Clinical and Translational Science_Principles of Human Research -Elsevier

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 Unique Challenges of Emergency Care Research
Examples of Early Success
Building an Emergency Care Research Site
Funding of Infrastructure in the Emergency Care Environment
The Role of Industry
Implementation of Emergency Care Research
Recruitment
Identification of Subjects
Consent and Enrollment
Trial Design Considerations
Retention of Patients and Strategies to Enhance Follow-Up
Conclusion
References
28. Psychiatric Disorders
28. Psychiatric Disorders
Introduction
Diagnostic Issues
Adults
Special Age- and Gender-Based Populations
Types of Studies
Epidemiological
Observational
Mechanism and Physiology
Disease Mechanisms
Treatment
Translational Research
Tools
Behavioral Measures
Biological Measures
Imaging
Genetics
Statistical and Design Issues
Power
Predictors and Moderators
Special Issues
Treatment Studies
Introduction
Informed Consent
Placebo Response
Defining Outcome
Blinding
Psychotherapy Studies
Behavioral Research in Medical Disorders
A Practical Schematic Approach (Fig. 28.1)
Summary
References
29. Research in Special Populations: Geriatrics
29. Research in Special Populations: Geriatrics
Introduction
What Is Different About Aging Research?
Disease and Aging
A Conceptual Model to Account for the Causes and Consequences of Altered System Structure and Function With Aging
The Effect of Aging on Practical Aspects of Clinical Research
How an Aging Perspective Affects Research Topics and Approaches
Overview
Translational Research
Clinical Trials
Population-Based Research
The Effect of Aging on the Pragmatics of Research
Overview
Samples
Measures
Important Measures for Aging Populations
Interventions
Analysis
Conclusions and Recommendations
References
30. Clinical Research in Neurology
30. Clinical Research in Neurology
Introduction
Features Unique to Neurologic Diseases
The Challenges
Target Selection
Animal Models
Blood-Brain Barrier
Intrathecal Administration
Biomarkers
Endpoints
Disease Examples
Multiple Sclerosis
Alzheimer Disease
Amyotrophic Lateral Sclerosis
Glioma
Acute Ischemic Stroke
Conclusion
References
31. Research in Pediatrics
31. Research in Pediatrics
Introduction
What Is Different About Pediatric Research?
Developmental Physiology
Absorption
Distribution
Metabolism
Elimination
Limitations Related to Body Size
Orphan (Rare) Diseases
Population Available for Study Is Smaller in Children Than in Adults
Small Numbers Mean Multicenter Trials Are Usually Required
Lack of Pediatric Guidelines for Most Drugs
Need for Very Long-Term Follow-up to Determine Outcomes
Late Effects of Childhood Cancer Treatment
Outcome of Premature Infants
Strategies Used During Neonatal Cardiac Surgery
Pediatric Conditions as Focus of Inquiry
Prematurity
Childhood Cancers That Do Not Occur in Adults
Regulatory and Ethical Environment for Pediatric Research (see also Chapters 23 and 24)
Risk Categories
Assent/Permission Procedures
Conclusion
Statutes and Regulations
Cases
References
32. Cancer as a Paradigm for Translational and Clinical Biomedical Research
32. Cancer as a Paradigm for Translational and Clinical Biomedical Research
Introduction
Cancer: From the Edwin Smith Papyrus to the Molecular Genetic Era
Defining Subgroups in Cancer
A Genetic Definition of Cancer
Translation of Cancer Gene Expression Profiling to the Clinic
Massive Parallel DNA Sequencing: Deciphering the Complexity of Cancer
Early Beginnings of Cancer Genomics
The Cancer Genome Atlas
Cancer Drivers and Personalized Medicine
Targets in Cancer Therapy
What Makes a Molecule a Good Target Candidate?
Oncogene Addiction
Druggable Versus Nondruggable Targets
From the Bench to the Bedside
Biomarkers and Clinical Trials
Biomarkers
Clinical Cancer Research
Current Strategies in Molecular Targeted Therapy
The Crusade to Overcome Drug Resistance in Cancer
Tumor Heterogeneity
Mechanisms of Resistance to Targeted Therapies and Future Perspectives in Drug Development
List of Acronyms and Abbreviations
References
33. Maintaining an Emphasis on Rare Diseases With Research Initiatives and Resources at the National Center for Advancing Trans ...
33. Maintaining an Emphasis on Rare Diseases With Research Initiatives and Resources at the National Center for Advancing Trans ...
Introduction
Translational Science Spectrum
Definition of Rare Diseases
International Classification of Diseases
Evolving Approaches to Rare Diseases Research
Importance of Genomewide Association Studies
Team Approach
Translational Research Efforts and Resources at NCATS and Other NIH Institutes
The Rare Diseases Clinical Research Network Program-A Model for Collaboration
Rare Diseases Research and Orphan Product Development
RDCRN and Clinical and Translational Science Awards Programs on Education and Training Resources
Assessment of Unmet Medical Device Needs for Rare Diseases
An Even Brighter Path Forward
References
34. Clinical and Translational Science Infrastructure
34. Clinical and Translational Science Infrastructure
Introduction
Reinventing the Clinical Research Infrastructure
Clinical and Translational Science Institutes
National Center for Advancing Translational Sciences
NCATS, CTSA, and Clinical Trial Recruitment Innovation
NCATS' Major Programs and Mission
NCATS' Innovative Technological Programs
NCATS' Rare Diseases Clinical Research Network
Human Genome Project
Clinical and Translational Science Award
Structural Components of CTSA
Scientific Review
Collective Initiatives of the CTSA Consortium
Conclusion
References
35. Education, Training and Career Choices: Training Basic, Clinical, and Translational Investigators
35. Education, Training and Career Choices: Training Basic, Clinical, and Translational Investigators
Introduction
Overview
Didactic Curriculum
Core Competencies Common to All Types of Research
Strength in a Core Content Area
Critical Review
Communication, Manuscript, and Grant Writing
Research Ethics and Responsible Conduct of Research
Study Design and Basic Epidemiology
Core Competencies for T-1 Translational Research
Biostatistics and Data Management
Pharmacology and Drug Development
Genetics/Genomics
Molecular Medicine
Core Competencies for Epidemiologic, Health Outcomes and T-2 Translational Research
Theory and Methods
Measurement
Analysis
Breadth in Exposure and Depth in Skills
Degree-Granting Programs in Clinical or Translational Research
The Mentored Research Experience
Qualities of a Good Mentor
Using a Mentor Effectively
The Mentorship Committee
Career Development Resources
Funding for Training Clinical and Translational Investigators
Further Reading
36. A Stepwise Approach to a Career in Translational Research
36. 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: Engaging Relevant Basic Researchers and Their 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
37. Physician Careers in the Pharmaceutical Industry
37. Physician Careers in the Pharmaceutical Industry
Introduction
Medical-Scientific Positions in the Pharmaceutical Industry
Experimental or Translational Medicine
Clinical Pharmacology
Clinical Research Physician
Medicine Safety and Pharmacovigilance
Medical Affairs
Regulatory Affairs/Regulatory Science
Pharmacoepidemiology and Health Outcomes Research
Project Leadership
Management
Medical Officer: Decisions That Require Medical Input
Safe Administration to Humans
Ethical Conduct of Clinical Research
Medical Information
A Pharmaceutical Career
Summary
References
38. Industry-Sponsored Clinical Research in Academia
38. Industry-Sponsored Clinical Research in Academia
Introduction
The Public Perspective
The Academic Health Center Perspective
The Industry Perspective
The Investigators' Perspective
Matching Industry Needs and Academic Health Center Priorities
Academic Clinical Trials Centers As a Solution
Financing Clinical Trial Centers
Information Technology Solutions to Improve Patient Enrollment
Conclusion
Acknowledgment
References
39. Governmental Support of Research
39. Governmental Support of Research
Introduction
Overview
United States Government Scientific Programs
The National Institutes of Health
Awards to Non-US Institutions From the NIH
The Centers for Disease Control and Prevention
Scientific Programs in Europe, Canada, and Australia/New Zealand
The European Community
National Initiatives
Scientific Programs in Asia, Africa and South/Central America and the Caribbean
The South African Medical Research Council
Balancing the Needs of Intramural and Extramural Research Units
Supporting Capacity Building Through Grants and Scholarships
New Initiatives to Recognize and Support Scientific Merit
Current Support for Clinical and Translational Research
Conclusion
References
Bibliography
40. The Role of Nonprofit, Nongovernmental Funding in Support of Biomedical Research
40. The Role of Nonprofit, Nongovernmental Funding in Support of Biomedical Research
Introduction
Overview of Philanthropic Funding on Biomedical Research
Distinctions Between Different Types of Philanthropic Funders
Voluntary Health Agencies
Independent Foundations
Individual Philanthropists-Major Gifts
Corporate Foundations
Funding Type
Recipient Type
Foundations Attached to Government Agencies
Concepts in Nonprofit Funding
Conclusion
Problem Set
Acknowledgments
Reference
41. Modern Drug Discovery and Development
41. Modern Drug Discovery and Development
Introduction
The Irony of Innovation
The Origins of Drug Discovery
Discovery of Small-Molecule Drugs
Discovery of Biological Therapies
Drug Discovery in the 21st Century
Drug Target Discovery
Lead Identification
Lead Optimization
Preclinical Development
Clinical Development
Phase 1 Studies
Proof of Concept (Phase 2)
Phase 3 Trials
Phase 4 Trials
New Drug Discovery Paradigms
The Move Toward Personalized Medicine
Example of the Personalized Medicine Paradigm in Drug Development
Conclusion
References
42. Pharmaceutical and Biotechnology Sector Support of Research
42. 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
Conclusion
Further Reading
43. The Future of Clinical Research
43. The Future of Clinical Research
Definition of Translational Human Research
Subgrouping of Biological Scientists
The Patient-Oriented Scientist at the Beginning of the 21st Century
The 21st Century and the Future
Novel New Approaches: Big Data and N-of-One
Summary
References