240
INTRODUCTION 240
UNITED STATES GOVERNMENT SCIENTIFIC PROGRAMS IN 2007 240
SCIENTIFIC PROGRAMS IN EUROPE, CANADA AND AUSTRALIA/NEW ZEALAND 247
SCIENTIFIC PROGRAMS IN ASIA, AFRICA AND SOUTH/CENTRAL AMERICA AND THE CARIBBEAN 249
CURRENT SUPPORT FOR CLINICAL AND TRANSLATIONAL RESEARCH 253
PUTTING GOVERNMENT HEALTH RESEARCH INTO PERSPECTIVE 254
ACKNOWLEDGMENT 254
BIBLIOGRAPHY 255
REFERENCES 256
Chapter 17 Support of Health Research by Private Philanthropy 258
OVERVIEW 258
INTRODUCTION: GROWTH IN AMERICAN PHILANTHROPY AND ITS ROLE IN SUPPORTING MEDICAL RESEARCH 258
TYPES OF NONPROFIT, NONGOVERNMENTAL FUNDING FOR MEDICAL RESEARCH 260
FUNDING ALONG THE CONTINUUM OF BIOMEDICAL AND HEALTH RESEARCH 264
FOUNDATION FUNDING STRATEGIES – ‘HOW’ TO FUND 270
APPROACHING FOUNDATIONS 271
SUMMARY 273
ACKNOWLEDGMENTS 274
REFERENCES 274
Chapter 18 Pharmaceutical and Biotechnology Sector Support of Research 276
INTRODUCTION 276
THE DRUG DEVELOPMENT PROCESS 276
BASIC SCIENCE WITHIN THE PHARMACEUTICAL AND BIOTECHNOLOGY SECTORS 277
DEVELOPMENTAL RESEARCH – A CONTRAST TO ACADEMIA AND GOVERNMENT 278
CLINICAL RESEARCH AND DEVELOPMENT 279
MARKETED PRODUCT RESEARCH 281
SUMMARY 281
FURTHER READING 282
Part VI: Human Genetics 284
Chapter 19 Introduction to Human Genetics 286
INTRODUCTION 286
BASIC MOLECULAR GENETICS 286
DNA STRUCTURE 286
DNA REPLICATION 287
TRANSCRIPTION 287
TRANSLATION 288
CHROMOSOME STRUCTURE AND FUNCTION 289
MITOSIS AND MEIOSIS 290
PATTERNS OF GENETIC TRANSMISSION 291
SINGLE GENE INHERITANCE (MENDELIAN INHERITANCE) 291
NONMEDELIAN INHERITANCE 292
MULTIFACTORIAL INHERITANCE (POLYGENIC INHERITANCE) 295
CYTOGENETICS AND CHROMOSOMAL DISORDERS 296
THE HUMAN GENOME 297
STRUCTURE AND ORGANIZATION OF THE GENOME 297
GENETIC VARIATION 298
MEDICAL APPLICATIONS 301
MOLECULAR DIAGNOSTIC TESTING 301
THERAPY OF GENETIC DISEASE 302
GENETIC COUNSELING 305
PHENOTYPING AND CLINICAL RESEARCH 307
THE PHENOTYPIC CHALLENGE 307
GENOTYPE–ENVIRONMENT INTERACTION 307
PHENOTYPIC COMPLEXITY 307
REFERENCES 308
BIBLOGRAPHY 308
Chapter 20 Epidemiologic and Population Genetic Studies 310
INTRODUCTION 310
DESIGN ISSUES IN GENETIC ASSOCIATION STUDIES 310
INTERPRETING RESULTS OF GENETIC ASSOCIATION STUDIES 314
FUTURE DIRECTIONS 318
REFERENCES 319
Chapter 21 Pharmacogenetics of Drug Metabolism 322
INTRODUCTION 322
PHARMACOGENETICS OF DRUG METABOLISM: HISTORICAL ASPECTS 323
GENETIC POLYMORPHISMS OF INDIVIDUAL DRUG METABOLIZING GENES 324
UGT 335
CONCLUSIONS 337
REFERENCES 337
Part VII: Human Pharmacology 340
Chapter 22 Introduction to Clinical Pharmacology 342
OVERVIEW 342
INTRODUCTION: MECHANISMS OF DRUG DISPOSITION AND INTERACTIONS 342
PRINCIPLES OF PHARMACOKINETICS 349
CONCLUSION 356
REFERENCES 356
Chapter 23 Toxicology and Genetics of Adverse Drug Events 360
THE MULTIFACTORIAL NATURE OF ADVERSE DRUG EVENTS 360
TYPES OF ADVERSE DRUG EVENTS 361
GENETICS TO GENOMICS 364
REFERENCES 364
Chapter 24 Good Clinical Practice and Good Laboratory Practice 366
OVERVIEW 366
GOOD CLINICAL PRACTICE 366
DEFINITION 366
RULES AND REGULATIONS 368
CLINICAL PRACTICE AND RESEARCH 369
KEY PARTICIPANTS IN CLINICAL RESEARCH 370
DOCUMENTATION AND RECORD KEEPING 374
DATA MANAGEMENT AND PRESENTATION 375
MONITORING AND COMPLIANCE 375
CONCLUSION 376
GOOD LABORATORY PRACTICE 376
DEFINITION AND SCOPE 376
ORGANIZATION AND PERSONNEL 377
MANAGEMENT OF THE TESTING FACILITY 377
TEST, REFERENCE AND CONTROL ARTICLES 378
PROTOCOL FOR AND CONDUCT OF A NONCLINICAL LABORATORY STUDY 379
RECORD KEEPING 379
REPORTING OF NONCLINICAL LABORATORY STUDY RESULTS 379
DISQUALIFICATION OF LABORATORY FACILITY RESOURCES 379
CONCLUSION 380
REFERENCES 380
Chapter 25 Modern Drug Discovery and Development 382
BACKGROUND: THE IRONY OF INNOVATION 382
DRUG DISCOVERY THROUGH THE TWENTIETH CENTURY 382
DRUG DISCOVERY IN THE TWENTY-FIRST CENTURY 384
PRECLINICAL DEVELOPMENT 387
CLINICAL DEVELOPMENT 389
NEW DRUG DEVELOPMENT PARADIGMS 396
REFERENCES 398
Part VIII: Societal Context of Human Research 402
Chapter 26 Translating Science to the Bedside: The Innovation Pipeline 404
REALITIES OF THE MARKETPLACE 404
IDEAS AND INNOVATIONS 407
WORKING WITH INDUSTRY 409
ENTREPRENEURSHIP 412
CLINICAL EVALUATION OF INNOVATIVE PRODUCTS 414
CONFLICTS OF INTEREST 417
SUMMARY 419
NOTES 419
BIBLIOGRAPHY 420
Chapter 27 Regulatory Environment 422
INTRODUCTION 422
THE US FOOD AND DRUG ADMINISTRATION 422
THE INVESTIGATIONAL NEW DRUG (IND) APPLICATION 425
OTHER REGULATORY AGENCIES 434
CONCLUSIONS 434
ACKNOWLEDGMENTS 435
BIBLIOGRAPHY 435
REFERENCES 435
Chapter 28 Ethical Issues in Translational Research and Clinical Investigation 436
INTRODUCTION 436
RESPONSIBILITY IN SCIENCE AND SOCIETY 437
ETHICS AND TRANSLATIONAL RESEARCH 437
GUIDING PRINCIPLES FOR THE RESPONSIBLE TRANSLATIONAL INVESTIGATOR 439
BEYOND ETHICS: REGULATIONS, COMPLIANCE AND PROFESSIONALISM IN TRANSLATIONAL RESEARCH 440
JUSTICE, BENEFICENCE AND RESPECT FOR PERSONS: FROM PRINCIPLES TO PRACTICE 441
REGULATION OF RESEARCH AND PROTECTION OF SUBJECTS 442
INDIVIDUALS AND THE CLINICAL RESEARCH PROCESS 447
PROFESSIONALISM IN CLINICAL RESEARCH 448
REFERENCES 448
Chapter 29 Clinical Research in the Public Eye 450
INTRODUCTION 450
THE CULTURAL CONTEXT OF RESEARCH 451
SCIENCE AND POLITICS 455
PUBLIC–PRIVATE COLLABORATION 457
CONCLUSION 458
ACKNOWLEDGMENTS 459
REFERENCES 459
Part IX: Research in Special Populations 462
Chapter 30 Acute Illnesses, Critical Care, Emergency and Surgical Patients 464
INTRODUCTION 464
TRIAL DESIGN 464
USUAL CARE IN CRITICALLY ILL PATIENTS 467
INFORMED CONSENT 469
OUTCOMES 473
ADVERSE EVENTS 476
CONCLUSION 478
REFERENCES 478
Chapter 31 Psychiatric Disorders 482
INTRODUCTION 482
DIAGNOSTIC ISSUES 482
TYPES OF STUDIES 483
TOOLS 485
STATISTICAL AND DESIGN ISSUES 489
SPECIAL ISSUES 490
A PRACTICAL SCHEMATIC APPROACH 493
REFERENCES 495
Chapter 32 Geriatrics 498
INTRODUCTION 498
WHAT IS DIFFERENT ABOUT AGING RESEARCH? 498
HOW AN AGING PERSPECTIVE AFFECTS RESEARCH TOPICS AND APPROACHES 502
THE EFFECT OF AGING ON THE PRAGMATICS OF RESEARCH 507
CONCLUSIONS AND RECOMMENDATIONS 513
REFERENCES 513
Chapter 33 Pediatrics 518
INTRODUCTION 518
WHAT IS DIFFERENT ABOUT PEDIATRIC RESEARCH? 518
ORPHAN (RARE) DISEASES 520
PEDIATRIC CONDITIONS AS FOCUS OF INQUIRY 523
REGULATORY AND ETHICAL ENVIRONMENT FOR PEDIATRIC RESEARCH 524
CONCLUSION 525
REFERENCES 526
Part X: Population-Based Research 530
Chapter 34 Pharmacoeconomics: The Economic Evaluation of New Medical Technology 532
INTRODUCTION 532
THE EVALUATION OF NEW MEDICAL TECHNOLOGY: THE PRODUCER’S PERSPECTIVE 532
THE EVALUATION OF NEW MEDICAL TECHNOLOGY: THE END USER’S PERSPECTIVE 534
THE EVALUATION OF NEW MEDICAL TECHNOLOGY: SOCIETY’S PERSPECTIVE 536
COST–BENEFIT, COST-EFFECTIVENESS AND COST-UTILITY ANALYSIS 538
CAN ONE EVER AVOID PUTTING MONETARY VALUES ON HEALTH BENEFITS? 543
UNRESOLVED CONTROVERSIES ON ECONOMIC VALUATIONS IN HEALTHCARE 545
NOTES 546
REFERENCES 546
Chapter 35 Introduction to Epidemiology 548
INTRODUCTION 548
DEFINITION AND ROLE OF EPIDEMIOLOGY 548
MEASURING OCCURRENCE OF DISEASE 550
MEASURING RISK AND ASSOCIATION 551
TYPES OF EPIDEMIOLOGICAL STUDIES 553
THREATS TO VALIDITY AND RELIABILITY 556
MOVING FROM ASSOCIATION TO CAUSATION 558
CLINICAL EPIDEMIOLOGY 560
SEX, GENDER, RACE AND ETHNICITY IN EPIDEMIOLOGY 560
SUMMARY 561
ACKNOWLEDGMENTS 561
RECOMMENDED RESOURCES 561
REFERENCES 561
Chapter 36 Health Services Research: Translating Discovery and Research into Practice and Policy 564
WHAT IS HEALTH SERVICES RESEARCH AND WHAT ARE ITS GOALS? 564
ASSESSING MEDICAL INTERVENTIONS: OUTCOMES, EFFECTIVENESS AND COST-EFFECTIVENESS 565
MEDICAL DECISION MAKING 568
QUALITY MEDICAL CARE 573
CONCLUSIONS 581
REFERENCES 582
Part XI: Prospectus 584
Chapter 37 The Future of Clinical Research 586
DEFINITION OF TRANSLATIONAL HUMAN RESEARCH 586
SUBGROUPING OF BIOLOGICAL SCIENTISTS 587
THE PATIENT-ORIENTED SCIENTIST AT THE BEGINNING OF THE TWENTY-FIRST CENTURY 589
THE TWENTY-FIRST CENTURY AND THE FUTURE 590
REFERENCES 591
Index 592
A 592
B 592
C 592
D 594
E 594
F 595
G 595
H 596
I 596
J 597
K 597
L 597
M 597
N 597
O 598
P 598
Q 599
R 599
S 599
T 600
U 600
V 600
W 600
X 600