Clinical and Translational Science - Principles of Human Research

Front Cover

Clinical and Translational Science

Copyright Page

Contents

List of contributors

Foreword

Acknowledgments

Introduction to Clinical Research

HISTORICAL BACKGROUND

ORGANIZATION OF THIS BOOK

REFERENCES

Part I: Fundamental Principles

Chapter 1 Patient-Oriented Research: Clinical Pathophysiology and Clinical Therapeutics

INTRODUCTION

TYPES OF PATIENT-ORIENTED RESEARCH

THE ROLE OF PATIENT-ORIENTED RESEARCH IN TRANSLATIONAL RESEARCH

SEQUENCE OF INVESTIGATION

CONCLUSIONS

REFERENCES

Chapter 2 Clinical Trials

INTRODUCTION

HISTORY

PHASES OF EVALUATION OF THERAPIES

CRITICAL GENERAL CONCEPTS

EXPRESSING CLINICAL TRIAL RESULTS

CONCEPTS UNDERLYING TRIAL DESIGN

GENERAL DESIGN CONSIDERATIONS

LEGAL AND ETHICAL ISSUES

HYPOTHESIS FORMULATION

PUBLICATION BIAS

STATISTICAL CONSIDERATIONS

META-ANALYSIS AND SYSTEMATIC OVERVIEWS

UNDERSTANDING COVARIATES AND SUBGROUPS

THERAPEUTIC TRUISMS

STUDY ORGANIZATION

INTEGRATION INTO PRACTICE

THE FUTURE

ACKNOWLEDGMENT

REFERENCES

Part II: Approaches

Chapter 3 Experimental Design

INTRODUCTION

HYPOTHESIS DEVELOPMENT

STUDY DESIGN OPTIONS

CONTROL OF BIAS

SAMPLE SIZE

ENDPOINTS

DATA MANAGEMENT

STATISTICAL ANALYSIS

CONCLUSION

REFERENCES

Chapter 4 Introduction to Biostatistics Ideas

BIOSTATISTICS: WHAT IS IT?

EVIDENCE: HOW MANY HEADS ON THIS COIN?

POPULATIONS AND DISTRIBUTIONS

SAMPLES

CLINICAL MEASURES OF INTEREST: WHAT DO WE WANT TO KNOW?

DATA AS SAMPLES: DISPLAY, LOOK AND THINK

THE MOST IMPORTANT PROBABILITY MODEL IN MEDICINE

THE CIRCLE OF INFERENCE

CENTRAL LIMIT THEOREM (CLT)

ESTIMATING THE TRUE POPULATION VALUE

TESTING PRE-SPECIFIED HYPOTHESES

THE MIGHTY P

REGRESSION ANALYSIS

THE MAIN POINTS ONCE AGAIN

REFERENCES

Chapter 5 Measurement of Biological Materials

INTRODUCTION

IMMUNOASSAYS AND IMMUNOCHEMISTRY

RADIOIMMUNOASSAYS

CHROMATOGRAPHY

MASS SPECTROMETRY (MS)

GENOMICS (GENE EXPRESSION MICROARRAYS)

PROTEOMICS

METABOLOMICS

REFERENCES

Chapter 6 Imaging Tools in Human Research

INTRODUCTION

IMAGING TECHNOLOGIES: A BRIEF OVERVIEW

IMAGING TECHNOLOGIES: HUMANS AND SMALL ANIMALS

SUMMARY

ACKNOWLEDGMENTS

REFERENCE

Chapter 7 Imaging Tools in Cardiovascular Research

INTRODUCTION

IMAGING AND RISK STRATIFICATION

PRESSURE WAVEFORM ANALYSIS AND ARTERIAL STIFFNESS

ARTERIAL IMAGING

ULTRASOUND IMAGING OF THE HEART

SUMMARY

REFERENCES

Chapter 8 Nanotechnology in Clinical and Translational Research

INTRODUCTION AND HISTORICAL PERSPECTIVE

NANOTECHNOLOGY IN BASIC RESEARCH APPLICATIONS SUPPORTING CLINICAL TRANSLATION

CLINICAL APPLICATIONS OF NANOTECHNOLOGY FOR RESEARCH

CONCLUSION AND FUTURE DIRECTIONS IN NANOMEDICINE

REFERENCES

Chapter 9 The Use of Questionnaires and Surveys

INTRODUCTION

THE PRACTICE OF QUESTIONNAIRE AND SURVEY MEASUREMENT

REFERENCES

Chapter 10 Information Technology

INTRODUCTION

CLINICAL DATA REPOSITORIES (CDRs)

PRINCIPLES OF DATA WAREHOUSING

INFORMATION TECHNOLOGY SUPPORT OF PARTICIPANT RECRUITMENT

PRINCIPLES OF DATA COLLECTION

DATA STANDARDS

CLINICAL TRIAL MANAGEMENT SYSTEMS

PUBLICLY AVAILABLE DATABASES

THE GROWING IMPACT OF THE WEB

SUMMARY

REFERENCES

Part III: Infrastructure

Chapter 11 Clinical and Translational Science Infrastructure

INTRODUCTION

BACKGROUND

REINVENTING THE CLINICAL RESEARCH INFRASTRUCTURE

CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTES

STRUCTURAL COMPONENTS OF A CLINICAL AND TRANSLATIONAL SCIENCE AWARD

CTSA SCIENTIFIC REVIEW

COLLECTIVE INITIATIVES OF THE CTSA CONSORTIUM

CONCLUSION

REFERENCES

Chapter 12 Industry-Sponsored Clinical Research in Academia

INTRODUCTION

THE PUBLIC PERSPECTIVE

THE AHC PERSPECTIVE

THE INDUSTRY PERSPECTIVE

THE INVESTIGATORS’ PERSPECTIVE

MATCHING INDUSTRY NEEDS AND AHC INTERESTS

ACADEMIC CLINICAL TRIALS CENTERS AS A SOLUTION

FINANCING CTCs

IT SOLUTIONS TO IMPROVE PATIENT ENROLLMENT

CONCLUDING REMARKS

ACKNOWLEDGMENT

REFERENCES

Part IV: Education, Training and Career Choices

Chapter 13 Training Basic, Clinical and Translational Investigators

INTRODUCTION

OVERVIEW

DIDACTIC CURRICULUM

DEGREE-GRANTING PROGRAMS IN CLINICAL OR TRANSLATIONAL RESEARCH

THE MENTORED RESEARCH EXPERIENCE

CAREER DEVELOPMENT RESOURCES

FUNDING FOR TRAINING CLINICAL AND TRANSLATIONAL INVESTIGATORS

REFERENCES

Chapter 14 A Stepwise Approach to a Career in Translational Research

DEFINITIONAL ISSUES

HISTORICAL PERSPECTIVE

STEP 1: THE STARTING POINT

STEP 2: THE NEED FOR NORMATIVE DATA AND CONTROL POPULATIONS

STEP 3: ENGAGEMENT OF RELEVANT BASIC RESEARCHERS AND TECHNOLOGIES

STEP 4: IDENTIFYING TRACTABLE PROBLEMS

STEP 5: IDENTIFYING APPROPRIATE MENTORS ACROSS A CAREER

STEP 6: OBTAINING SUCCESSFUL INDEPENDENT FUNDING

STEP 7: THE PERILS OF SENIOR LEADERSHIP

SUMMARY

REFERENCES

Chapter 15 Physician Careers in Industry

INTRODUCTION

PHASE 1 STUDIES

PHASE 2 STUDIES

PHASE 3 STUDIES

PHASE 4 STUDIES

CAREERS IN THE PHARMACEUTICAL INDUSTRY

CONCLUSION

REFERENCES

Part V: Funding

Chapter 16 Governmental Support of Research

OVERVIEW

INTRODUCTION

UNITED STATES GOVERNMENT SCIENTIFIC PROGRAMS IN 2007

SCIENTIFIC PROGRAMS IN EUROPE, CANADA AND AUSTRALIA/NEW ZEALAND

SCIENTIFIC PROGRAMS IN ASIA, AFRICA AND SOUTH/CENTRAL AMERICA AND THE CARIBBEAN

CURRENT SUPPORT FOR CLINICAL AND TRANSLATIONAL RESEARCH

PUTTING GOVERNMENT HEALTH RESEARCH INTO PERSPECTIVE

ACKNOWLEDGMENT

BIBLIOGRAPHY

REFERENCES

Chapter 17 Support of Health Research by Private Philanthropy

OVERVIEW

INTRODUCTION: GROWTH IN AMERICAN PHILANTHROPY AND ITS ROLE IN SUPPORTING MEDICAL RESEARCH

TYPES OF NONPROFIT, NONGOVERNMENTAL FUNDING FOR MEDICAL RESEARCH

FUNDING ALONG THE CONTINUUM OF BIOMEDICAL AND HEALTH RESEARCH

FOUNDATION FUNDING STRATEGIES – ‘HOW’ TO FUND

APPROACHING FOUNDATIONS

SUMMARY

ACKNOWLEDGMENTS

REFERENCES

Chapter 18 Pharmaceutical and Biotechnology Sector Support of Research

INTRODUCTION

THE DRUG DEVELOPMENT PROCESS

BASIC SCIENCE WITHIN THE PHARMACEUTICAL AND BIOTECHNOLOGY SECTORS

DEVELOPMENTAL RESEARCH – A CONTRAST TO ACADEMIA AND GOVERNMENT

CLINICAL RESEARCH AND DEVELOPMENT

MARKETED PRODUCT RESEARCH

SUMMARY

FURTHER READING

Part VI: Human Genetics

Chapter 19 Introduction to Human Genetics

INTRODUCTION

BASIC MOLECULAR GENETICS

DNA STRUCTURE

DNA REPLICATION

TRANSCRIPTION

TRANSLATION

CHROMOSOME STRUCTURE AND FUNCTION

MITOSIS AND MEIOSIS

PATTERNS OF GENETIC TRANSMISSION

SINGLE GENE INHERITANCE (MENDELIAN INHERITANCE)

NONMEDELIAN INHERITANCE

MULTIFACTORIAL INHERITANCE (POLYGENIC INHERITANCE)

CYTOGENETICS AND CHROMOSOMAL DISORDERS

THE HUMAN GENOME

STRUCTURE AND ORGANIZATION OF THE GENOME

GENETIC VARIATION

MEDICAL APPLICATIONS

MOLECULAR DIAGNOSTIC TESTING

THERAPY OF GENETIC DISEASE

GENETIC COUNSELING

PHENOTYPING AND CLINICAL RESEARCH

THE PHENOTYPIC CHALLENGE

GENOTYPE–ENVIRONMENT INTERACTION

PHENOTYPIC COMPLEXITY

REFERENCES

BIBLOGRAPHY

Chapter 20 Epidemiologic and Population Genetic Studies

INTRODUCTION

DESIGN ISSUES IN GENETIC ASSOCIATION STUDIES

INTERPRETING RESULTS OF GENETIC ASSOCIATION STUDIES

FUTURE DIRECTIONS

REFERENCES

Chapter 21 Pharmacogenetics of Drug Metabolism

INTRODUCTION

PHARMACOGENETICS OF DRUG METABOLISM: HISTORICAL ASPECTS

GENETIC POLYMORPHISMS OF INDIVIDUAL DRUG METABOLIZING GENES

UGT

CONCLUSIONS

REFERENCES

Part VII: Human Pharmacology

Chapter 22 Introduction to Clinical Pharmacology

OVERVIEW

INTRODUCTION: MECHANISMS OF DRUG DISPOSITION AND INTERACTIONS

PRINCIPLES OF PHARMACOKINETICS

CONCLUSION

REFERENCES

Chapter 23 Toxicology and Genetics of Adverse Drug Events

THE MULTIFACTORIAL NATURE OF ADVERSE DRUG EVENTS

TYPES OF ADVERSE DRUG EVENTS

GENETICS TO GENOMICS

REFERENCES

Chapter 24 Good Clinical Practice and Good Laboratory Practice

OVERVIEW

GOOD CLINICAL PRACTICE

DEFINITION

RULES AND REGULATIONS

CLINICAL PRACTICE AND RESEARCH

KEY PARTICIPANTS IN CLINICAL RESEARCH

DOCUMENTATION AND RECORD KEEPING

DATA MANAGEMENT AND PRESENTATION

MONITORING AND COMPLIANCE

CONCLUSION

GOOD LABORATORY PRACTICE

DEFINITION AND SCOPE

ORGANIZATION AND PERSONNEL

MANAGEMENT OF THE TESTING FACILITY

TEST, REFERENCE AND CONTROL ARTICLES

PROTOCOL FOR AND CONDUCT OF A NONCLINICAL LABORATORY STUDY

RECORD KEEPING

REPORTING OF NONCLINICAL LABORATORY STUDY RESULTS

DISQUALIFICATION OF LABORATORY FACILITY RESOURCES

CONCLUSION

REFERENCES

Chapter 25 Modern Drug Discovery and Development

BACKGROUND: THE IRONY OF INNOVATION

DRUG DISCOVERY THROUGH THE TWENTIETH CENTURY

DRUG DISCOVERY IN THE TWENTY-FIRST CENTURY

PRECLINICAL DEVELOPMENT

CLINICAL DEVELOPMENT

NEW DRUG DEVELOPMENT PARADIGMS

REFERENCES

Part VIII: Societal Context of Human Research

Chapter 26 Translating Science to the Bedside: The Innovation Pipeline

REALITIES OF THE MARKETPLACE

IDEAS AND INNOVATIONS

WORKING WITH INDUSTRY

ENTREPRENEURSHIP

CLINICAL EVALUATION OF INNOVATIVE PRODUCTS

CONFLICTS OF INTEREST

SUMMARY

NOTES

BIBLIOGRAPHY

Chapter 27 Regulatory Environment

INTRODUCTION

THE US FOOD AND DRUG ADMINISTRATION

THE INVESTIGATIONAL NEW DRUG (IND) APPLICATION

OTHER REGULATORY AGENCIES

CONCLUSIONS

ACKNOWLEDGMENTS

BIBLIOGRAPHY

REFERENCES

Chapter 28 Ethical Issues in Translational Research and Clinical Investigation

INTRODUCTION

RESPONSIBILITY IN SCIENCE AND SOCIETY

ETHICS AND TRANSLATIONAL RESEARCH

GUIDING PRINCIPLES FOR THE RESPONSIBLE TRANSLATIONAL INVESTIGATOR

BEYOND ETHICS: REGULATIONS, COMPLIANCE AND PROFESSIONALISM IN TRANSLATIONAL RESEARCH

JUSTICE, BENEFICENCE AND RESPECT FOR PERSONS: FROM PRINCIPLES TO PRACTICE

REGULATION OF RESEARCH AND PROTECTION OF SUBJECTS

INDIVIDUALS AND THE CLINICAL RESEARCH PROCESS

PROFESSIONALISM IN CLINICAL RESEARCH

REFERENCES

Chapter 29 Clinical Research in the Public Eye

INTRODUCTION

THE CULTURAL CONTEXT OF RESEARCH

SCIENCE AND POLITICS

PUBLIC–PRIVATE COLLABORATION

CONCLUSION

ACKNOWLEDGMENTS

REFERENCES

Part IX: Research in Special Populations

Chapter 30 Acute Illnesses, Critical Care, Emergency and Surgical Patients

INTRODUCTION

TRIAL DESIGN

USUAL CARE IN CRITICALLY ILL PATIENTS

INFORMED CONSENT

OUTCOMES

ADVERSE EVENTS

CONCLUSION

REFERENCES

Chapter 31 Psychiatric Disorders

INTRODUCTION

DIAGNOSTIC ISSUES

TYPES OF STUDIES

TOOLS

STATISTICAL AND DESIGN ISSUES

SPECIAL ISSUES

A PRACTICAL SCHEMATIC APPROACH

REFERENCES

Chapter 32 Geriatrics

INTRODUCTION

WHAT IS DIFFERENT ABOUT AGING RESEARCH?

HOW AN AGING PERSPECTIVE AFFECTS RESEARCH TOPICS AND APPROACHES

THE EFFECT OF AGING ON THE PRAGMATICS OF RESEARCH

CONCLUSIONS AND RECOMMENDATIONS

REFERENCES

Chapter 33 Pediatrics

INTRODUCTION

WHAT IS DIFFERENT ABOUT PEDIATRIC RESEARCH?

ORPHAN (RARE) DISEASES

PEDIATRIC CONDITIONS AS FOCUS OF INQUIRY

REGULATORY AND ETHICAL ENVIRONMENT FOR PEDIATRIC RESEARCH

CONCLUSION

REFERENCES

Part X: Population-Based Research

Chapter 34 Pharmacoeconomics: The Economic Evaluation of New Medical Technology

INTRODUCTION

THE EVALUATION OF NEW MEDICAL TECHNOLOGY: THE PRODUCER’S PERSPECTIVE

THE EVALUATION OF NEW MEDICAL TECHNOLOGY: THE END USER’S PERSPECTIVE

THE EVALUATION OF NEW MEDICAL TECHNOLOGY: SOCIETY’S PERSPECTIVE

COST–BENEFIT, COST-EFFECTIVENESS AND COST-UTILITY ANALYSIS

CAN ONE EVER AVOID PUTTING MONETARY VALUES ON HEALTH BENEFITS?

UNRESOLVED CONTROVERSIES ON ECONOMIC VALUATIONS IN HEALTHCARE

NOTES

REFERENCES

Chapter 35 Introduction to Epidemiology

INTRODUCTION

DEFINITION AND ROLE OF EPIDEMIOLOGY

MEASURING OCCURRENCE OF DISEASE

MEASURING RISK AND ASSOCIATION

TYPES OF EPIDEMIOLOGICAL STUDIES

THREATS TO VALIDITY AND RELIABILITY

MOVING FROM ASSOCIATION TO CAUSATION

CLINICAL EPIDEMIOLOGY

SEX, GENDER, RACE AND ETHNICITY IN EPIDEMIOLOGY

SUMMARY

ACKNOWLEDGMENTS

RECOMMENDED RESOURCES

REFERENCES

Chapter 36 Health Services Research: Translating Discovery and Research into Practice and Policy

WHAT IS HEALTH SERVICES RESEARCH AND WHAT ARE ITS GOALS?

ASSESSING MEDICAL INTERVENTIONS: OUTCOMES, EFFECTIVENESS AND COST-EFFECTIVENESS

MEDICAL DECISION MAKING

QUALITY MEDICAL CARE

CONCLUSIONS

REFERENCES

Part XI: Prospectus

Chapter 37 The Future of Clinical Research

DEFINITION OF TRANSLATIONAL HUMAN RESEARCH

SUBGROUPING OF BIOLOGICAL SCIENTISTS

THE PATIENT-ORIENTED SCIENTIST AT THE BEGINNING OF THE TWENTY-FIRST CENTURY

THE TWENTY-FIRST CENTURY AND THE FUTURE

REFERENCES

Index

A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Q

R

S

T

U

V

W

X