علم بالینی و ترجمه‌ای: اصول پژوهش انسانی

Clinical and Translational Science: Principles of Human Research, Second Edition, is the most authoritative and timely resource for the broad range of investigators taking on the challenge of clinical and translational science, a field that is devoted to investigating human health and disease, interventions, and outcomes for the purposes of developing new treatment approaches, devices, and modalities to improve health. This updated second edition has been prepared with an international perspective, beginning with fundamental principles, experimental design, epidemiology, traditional and new biostatistical approaches, and investigative tools. It presents complete instruction and guidance from fundamental principles, approaches, and infrastructure, especially for human genetics and genomics, human pharmacology, research in special populations, the societal context of human research, and the future of human research. The book moves on to discuss legal, social, and ethical issues, and concludes with a discussion of future prospects, providing readers with a comprehensive view of this rapidly developing area of science. Introduces novel physiological and therapeutic strategies for engaging the fastest growing scientific field in both the private sector and academic medicine Brings insights from international leaders into the discipline of clinical and translational science Addresses drug discovery, drug repurposing and development, innovative and improved approaches to go/no-go decisions in drug development, and traditional and innovative clinical trial designs Book cover Clinical and Translational Science: Principles of Human Research Copyright List of Contributors Acknowledgments 1. Introduction to Clinical Research 1. Introduction to Clinical Research Historical Background Organization of This Book Note References 2. Patient-Oriented Research 2. Patient-Oriented Research Introduction Types of Patient-Oriented Research Observational Studies Mechanism Studies Therapeutic Studies Clinical Trials The Role of Patient-Oriented Research in Translational Research Interaction of Basic Science and Patient-Oriented Research Interaction of Patient-Oriented Research and the Community The Role of the Patient in Patient-Oriented Research Sequence of Investigation Hypothesis Generation Designing the Study Study Population Recruitment and Retention of the Study Population Deciding on Measurements Feasibility Confounding Subject Safety and the Institutional Review Board Database Development Data Analysis Plan Tools of the Patient-Oriented Researcher Funding for Patient-Oriented Research Conclusions References 3. Clinical Trials 3. Clinical Trials Introduction History Phases of Evaluation of Therapies Critical General Concepts Purposes of Clinical Trials Validity Generalizability Trade-off of Validity and Generalizability Expressing Clinical Trial Results Concepts Underlying Trial Design Treatment Effects Are Modest Qualitative Interactions Are Uncommon Quantitative Interactions Are Common Unintended Biological Targets Are Common Interactions Among Therapies Are Not Predictable Long-Term Effects May Be Unpredictable General Design Considerations Pragmatic Versus Explanatory Entry Criteria Data Collection Instrument Ancillary Therapy and Practice Multiple Randomization Adaptive Trial Designs Legal and Ethical Issues Medical Justification Groups of Patients Versus Individuals Blinding Endpoint Adjudication Intensity of Intervention Surrogate Endpoints Conflict of Interest Special Issues With Device Trials Hypothesis Formulation Primary Hypothesis Secondary and Tertiary Hypotheses Intention to Treat Publication Bias Statistical Considerations Type I Error and Multiple Comparisons Type II Error and Sample Size Noninferiority Sample Size Calculations Metaanalysis and Systematic Overviews Understanding Covariates and Subgroups Therapeutic Truisms Study Organization Executive Functions The Steering Committee The Data and Safety Monitoring Committee The Institutional Review Board Regulatory Authorities Industry or Government Sponsors Coordinating Functions Intellectual Leadership Data Coordinating Center Site Management Organization Supporting Functions Information Technology Finance Human Resources Contracts Management Pharmacy and Supplies Randomization Services Project Management Integration Into Practice The Future Acknowledgment References 4. Introduction to Epidemiology 4. Introduction to Epidemiology Introduction: Definition and Role of Epidemiology Measuring Occurrence of Disease Defining Diseases, Outcomes, and Other Health-Related States or Events Calculating Incidence and Prevalence Measuring Risk and Association Calculating Risk Quantifying Associations Types of Epidemiological Studies Cross-sectional Studies Cohort Studies Case-Control Studies Hybrid Study Designs Study Design: Summary Threats to Validity and Reliability Defining and Measuring Threats to Validity and Reliability Selection Bias Information Bias Confounding Interaction Estimating and Avoiding Threats to Validity Estimating and Avoiding Threats to Reliability Moving From Association to Causation Clinical Epidemiology Sex, Gender, Race, and Ethnicity in Epidemiology Conclusion Acknowledgment References Recommended Resources 5. The Patient-Centered Outcomes Research Institute: Current Approach to Funding Clinical Research and Future Directions 5. The Patient-Centered Outcomes Research Institute: Current Approach to Funding Clinical Research and Future Directions Introduction: The Patient-Centered Outcomes Research Institute Patient-Centered Comparative Effectiveness Research Defining Patient-Centered Comparative Effectiveness Research Establishing National Priority Areas for Patient-Centered Comparative Effectiveness Research Patient and Stakeholder Engagement in Research PCORI's Efforts to Engage Patients and Stakeholders in Setting Research Priorities and Selecting Research Applications ... Engaging Patients and Stakeholders in Conducting Research PCORI's Rubric for Patient and Stakeholder Engagement Methodology Standards for Patient-Centered Comparative Effectiveness Research PCORI's Methodology Committee PCORI's Methodology Standards Pragmatic Research Defining Features of Pragmatic Research PCORI's Efforts to Support Pragmatic Research Study Designs for Pragmatic Research and Other Comparative Effectiveness Research Integrating Research Into the Learning Health-Care System The Case for Locating Clinical Research Within Health-Care Delivery Electronic Health Records and Insurance Claims Data The Use of Clinical Registries in Research The National Patient-Centered Outcomes Research Network Conclusion: Vision of Clinical Research in the 21st Century Glossary List of Acronyms and Abbreviations References 6. Health-Care Technology Assessment (HTA) 6. Health-Care Technology Assessment (HTA) Summary Introduction The Evaluation of New Medical Technology: The Producer's Perspective Private, Investor-Owned Producers of New Medical Technology Public Producers of New Technology The Evaluation of New Medical Technology: The End User's Perspective The Ethical Precepts Driving Markets The Implications of the Market Approach for the Producers of New Medical Technology The Evaluation of New Medical Technology: Society's Perspective The General Framework for Technology Assessment in Health Care Defining Net Incremental Benefits Whose Costs and Benefits? The Issue of Discounting Costs and Benefits Should Benefits Be Age Adjusted? Cost-Benefit, Cost-Effectiveness, and Cost-Utility Analysis Cost-Benefit Analysis Cost-Effectiveness Analysis99For a rigorous review of this method, see Garber (2000). Cost-Utility Analysis: Quality-Adjusted Life Years and Disability-Adjusted Life Years Lost Quality-Adjusted Life Years Quality-Adjusted Life Years as Quality-Adjusted Life Expectancy Disability-Adjusted Life Years Lost Change in Quality-Adjusted Life Years and Disability-Adjusted Life Years Lost Achieved Through Health Care Can One Ever Avoid Putting Monetary Values on Health Benefits? Comparing Alternative Treatments Cost-Effectiveness Analysis and Cost-Utility Analysis and National Health Policy Unresolved Controversies on Economic Valuations in Health Care Methodological Issues1010For a thorough review of these methodological issues, see Dolan (2000). Objections on Ethical Grounds Objection on Commercial Grounds References 7. Health Services Research: Translating Discovery and Research Into Practice and Policy 7. Health Services Research: Translating Discovery and Research Into Practice and Policy Introduction What Is Health Services Research and What Are Its Goals? Assessing Medical Interventions: Outcomes, Effectiveness, and Cost-Effectiveness Assessing Medical Interventions Metaanalysis and Data Synthesis Administrative Claims Data Functional Status and Quality of Life Cost-Effectiveness Decision Modeling Medical Decision-Making The Medical Decision-Making Task Types of Medical Decision-Making Reasoning Descriptive Decision-Making Research Prescriptive Decision-Making Preference and Utility Assessment Evidence-Based Medicine Facilitating Appropriate Behaviors Changing Physician and Patient Behavior Communicating and Translating Information Into Decisions and Practice Quality Medical Care Quality Measurement and Assessment Variations in Care Data Sources Medical Errors and Safety Patient Adherence Disparities and Inequities of Care Quality Management and Improvement Conclusions References 8. Measurement of Biological Materials 8. Measurement of Biological Materials Introduction Immunoassays and Immunochemistry Background Basic Principles Enzyme Immunoassays Overview Assay Methodology Other Types of Immunoassays Fluorescent and Chemiluminescent Immunoassays Precipitation and Particle Immunoassays Radioimmunoassay Multiplex Immunoassays Characterization of Immunoassay Performance Mass Spectrometry and Chromatography Background Basic Principles Gas Chromatography Overview Types of Stationary Phases Types of Detectors Liquid Chromatography Overview Types of Stationary Phases Types of Detectors Ultrahigh-Performance Liquid Chromatography Mass Spectrometry Background Methods of Ionization Electron Impact Ionization Chemical Ionization Electrospray Ionization Matrix-Assisted Laser Desorption Ionization Mass Analyzers and Modes of Analysis Mass Spectrometry and Clinical Research Genomics Background Basic Principles and Methodological Considerations Summary and Applications to Clinical and Translational Research Proteomics, Lipidomics, Metabolomics, and Multiomics Background Basic Principles and Methodological Considerations Matrix-Assisted Laser Desorption Ionization Mass Spectroscopy Electrospray Ionization Mass Spectroscopy Applications of -Omic Analysis Profiling Identification Quantification Summary and Applications to Clinical and Translational Research Conclusion References 9. Imaging Tools in Clinical Research: Focus on Imaging Technologies 9. Imaging Tools in Clinical Research: Focus on Imaging Technologies Introduction Imaging Technologies Overview Computed Tomography Technological Advances Clinical Care and Research Applications Detection CT Colonography Lung Cancer Screening Coronary Artery Calcium Scoring Diagnosis CT Coronary Artery Angiography Brain Perfusion Lesion Characterization Tumor Staging and Treatment Response Magnetic Resonance Imaging Technological Advances Clinical and Research Applications Detection Breast MRI Lesion Characterization Prostate MRI Chest MRI Brain MRI Staging and Surgical Planning Brain MRI Ultrasound Technological Advances Clinical Applications Detection Obstetric Ultrasound Diagnosis Gynecological Ultrasound Lesion Characterization Breast Ultrasound Liver Ultrasound Treatment Response Nuclear Medicine Single Photon Emission Computed Tomography Positron Emission Tomography Technical Advances Hybrid Systems Molecular Imaging Optical Imaging Optical Imaging Approaches Fluorescence Bioluminescence Optical Imaging Techniques Fluorescence-Guided Surgery Intravascular Fluorescence Imaging Diffuse Optical and Fluorescence Tomography Multispectral Optoacoustic Imaging Conclusion References 10. Imaging Tools in Human Research: Focus on Image-Guided Intervention 10. Imaging Tools in Human Research: Focus on Image-Guided Intervention Introduction Image-Guided Biopsy Breast Lung Prostate Image-Guided Therapy Ablation Radiofrequency Ablation Microwave Ablation Cryoablation Ethanol Ablation Focused Ultrasound Targeted Drug Delivery Hybrid Operating Room Neurosurgery Minimally Invasive Thoracotomy for Lung Nodules Treatment Planning in Radiation Oncology-The Role of the Radiologist Image-Guided Brachytherapy in Prostate and Cervical Cancer Conclusion References 11. Nanotechnology in Clinical and Translational Research 11. Nanotechnology in Clinical and Translational Research Introduction and Historical Perspective History of Nanotechnology in Medicine Rationale for Nanotechnology in Medicine and Research Nanotechnology in Basic Research Applications Supporting Clinical Translation Knockout of Specific Biomarkers and Genes Structural Analysis of Proteins Artificial Substrates to Examine Cellular Functions Clinical Applications of Nanotechnology for Research Nanoparticle-Targeted Drug Delivery Specific Delivery of Agents to Cells That Abnormally Express or Overexpress a Cell-Surface Molecule Dendrimers as Nanoparticle Scaffolds Multifunctional Single Dendrimer Nanodevices for In Vitro Testing Multifunctional Single Dendrimer Nanodevices Biodistribution of Fluorescent Dendrimer Conjugate Targeted Drug Delivery to Tumor Cells Through the Folate Receptor Future of Nanoparticle Targeting Technology Nanoparticles for Analytical Techniques Nanoparticle-Based In Vitro Quantification of DNA Nanoparticle-Based In Vitro Quantification of Proteins Nanoparticle-Based In Vivo Quantification of Proteins Conclusion and Future Directions in Nanomedicine References 12. The Use of Questionnaires and Surveys 12. The Use of Questionnaires and Surveys Introduction The Practice of Questionnaire and Survey Measurement The Emergence of Questionnaire and Survey Measurement in Clinical Investigation Items, Scales, Questionnaires, and Instruments The Role of Psychometrics Questionnaires Used to Assess Patient-Reported Outcomes Choosing the Appropriate Questionnaire The Different Types of Questionnaires Types of Health Outcomes Assessed Using Questionnaires Evaluating Questionnaires and Survey Instruments Reliability, Validity, Sensitivity, and Responsiveness Item Response Theory, Dynamic Questionnaires, and Computer Adaptive Testing Statistical and Analysis Considerations Analysis and Interpretation of Multiple, Hierarchical, and Correlated Scales Interpreting a Minimal Clinically Important Difference Summary and Conclusions Glossary List of Acronyms and Abbreviations References 13. Information Technology 13. Information Technology Introduction Clinical Data Repositories Harnessing the Clinical Enterprise as a Data Source Clinical Data Repositories: A Problematic Data Source The Expanding Use of Preresearch Clinical Registries Design for Research Data Warehouses Metadata Aggregating Data Work Processes Considerations for Warehousing Genomic Data [Also See Chapters 16-19Chapter 16Chapter 17Chapter 18Chapter 19 (Human Genetic ... Research Data Warehouse Versus Population Management Databases Information Technology Support of Participant Recruitment Strategies for Participant Recruitment Reaching Only Interested Participants Identifying Only Eligible Participants Principles of Data Collection Automation and the Human Element Data Validity: Capturing Data With Consistent Metadata Continuous Quality Assurance ``Stand-alone'' Electronic Data Capture Integration With Clinical Documentation Problems With Integrated Models Data Standards Use of Web Standards Content Standards Clinical Trial Management Systems Publicly Available Databases Biomedical Literature Clinical Trials and Research Evidence-Based Medicine The Growing Impact of Big Data and the Cloud Conclusion References Chapter 14 - Principles of Biostatistics Chapter 14 - Principles of Biostatistics INTRODUCTION TYPES OF DATA DESCRIPTIVE STATISTICS Central Limit Theorem A Cautionary Note on the Application of Central Limit Theorem TESTING AND SUMMARIZING RELATIONSHIP BETWEEN TWO VARIABLES p-Value and Confidence Intervals Type I and II Error Rates BASELINE COMPARISONS AND PRIMARY OUTCOME ANALYSIS GENERALIZED LINEAR MODELS Linear Regression Model for the Continuous Data Logistic Regression Model for the Binary Data Ordinal Outcomes Nominal Outcomes Survival Analysis for the Censored Data MODEL BUILDING Distribution of the Explanatory Variables Confounding Interaction Effects Nonlinearity Model Selection Collinearity MULTIPLE COMPARISONS MISSING DATA LINEAR MIXED-EFFECTS MODELS (CLUSTERED OR LONGITUDINAL STUDIES) CONCLUSION REFERENCES 15. Good Clinical Practice and Good Laboratory Practice 15. Good Clinical Practice and Good Laboratory Practice Overview Good Clinical Practice Introduction Definition Rules and Regulations Clinical Practice and Research Key Participants in Clinical Research Sponsor Institutional Review Board Investigator Documentation and Record Keeping Data Management and Presentation Monitoring and Compliance Conclusion Good Laboratory Practice Introduction Definition and Scope Organization and Personnel Management of the Testing Facility Study Director Quality Assurance Unit Quality Assurance Test, Reference, and Control Articles Protocol for and Conduct of a Nonclinical Laboratory Study Reporting of Nonclinical Laboratory Study Results Record Keeping Documentation and Maintenance of Records Storage and Retrieval of Records and Data Retention of Records Disqualification of Laboratory Facility Resources Purposes and Goals of Disqualification Grounds for Disqualification Reinstatement of a Disqualified Testing Facility Conclusion Glossary List of Acronyms and Abbreviations References 16. Introduction to Human Genetics∗ 16. Introduction to Human Genetics∗ Introduction Basic Molecular Genetics DNA Structure DNA Replication Transcription Translation Chromosome Structure and Function Mitosis and Meiosis Mitosis Meiosis Gametogenesis Patterns of Genetic Transmission Single Gene Inheritance (Mendelian Inheritance) Autosomal Dominant Inheritance Penetrance and Expressivity Autosomal Recessive Inheritance X-Linked Inheritance Non-Mendelian Inheritance Genomic Imprinting Mitochondrial Inheritance Digenic Inheritance Anticipation and Triplet Repeat Disorders Multifactorial Inheritance (Polygenic Inheritance) Cytogenetics and Chromosomal Disorders Methods of Chromosomal Analysis Chromosomal Abnormalities Abnormalities of Chromosome Number Abnormalities of Chromosome Structure Microdeletion Syndromes The Human Genome Structure and Organization of the Genome Genetic Variation Mutation and Polymorphism Types of Mutations Single Nucleotide Polymorphisms and Copy Number Variation Genotype-Phenotype Correlations Medical Applications Molecular Diagnostic Testing Approaches to Genetic Testing Indications for Genetic Testing Therapy of Genetic Disease Clinical Phenotype Metabolic Therapies Replacement of Defective Protein Organ Transplantation Small Molecule Therapy Gene-Based Therapies Genetic Counseling Phenotyping and Clinical Research Genotype-Environment Interaction Phenotypic Complexity Approaches to Gene Discovery Conclusion References Bibliography 17. Epidemiologic and Population Genetic Studies 17. Epidemiologic and Population Genetic Studies Introduction Design Issues in Genetic Association Studies Population Issues: Defining a Phenotype and Selecting Epidemiologic Study Design Definition of Phenotype Is the Disease Phenotype Actually a Syndrome? Epidemiologic Study Design Case-Control Studies Cohort or Population Studies Family-Based Studies Comparison of Family-Based Versus Case-Control Studies Genetic Study Design: Genome-Wide Association Study Versus Hypothesis-Driven (Candidate Gene) Approaches Hypothesis-Free Testing: Genome-Wide Association Study Candidate Gene or Region-Based Testing, With a Focus on SNP Selection Reviewing the Past Literature Locating SNP Within the Gene Identifying Linkage Disequilibrium-Tagging SNP Summary on Study Design Interpreting Results of Genetic Association Studies Genotype Quality Control Genotype Completion Rate Reproducible Genotyping Hardy-Weinberg Equilibrium Mendelian Errors and Nonpaternity in Family-Based Studies Correction for Multiple Comparisons Traditional Method: Controlling Family-Wise Error Rate False Discovery Rate Permutation Testing/Empirical Distribution Conditional Power in Family-Based Testing Replication Population Stratification Ethnic Matching of Cases and Controls Structured Association Genomic Control Family-Based Study Design Power Future Directions Emerging Biologic Targets Whole Genome Sequencing Structural Variation (With Emphasis on Copy Number Variations) Expression Epigenetics Integrative Statistical Approaches From Association to Functional Variant Conclusion References 18. Pharmacogenetics of Drug Metabolism 18. Pharmacogenetics of Drug Metabolism Introduction Pharmacogenetics of Drug Metabolism: Historical Aspects Genetic Polymorphisms of Individual Drug-Metabolizing Genes CYP1A2 Clozapine Caffeine Summary CYP2B6 Efavirenz Other Substrates Summary CYP2C8 CYP2C9 Warfarin Phenytoin CYP2C19 Proton Pump Inhibitors Clopidogrel Cyclophosphamide CYP2D6 Substrates Tamoxifen Codeine Antidepressants CYP3A5 Tacrolimus Vincristine N-acetyltransferase 2 Isoniazid Thiopurine Methyltransferase UDP-Glucuronosyltransferase Butyrylcholinesterase Conclusions References 19. Statistical Techniques for Genetic Analysis 19. Statistical Techniques for Genetic Analysis Introduction Genetic Determination of Complex Disease Twin Studies Family Studies Adoption Studies Genetic Linkage Studies Common Genetic Study Designs and Statistical Tests Case-Control Studies Attributes of Case-Control Data Statistical Tests for Case-Control Data Population-Based Studies Attributes of Population-Based Data Common Statistical Tests for Population-Based Data Family-Based Association Studies Attributes of Family-Based Association Studies Common Statistical Tests for Family-Based Data Genomewide Association Studies Population Stratification Adjustment Multiple Testing Adjustment Next-Generation Sequencing Rare Genetic Variant Analysis Rare Variants Defined Rare-Variant Tests Metaanalysis Techniques Gene-by-Environment Analysis Multivariant Approaches Multiple Regression Analyses Discrimination Methods Network Medicine Basic Network Theory Correlation Coexpression Networks Pathway Analyses Integrative Omics Phenotypic Limitations Computer Programs Summary and Conclusions Glossary List of Acronyms and Abbreviations References 20. Introduction to Clinical Pharmacology 20. Introduction to Clinical Pharmacology Introduction: Mechanisms of Drug Disposition and Interactions Transporters and Drug Absorption, Distribution, and Excretion Intestinal Transporters Multidrug Resistance Protein 1 (P-Glycoprotein) Breast Cancer Resistance Protein (Also Known as ABCG2) Hepatic Transporters Organic Anion Transporting Polypeptide Multidrug Resistance Protein 2 (ABCC2) Renal Transporters Blood-Brain Barrier Drug-Metabolizing Enzymes CYP2C9/CYP2C19 CYP2D6 CYP3A4/CYP3A5 Drug-Drug Interactions Clinically Important Drug-Metabolism-Associated Interactions Transporters and Drug Interactions Induction and Regulation of Drug-Metabolizing Enzymes and Transporters Principles of Pharmacokinetics Introduction to Pharmacokinetics Pharmacokinetic Concepts Clearance Volume of Distribution Half-Life Bioavailability Dose Selection Continuous Intravenous Infusion Intravenous Loading Dose Intermittent Dose Administration Conclusion References 21. Adverse Drug Events 21. Adverse Drug Events The Multifactorial Nature of Adverse Drug Events Types of Adverse Drug Events System Errors Linking Events to Drug Administration-the ``Easy'' Examples Linking Events to Drug Administration-the ``Hard'' Examples Adverse Drug Events Due to Aberrant Drug Disposition (Variable Pharmacokinetics) High-Risk Pharmacokinetics Disease Pharmacogenetics, Drug Disposition, and ADEs Drug Interactions Adverse Drug Events Not Due to Elevated Drug or Metabolite Concentrations Genetics of Variable Pharmacodynamics Genetics to Genomics References 22. Translating Science to the Bedside: The Innovation Pipeline 22. Translating Science to the Bedside: The Innovation Pipeline Realities of the Marketplace What Are the Phases Involved in Taking Ideas/Discoveries to the Patient's Bedside? What Are the Critical Issues to Con ... How Does This Differ for Various Types of Technology? What Are the Market Pressures for Devices, Software, Diagnostics, The ... What Funding Sources Support Development and Creation of Products and Services? What Are the Roles of Government, Philanthropy, and Industry? Types of Relationship: Sponsored Research, Grants, Codevelopment, and Gifts What Resources Are Available at Academic Health-Care Systems to Help Translational Researchers Bring Products and Technolog ... Ideas and Innovations What Is Intellectual Property? What Is a Patent? How Do I Protect My Idea? Who Owns My Invention? What Is a Copyright? Why Are Patents and Copyrights Important? What Are the Options for Getting an Idea to Market? How Far Must an Idea Progress Before It Is Ready for Commercialization? What Is a Royalty? How Do Companies Decide Economic Feasibility? Working With Industry The Academic Health-Care System as a ``Living Laboratory'' How Can Academic-Industry Relationships Yield Mutual Value and Benefit Through Joint Intellectual Effort? What Makes Academic Health-Care Systems a Unique Resource for Industry? What Are the Characteristics of Effective Strategic Alliances? How Are Strategic Academic-Industry Relationships Developed and Structured? How Can I Get Outside Companies Interested in My Idea? Common Challenges Entrepreneurship Market Opportunity: What Problem Am I Solving? Technology: What Is the Status of the Core Technology? Financial: How Much Money Will It Take to Get This Idea to Market? Where Will It Come From? Management: How Do I Think About the Right People, Skills, and Change of Control? Legal and Regulatory Affairs: What Kind of Help Do Entrepreneurs Need at the Early Stages? Clinical Evaluation of Innovative Products How Does Clinical Evaluation Differ From Earlier Stages of Innovation? How Is the Complex Relationship Between Safety and Innovation Managed? What Are the Role and Responsibilities of the Principal Investigator? What Are the Roles and Responsibilities of the Sponsor? What Is the Role and Responsibility of the Food and Drug Administration? How Do Academic Health Centers Support and Guide These Roles? Why Is a Clinical Trial Agreement Needed? How Do I Get Started? Conflicts of Interest What Are Conflicts of Interest? Required Components of Conflict of Interest Policies Food and Drug Administration Public Health Service and National Science Foundation Regulations False Claims Act Fraud and Abuse Laws Tax-Exempt Status Guidance From Professional Organizations Professional Journals Institutional Policies of Academic Health-Care Systems Translating Science to the Bedside Cores in Academic Health Centers How the Innovation Office Help Partners HealthCare Researchers The Important Link With Industry How the Partners Innovation Funds Assist Innovators The Commercialization of Information Technology Material Transfers, Research Grants, and Patents The Operating Philosophy of Partners HealthCare Innovation Summary Statutes and Federal Regulations Cases ENDNOTES References 23. Regulatory Environment 23. Regulatory Environment Introduction The US Food and Drug Administration Overview Organization Legal Authority Nonclinical Testing The Investigational New Drug Application Is an Investigational New Drug Application Required? Types of Investigational New Drug Applications The Investigational New Drug Application Review Process Maintaining the Investigational New Drug Application Guiding Drug Development The Marketing Application Efficacy, Safety, and the Marketing Application The Marketing Application Review Process FDA Decision Regarding Approvability of the Marketing Application Expanded Regulatory Authority on Postmarket Drug Safety Risk Evaluation and Mitigation Strategies Required Postmarketing Studies or Trials Postmarketing Safety Labeling Changes Other Regulatory Agencies Conclusions Glossary List of Acronyms and Abbreviations Acknowledgments References 24. Ethical Issues in Translational Research and Clinical Investigation 24. Ethical Issues in Translational Research and Clinical Investigation Introduction The Ethical Dimension of Scientific Inquiry Responsibility in Science and Society Responsibilities of Scientists Societal Responsibilities 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 Research Risks, Harm, and Injury Benefits Special Populations Issues in Collection of DNA and Other Biospecimens for Research Regulation of Research and Protection of Subjects Research and Regulations in the United States The Role of the Sponsors Nongovernmental Agencies and Associations Public Perception of Clinical Research Protection of Human Subjects Review and Oversight Institutional Review Boards and Ethics Committees Data and Safety Monitoring Boards, Medical Monitors, and Subject Advocates Medicolegal Framework, Liability, and Risk Management Individuals and the Clinical Research Process Motivation and Expectations of the Volunteer Subject Motivation of the Scientist and Conflicts of Interest Professionalism in Clinical Research References 25. Clinical Research in the Public Eye 25. Clinical Research in the Public Eye Introduction The Cultural Context of Research The Lens of Health and Health Care Shifting Power to the Patient Public Input and National Institutes of Health Public Perception of Research Privacy Issues The Internet and an Empowered Public Continuing Challenges Electronic Media Technology Changes Everything Research Information and the News Media: Scientists' Role The Celebrity Factor Unrealistic Expectations? Science and Politics The Small Voice of Science: Stepping Up to Strengthen It The Role and Influence of the White House How Congress Influences Medical Research Making the Case for Research to Congress The Role and Influence of Patient Advocacy Organizations The Role and Influence of Philanthropy Public-Private Collaboration Conclusion Acknowledgment References 26. Research in Special Populations: Acute Illnesses; Critical Care; and Surgical Patients 26. Research in Special Populations: Acute Illnesses; Critical Care; and Surgical Patients Introduction Trial Design Type of Study Selecting a Control Group Placebo-Controlled Studies in Surgical Patients or Nonsurgical Invasive Procedures Usual Care in Critically Ill Patients Studies Comparing Usual Care Components Protocolized Nonstudy Treatment Informed Consent Surrogate Informed Consent Waiver of Consent in Emergency Research Outcomes Associated Versus Attributable Outcomes Endpoints Adverse Events Conclusion References 27. Research in the Emergency Care Environment 27. Research in the Emergency Care Environment Introduction The Environment and Uniqu Clinical and translational science are fields devoted to investigating human health and disease, interventions, and outcomes for the purposes of developing new treatment approaches, devices, and modalities to improve health. New molecular tools and diagnostic technologies based on clinical and translational research have lead to a better understanding of human disease and the application of new therapeutics for enhanced health. This book is designed as the most authoritative and up-to-date resource for the broad range of investigators in various medical specialties taking on the challenge of clinical and translational science. Prepared with an international perspective, Clinical and Translational Science begins with experimental design and investigative tools to set the scene for readers. It then moves on to human genetics and pharmacology with a focus on statistics, epidemiology, genomic information, drug discovery and development, and clinical trials. Finally, legal, social, and ethical issues of clinical research are discussed concluding with a discussion of future prospects to provide readers with a comprehensive view of this developing area of science. Discusses practical biological, physiological, cellular, and therapeutic applications for one of the fastest growing fields in private practice and academic medicine. Includes contributions from international leaders providing insight into background and future understanding for clinical and translational science. Presents the structure for complete instruction and guidance on the subject from fundamental principles, approaches and infrastructure to human genetics, human pharmacology, research in special populations, the societal context of human research, and the future of human research