Principles and Practice of Clinical Research

Cover
Principles and Practice of Clinical Research
Copyright
Contents
List of Contributors
Acknowledgments
Preface
1. A Historical Perspective on Clinical Research
	The Earliest Clinical Research
	Greek and Roman Influence
	Middle Ages and Renaissance
	Seventeenth Century
	Eighteenth Century
	Nineteenth Century
	Twentieth Century and Beyond
	Summary Questions
	References
I ETHICAL, REGULATORY AND LEGAL ISSUES
	2. Ethical Principles in Clinical Research
		Distinguishing Clinical Research From Clinical Practice
		Ethics and Clinical Research
		History of Ethical Attention to Clinical Research
			Benefit to the Individual
			Benefit to Society
			Protection of Research Subjects
			Research as a Benefit
			Community Involvement in Research
		Codes of Research Ethics and Regulations
		Research on Bioethical Questions
		Ethical Framework for Clinical Research
			Value and Validity
			Fair Subject Selection
			Favorable Risk/Benefit Ratio
			Independent Review
			Informed Consent
			Respect for Enrolled Subjects
		Ethical Considerations in Randomized Controlled Trials
		Conclusion
		Summary Questions
		References
	3. Integrity in Research: Principles for the Conduct of Research
		Guidelines and Principles for the Conduct of Research
		Scientific Integrity and Research Misconduct
		Responsibilities of Research Supervisors and Trainees
		Data Management, Archiving, and Sharing
			Data Management
			Archiving
			Data Sharing
		Research Involving Human and Animal Subjects
		Collaborative and Team Science
		Conflict of Interest and Commitment
		Peer Review
		Publication Practices, Responsible Authorship, and Results Reproducibility
			Publication Practices
			Authorship
			Reproducibility
		Study Questions
		Acknowledgments
		References
		Further Reading
	4. Institutional Review Boards
		Historical, Ethical, and Regulatory Foundations of Current Requirements for Research Involving Human Subjects
			Historical Foundations
			Ethical Foundations
			Regulatory Foundations
		Institutional Review Boards
			Key Concepts and Definitions From the Common Rule
				Research
			Exempt Research Activities
			Minimal Risk and Expedited Review Procedures
			Institutional Review Board's Review of Research
				Institutional Review Board Membership
				Criteria for Institutional Review Board Approval of Research
				Continuing Review of Research
		Clinical Researchers and Institutional Review Boards
		Evaluation and Evolution of the Current System of Research Oversight and Institutional Review Boards
			Proposed Changes to Current Oversight of Research With Human Subjects
			Critique and Proposed Changes to Institutional Review Board Operations
		Conclusion
		Summary Questions
		References
	5. Accreditation of Human Research Protection Programs
		A Brief History
		Principles of Accreditation
			What AAHRPP Expects From Organizations
			What Organizations Can Expect From AAHRPP
		Human Research Protection Programs: The Shift to Shared Responsibility
		The Accreditation Standards
			Domain I: Organization
			Domain II: Institutional Review Board or Ethics Committee
			Domain III: Researcher and Research Staff
		Steps to Accreditation
		Value of Accreditation
		Summary Questions
		References
	6. The Regulation of Drugs and Biological Products by the Food and Drug Administration
		Background
		Mission and Terminology
		Drug and Biological Product Life Cycle
			Discovery/Nonclinical Investigation
			Clinical Trials
			Responsibilities and Documentation
				Sponsors
				Investigators
				Clinical Protocol
				Institutional Review Board
				Food and Drug Administration
				Investigator Brochure
				Investigational New Drug Safety Reports
			Marketing Approval/Licensure
				Pre-New Drug Application/Biologics License Application Submission
				Application
				Food and Drug Administration Review
			Postapproval
		Compliance
		Summary
		Summary Questions
	7. International Regulation of Drugs and Biological Products
		Introduction
		Background
			Early Operations and Achievements of International Conference on Harmonisation
			Recent Evolution and Reforms
			Membership in the New International Council on Harmonisation
			Organization of the New International Council on Harmonisation
			Financing the New International Council on Harmonisation
		Overview of the International Council on Harmonisation Technical Harmonization Process
			Nomination and Selection of Topics for Harmonization
			International Council on Harmonisation Five-Step Harmonization Procedure
		International Council on Harmonisation Guidelines Most Relevant to Clinical Research
		Future Work in Regulatory Harmonization
		References
	8. Clinical Research in International Settings: Opportunities, Challenges, and Recommendations
		Introduction
		Challenges
			Inadequate Human Resources
			Deficient Research Infrastructures
			Subpar Health-Care Systems
			Information Gaps
			Political Instability, Civil Disorders, and Natural Disasters
			Economic and Seasonal Migration
			Physical Barriers
			Study Participant Characteristics
			Ethical Issues
		Recommendations
			Understand the Local Setting
			Train, Mentor, and Closely Supervise
			Develop and Enhance Local Institutional Review Board Capacity
			Develop Office for Sponsored Research/Office of Clinical Research
			Prepare Data Safety and Monitoring Plan for Adverse Events
			Provide Ancillary Care
			Use Technology for Effective Communication
			Have Long-Term Plans
			Integrate With Existing Infrastructure
		Conclusion
		Summary Questions
		References
	9. The Role and Importance of Clinical Trial Registries and Results Databases
		Introduction
		Background
			Definitions
			Rationale for Clinical Trial Registration and Results Reporting
			History of ClinicalTrials.gov
		Current Policies
			Policies Affecting Clinical Trials in the United States
			International Landscape
		Registering Clinical Trials at ClinicalTrials.gov
			Data Standards and the Minimal Data Set
			Points to Consider
				Interventional Versus Observational Studies
				What Is a Single Clinical Trial?
				Importance of the Protocol
				Keeping Information Up-to-Date
		Reporting Results to ClinicalTrials.gov
			Data Standards and the Minimal Data Set
			Points to Consider
				Data Preparation
				Review Criteria
				Relation of Results Reporting to Publication
			Key Scientific Principles and Best Practices for Reporting
				Issues in Reporting Outcome Measures
				Issues Related to Analysis Population
		Using ClinicalTrials.gov Data
			Intended Audience
			Search Tips for ClinicalTrials.gov
			Points to Consider When Using ClinicalTrials.gov to Study the Overall Clinical Research Enterprise
		Looking Forward
		Conclusion
		Summary/Discussion Questions
		References
	10. Data and Safety Monitoring
		Why Monitor?
		Who Monitors?
			Data and Safety Monitoring Board
			History of Data and Safety Monitoring Boards
			When Is a Data and Safety Monitoring Board Needed?
		What to Monitor?
			Monitoring Participant Safety
			Monitoring Trial Conduct
				Participant Flow
				Participants' Baseline Characteristics
				Randomization Outcome
				Regulatory Compliance
				Trial Performance
					Protocol Compliance by Research Staff
					Recruitment
					Participants' Treatment Adherence (Treatment Exposure)
					Data Completeness (Availability of Primary and Other Key Endpoints)
					Attendance at Follow-Up Visits (Retention)
				Data Quality
					Flags and Triggers
			Interim Analyses
				Sample Size Recalculation
					Sample Size Recalculation Based Only on Nuisance Parameters
					Sample Size Recalculation Based on Nuisance Parameters and Observed Treatment Effect
				Interim Analyses for Efficacy, Futility, and/or Harm
					Sequential Designs (Also Known as Group Sequential Tests or Repeated Significance Tests)
					Stochastic Curtailment Tests
		When and How Often to Monitor?
		Special Topics
			General Structure of Data and Safety Monitoring Board Meetings
			Masking of the Data and Safety Monitoring Board
		Summary
		Summary Questions
		Acknowledgments
		References
	11. Unanticipated Risk in Clinical Research∗
		The Reasons
		The Drug
		The Target
		The Trials
		Cassandra Revealed
		Extended Studies
		Fialuridine Toxicity
		Reassessing the Preclinical Studies
		Research Oversight
		The Investigations Begin
		Scientific Misconduct
		The Food and Drug Administration
		The National Institutes of Health
		The Institute of Medicine
		The Media
		The Congress
		The Law
		Epilogue
			Drug Development
				Is Preclinical Testing of New Drugs a Reliable Predictor of Toxicity?
				Are Patients in Drug Trials Monitored Carefully and Objectively Enough?
			Clinical Research Training
			Personal Perspectives
		Acknowledgments
		References
		Further Reading
	12. Legal Issues in Clinical Research
		INTRODUCTION
		PROTECTING INDIVIDUAL PARTICIPANT INTERESTS
			Independent Review and Monitoring
			Informed Consent, Surrogate Consent, Advance Directives, and Children's Assent
				The Content of Informed Consent Processes
				Who Can Provide Informed Consent—Adults
				Who Can Provide Informed Consent—Children
		SPECIAL PROTECTIONS FOR FETAL TISSUE, HUMAN EMBRYOS, AND HUMAN EMBRYONIC STEM CELLS
		CONFLICT OF INTEREST AND FINANCIAL DISCLOSURE
		PUBLIC TRANSPARENCY: REGISTRATION AND RESULTS REPORTING
		RECORDKEEPING AND PRIVACY PROTECTION
			Record Keeping Generally
				Storing and Using Research Data—Health Insurance Portability and Accountability Act, the Privacy Act, and Certificates of C ...
		DATA SHARING AND INDIVIDUAL CONSENT
		CONCLUSION
		SUMMARY/DISCUSSION QUESTIONS
		References
	13. National Institutes of Health Policy on the Inclusion of Women and Minorities as Subjects in Clinical Research
		National Institutes of Health Policy
		Scientific Considerations and Peer Review
		Role of the Institutional Review Board
		Challenges to Enrolling Volunteers
		Women of Childbearing Potential, Pregnant Women, and Children
		Demographic Trends in Clinical Trial Participation
		What Have We Learned?
		Conclusion
		Summary Questions
		References
		Further Reading
	14. Clinical Research: A Patient Perspective
		The Patient–Scientist Partnership
			A Good Start
		Walking Away: Why Patients Refuse to Participate in Clinical Trials
			Why African Americans Are Underrepresented in Clinical Trials
			Why the Elderly Are Underrepresented in Clinical Trials
		The Trial Begins: Understanding the Patient Experience
			The Worst News
			A New World
			The Lay Expert
		Understanding the Caregiver
		The Role of the Patient Representative
		The Role of Palliative Care
		Managing Difficult News
		Effective Patient Communications: Recommendations and Considerations
		The Assertive Patient: Ally in Scientific Research
		Conclusion
		Further Reading
II STUDY DESIGN AND BIOSTATISTICS
	15. Development and Conduct of Studies
		Development and Conduct of Studies
		How to Choose a Study Design
		Development and Importance of a Study Protocol
			Statement of Design
			Study Sample
			Inclusionary and Exclusionary Criteria
			Identifying and Defining the Outcomes of Interest
			Dosing/Intervention Intensity
			Definition of Treatment/Intervention Development
			Masking/Blinding
			Data Collection
			Recruitment and Retention
			Data Analysis
				Overall Analyses
				Subgroup Analysis
			Protocol Modifications
			Authorship
		Equipoise
		Manual of Operating Procedures
			Recruitment and Retention
			Adherence
			Masking
			Dose Ranging
			Laboratory Methods and Measurement Error
			Treatment Fidelity
		Reporting the Results
		Conclusions
		Summary Questions
		Acknowledgments
		Disclosures
		References
	16. Writing a Protocol
		Introduction
		Regulatory Oversight
		Writing a Protocol
			Clinical Trials
		Elements of a Protocol
			Key Protocol Components
				Precis
				Introduction or Background
				Hypotheses and Objectives
				Study Design and Methods
					Recruitment
					Screening
					Procedures
				Risks, Discomforts, and Inconveniences
				Protocol Risk Category Determination
				Protocol Benefit Category Determination
				Overall Benefit-to-Risk Ratio Determination
				Data and Safety Monitoring
				Quality Assurance Monitoring
				Unanticipated Problem, Adverse Event, and Deviation/Violation Reporting
				Study Population: Eligibility Criteria
					Vulnerable Populations
				Alternatives to Participation
				Privacy
				Confidentiality
				Statistical Analysis
				Management of Data and Samples
				Qualifications of Investigators
				Legal Agreements
				Conflict of Interest
				Compensation
				Consent Process and Documents
					Persons Providing Consent
					Individuals Obtaining Consent
					Consent Process
					Consent Form
				References
				Appendices
		Summary
		Acknowledgments
		References
	17. Design of Observational Studies
		Introduction
		Ecological (Correlational) Studies
		Case Reports and Case Series
			Objectives and Design
			Observations and Analysis
			Advantages and Disadvantages
		Single Time Point Studies: Cross-sectional Studies, Prevalence Surveys, and Incidence Studies
			Objectives and Design
			Observations and Data Analysis
			Advantages and Disadvantages
		Case-Control Studies
			Objectives and Design
			Observations and Data Analysis
			Advantages and Disadvantages
		Cohort Studies: Retrospective, Prospective, and Studies Nested Within a Cohort
			Objectives and Design
				Nonconcurrent, Historical, or Retrospective Cohort Studies
				Concurrent or Prospective Cohort Studies
				Nested Case-Control Studies
				Nested Case-Cohort Studies
			Observations and Data Analysis
			Advantages and Disadvantages
		Odds Ratios, Risk Ratios, Relative Risks, and Attributable Risk
		Mistakes, Misconceptions, and Misinterpretations
			Always Trusting Bivariate Associations Based on Observational Study Data
			Assuming Odds Ratios and Relative Risks Will Have a Similar Magnitude
			Misinterpreting Relative Measures
			Implying Causation (Even When We Do Not Mean to Do It)
			Confusing Causation, Prediction, Association, and Confounding
			Assuming Observational and Randomized Studies Never Agree
			Trying to Design a Randomized Study When We Need an Observational Study
			Assuming an Observational Study Is “Safe” and Does Not Need External Monitoring
		Conclusions
		Questions
		Acknowledgments
		Disclosures
		References
	18. Design of Clinical Trials and Studies
		Design of Clinical Trials
		The Purpose of Clinical Trials and Clinical Studies
		Understanding the Spectrum of the Research Continuum
			Phase I Studies
			Phase II Studies
			Phase III Studies
			Phase IV Studies
			Dissemination and Implementation Studies
			Comparative Effectiveness Research
			Explanatory Versus Pragmatic Trials
			Quasiexperimental Studies
		Clinical Trial Designs
			Crossover Designs
			Enriched Enrollment Designs
			Factorial Designs
			Parallel Groups Designs
			Sequential Trial Designs and Interim Analyses
			Group-Randomized Trial Designs
			Adaptive Treatment Designs
		Critical Issues in Clinical Study Design
			Blinding or Masking
			Intervention Development
			Choosing the Comparison Group
		Control Groups
			Wait-List Control
			Time and Attention Control
			Placebo Control
			Sham Control
			Usual and Standard Care Controls
			Multiple Control Groups
		Placebo Responses
			Background
			Identifying Placebo Responders
		Mistakes and Misconceptions
			Not Looking at the CONSORT Statement Before, During, and After a Study
			Waiting Until the Large Definitive Study to Worry About the Details
				Failing to Increase the Treatment Effect
				Failing to Decrease the Variance
			Not Taking Care When Choosing a Control Group
			Always Assuming Placebo Groups Are Unethical
			Assuming Placebo Treatment Is (Im)Possible in Long-Term Studies
			Confusing Placebo Response and Regression to the Mean
			Using a Factorial or Partial Factorial Design Instead of a Parallel Group Design
			Assuming Small, Open-Label, Nonrandomized, Uncontrolled Studies Offer No Evidence
		Conclusions
		Summary Questions
		Acknowledgments
		Disclosures
		References
		Further Reading
	19. The Role of Comparative Effectiveness Research
		Introduction
		A History of Comparative Clinical Effectiveness Research
		The Patient-Centered Outcomes Research Institute
		The Role of Comparative Clinical Effectiveness Research in the Nation's Medical Research Enterprise
		The Methods of Comparative Clinical Effectiveness Research
			Getting the Research Question Right
			Choosing the Study Population
			Selecting Appropriate Interventions and Comparator(s)
			Choosing Clinical Outcomes to Be Measured
			The Role of Engagement in Specifying Research Questions
		Study Designs for CER Studies
			Experimental Study Designs for CER
			Observational Study Designs for CER
			Cohort Designs
			Adjusting for and Avoiding Confounding in Observational CER Studies
			Assessing Treatment Heterogeneity
		Evidence Synthesis in CER
		Building a National Infrastructure for the Conduct of Comparative Effectiveness Research
		Conclusions
		References
	20. Using Large Data Sets for Population-Based Health Research
		Introduction
		What Are the Original Sources for These Data?
		Uses of Secondary Data in Health Research
			Monitoring Secular Trends
			Health Disparities Research
			Geographic Variation
			Evaluating Specific Diseases and Treatments
		Strengths
		Limitations (and Solutions)
			Data Quality
			Missing Data
			Lack of Clinical Detail
			Data Mining and Statistical Significance
			Generalizability and the Ecological Fallacy
		Surveys
		Linking Data Sets
		Ethical Considerations
		Future Directions and Conclusions
		Summary Questions
		References
	21. Measures of Function and Health-Related Quality of Life
		Introduction to Patient-Reported Outcomes, Measures of Function, and Health-Related Quality of Life
		Systematic Reviews
			Standard Systematic Reviews
				Scoping Reviews
				Alternative Reviews
		Outcomes: Functional Measures and Patient-Reported Outcomes
			Role of Patient-Reported Outcomes in Functional Outcome Measures
			Measurement and Methodology
				Psychometric Properties
					Methodology in Measurement Development
						Factor Analysis
						Item Response Theory
					Use of Patient-Reported Outcomes in Large Data Sets
				National Health and Nutrition Examination Survey
			Function
				Function—Measurement and Use
				Utility of Functional Measures
				Features to Look for in a Functional Measure
					Reliability, Validity, and “Value-Added” Features
				Examples of Functional Measures
				Selecting a Functional Measure
					Selection Considerations: Diagnostic Criteria Versus Functional Measures
					Example: Liver Disease Versus Symptoms Related to Function
			Disease-Specific Measures
				Examples of Disease-Specific Measures
					Case Example: Chronic Liver Disease Questionnaire75
		Summary Questions
		References
		Further Reading
	22. Meta-analysis of Clinical Trials
		Techniques of Meta-analysis
			Formulating the Question
			Defining Eligibility Criteria
			Identifying Studies and Data Extraction
			Statistical Analysis
				Determining a Measure of Treatment Effect for Individual Studies
				Combining Studies: Fixed Versus Random Effect
				Heterogeneity
				Publication Bias
				Subgroup Analysis and Metaregression
				Software
				Reporting and Interpreting Results
		Meta-analysis of Clinical Trials of Antiinflammatory Agents in Sepsis
			Background: The Role of Inflammation in Mediating Sepsis
			Formulating the Question
			Defining Eligibility Criteria, Identifying Studies, and Data Extraction
			Analyzing the Data
		Conclusions
		Summary Questions
		References
	23. Issues in Randomization
		What Is Randomization?
		Importance of Randomization
		History of the Randomized Trial
		Randomization Methods
			Simple Randomization
			Block Randomization
			Stratified Randomization
			Pseudorandomization Methods
		Issues in Implementation
			Sound Allocation
			Mechanisms of Randomization
			Monitoring
		Special Considerations
			Adaptive Randomization Methods
			Documentation
			Threats to the Integrity of Randomization
		Conclusion
		Summary Questions
		Acknowledgment
		Disclosures
		References
	24. Hypothesis Testing
		Introduction
			Three Motivating Examples
			Statistical Inference
		Basic Concepts in Hypothesis Testing
		Formulation of Statistical Hypotheses in the Motivating Examples
			Hypotheses for the Beta-Interferon/Magnetic Resonance Imaging Study
			Hypotheses for the Felbamate Monotherapy Trial
			Hypotheses for the ISIS-4 Trial: Comparing the Magnesium and No Magnesium Arms
		One-Sample Hypothesis Tests With Applications to Clinical Research
			Tests for Normal Continuous Data
			Determining Statistical Significance
				Critical Values
				Confidence Intervals
				z Tests or t Tests
			Binary Data
				Developing a Test
				Exact Tests
				Confidence Intervals
			Example
		Two-Sample Hypothesis Tests With Applications to Clinical Research
			Tests for Comparing the Means of Two Normal Populations
				Paired Data
				Unpaired Data
			Tests for Comparing Two Population Proportions
		Hypothesis Tests for the Motivating Examples
			Hypothesis Tests for the Beta-Interferon/Magnetic Resonance Imaging Study
			Hypothesis Tests for the Felbamate Monotherapy Trial
			Hypothesis Tests for the ISIS-4 Trial: Comparing the Magnesium and No Magnesium Arms
		Common Mistakes in Hypothesis Testing
		Misstatements and Misconceptions
		Special Considerations
			Comparing More Than Two Groups: One-Way Analysis of Variance
			Simple and Multiple Linear Regression
			Multiple Comparisons
			Nonparametric Versus Parametric Tests
		Conclusion
		Summary Questions
		Acknowledgments
		Disclaimers
		References
	25. Power and Sample Size Calculations
		Introduction
			Basic Concepts
			Notational Conventions
			Review of the Normal and t-Distributions
		Sample Size Calculations for Precision in Confidence Interval Construction
			Confidence Intervals for Means of Continuous Data
			Confidence Intervals for Binomial Proportions
		Sample Size Calculations for Hypothesis Tests: One Sample of Data
			Calculations for Continuous Data Regarding a Single Population Mean
			Calculations for Binary Data Regarding a Single Population Proportion
			Two-Stage Designs for a Single Population Proportion
		Sample Size Calculations for Hypothesis Tests: Paired Data
			Calculations for Paired Continuous Data
			Calculations for Paired Binary Data
		Sample Size Calculations for Hypothesis Tests: Two Independent Samples
			Calculations for Continuous Data With Equal Variances and Equal Sample Sizes
			Calculations for Continuous Data With Unequal Variances or Unequal Sample Sizes
			Calculations for Two Independent Samples of Binary Data
		Advanced Methods and Other Topics
			Alternative Statistics and Sample Size Calculation Methods
			Several Advanced Study Designs
			Retention of Subjects
			Statistical Computing
		Conclusion
		Exercises
		Acknowledgments
		Disclaimers
		References
	26. An Introduction to Survival Analysis
		Introduction
		Features of Survival Data
		Survival Function
			Kaplan–Meier and Product-Limit Estimators
				Calculation and Formula for an Estimate
				Calculation of Variance
			Comparing Two Survival Functions
				Comparing Two Survival Functions at a Given Time Point
				Comparing Two Survival Functions Using the Whole Curve: Log-Rank Test
				Example 1: Chronic Active Hepatitis Study
				Stratified Log-Rank Test
			Proportional Hazards Model
				Calculation and Formulas
		Common Mistakes
		Conclusion
		Questions
		Acknowledgments
		Disclaimer
		References
	27. Intermediate Topics in Biostatistics
		Special Topics in Trial Design
			Interim Monitoring and Alpha Spending
				Introduction
				Efficacy Boundaries
				Futility
				Summary
			Adaptive Designs
			Superiority, Noninferiority, and Equivalence
			Special Considerations for Sample Size
				Considerations for Early Phase Studies
				Unequal Sample Sizes
		Special Considerations in Data Analysis
			A Trick for Confidence Interval Estimation When No Events Occur
			Data Dependencies
				Correlation
				Relationships in Organization, Space, and Time
			Essential Issues in Microarrays, Functional MRI, and Other Applications With Massive Data Sets
		Regression to the Mean
			Introduction
			What Is Regression to the Mean?
			Examples
				Example 1 Change After Exceeding a Threshold
				Example 2 Placebo Effect
				Example 3 Screening Period Versus Trial Event Rates
			Ways to Address Regression to the Mean
			Summary
		Diagnostic Testing
			Measures of Accuracy
			Considerations for Study Design
			Common Mistakes and Biases
			Summary
		Special Considerations in Survival Analysis
			Changes Over Time in Coefficients and Covariates
				Time-Varying Coefficients or Time-Dependent Hazard Ratios
				Time-Dependent Covariates
			Dependent or Informative Censoring
				Changes in Inclusion/Exclusion Criteria and Nonindependent Censoring
				Competing Risks
				Left and Interval Censoring
			Recurrent Events Analysis
			Sample Size
		Missing Data
			Introduction
			Types of Missing Data
			Methods for Handling Missing Data
			Common Mistakes
			Summary
		Causal Inference in Observational Studies
		Concluding Remarks
		Summary Questions
		Acknowledgments
		Disclaimers
		References
	28. Large Clinical Trials and Registries—Clinical Research Institutes
		Introduction
		History
		Phases of Evaluation of Therapies
		Critical General Concepts
			Validity
			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 Easily Predictable
			Long-Term Effects May Be Unpredictable
		General Design Considerations
			Pragmatic Versus Explanatory
			Entry Criteria
			Data Collection Form
			Ancillary Therapy
			Multiple Randomization
			Pick the Winner
		Legal and Ethical Issues
			Medical Justification
			Groups of Patients Versus Individuals
			Blinding
			Endpoint Adjudication
			Intensity of Intervention
			Biomarkers and 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
		Meta-analysis and Systematic Reviews
		Understanding Covariates and Subgroups
		Therapeutic Truisms
		Operational Organization for Large-Scale Clinical Research
			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 and Regulatory Affairs
		Integration Into Practice
		Controversies and Personal Perspective
			Governmental Regulation Versus Professional Responsibility to Drive the Creation of Evidence
			Composite and Surrogate Endpoints
			Randomized Trials Versus Observational Studies
			Sharing of Information
		The Future
		Summary Questions
		References
III TECHNOLOGY TRANSFER, DATA MANAGEMENT, AND SOURCES OF FUNDING SUPPORT FOR RESEARCH
	29. Intellectual Property and Technology Transfer
		Introduction
		Part One: Intellectual Property Generally
			Background: Intellectual Property Defined
			Patents—Historical Overview
				First Steps: Before the American Revolution
				United States Constitution
				United States, 1789–1951: Systemic Adjustments
				United States: The Modern Framework
					The 1952 Patent Act
					The “Federal Circuit”
					US Patent Reform of 2011
				Patent Treaties
			Modern Philosophy of Patent Law
				Fairness and the “Quid Pro Quo”
				Incentives for Product Development
				Economic Engine
			Core Concepts of US Patent Law
				What Is a Patent?
					Patents Internationally
					Utility, Plant, Design
					Specific Rights Conveyed by Patents
				Substantive Criteria for Patentability
					Patentable Subject Matter
						General Principles
						“Mere Associations:” LabCorp v. Metabolite
						Living Organisms and DNA: From Chakrabarty to Mayo to Myriad
						Algorithms and Software: Benson-Flook-Diehr, State Street, and Bilski
					“Utility” (“Industrial Applicability”)
					“Novelty”
						General Principles
						Competing Claims of First-To-Invent: The “Interference”
					“Nonobviousness”
						General Principles
						“Secondary Considerations”
						“Obvious to Try”
					Written Description, Enablement, and Best Mode
						Written Description
						Enablement
						Best Mode
				Other Key Terms Defined
					“Prior Art”
					“Conception” Versus “Reduction to Practice”
					“Prophetic Conception” Versus “Simultaneous Conception and Reduction to Practice”
					“Inventorship” and “Joint Inventorship”
					Transfers of Ownership: “Assignment” Versus “License”
				Patent Infringement (United States)
					Civil Liability: In General
					Civil Liability: Contributory and Induced Infringement
					Major Defenses
					Specific Exemptions and Immunities
						Research-Use Exemption: Madey v. Duke University
						Generic Drugs: The “Bolar Amendment” and Merck vs. Integra
						The Medical Practitioner Exemption (“Frist-Ganske Amendment”)
						US Government as Infringer
					Remedies: Types and Measures
					“Declaratory Judgment” Actions
					Importation and the International Trade Commission
					Practical Issues of Litigation
			Basic Elements of the Patent Application Process
				Content of a Patent Application
					Specification
					Claims
					Technical Items
					One Invention per Application (“Unity”)
					The Duty of Disclosure and “Inequitable Conduct”
				US Applications: Types and Filing Procedures
					Basic Types of Applications
					Timing Considerations
						Export Control
						Publication
						Patent Life
					Prosecution of a Patent Application
					Options “After Issuance”
				International Applications and Filing Procedures
					Patent Cooperation Treaty Applications
					Regional Patent Offices
					Combining US and Patent Cooperation Treaty Filings
					General Strategy Notes
				Current Major Efforts to Alter US Patent Laws
					International Harmonization
					Patents on Genes and “Mere Associations”
					Abusive Tactics: “Patent Trolls” and “Inequitable Conduct”
					Compulsory Licensing and Breaking Patents
			Copyrights, Trademarks, and Trade Secrets
				Copyrights
				Trademarks
				Trade Secrets
					General Principles
					Key Statutes Relating to Trade Secrets and Federal Employees
		Part Two: Patents and Technology Transfer
			Critical Laws Concerning Patents and Federally Supported Research
				Federal Funding of Private “Extramural” Research: The Bayh–Dole Act
					History and Philosophy
					Organization of Clauses
					Key Concepts—§§ 200 and 201
					Core Terms Required in Bayh–Dole Funding Agreements—§ 202
					§ 202—Reporting Obligations (iEdison and RePORT)
					§ 202—Determination of Exceptional Circumstances
					“March-In”—§ 203
						Case Study: CellPro
						Case Study: Abbott and Pfizer
						Case Study—Genzyme
					Duty of US Manufacture—§ 204
					Funding Agreements Outside the Bayh–Dole Act Involving Patent Rights
				Federal “Intramural” Research: The Stevenson-Wydler Act and the Federal Technology Transfer Act
					History and Philosophy of Stevenson-Wydler and Federal Technology Transfer Act
					Key Concepts and Major Clauses
					Subsequent Supporting Acts
				Patenting and Licensing by Federal Agencies
					Patenting and Licensing by Agency
						Various Agency Missions
						Scope of Licensing Authority
						Exclusive and Coexclusive Licensing—Additional Considerations
						Results
					Inventions by the National Institutes of Health
						Patent and Patent-Related Policies
							General
							Research Tools
							Sharing of Data and Model Organisms
							National Institutes of Health Portfolio Size and Scope
						The National Institutes of Health Licensing Program
							National Institutes of Health General Licensing Policies
							Best Practices for Licensing Genomic Inventions
							Scope of Licensing Authority
							Types and Structure of National Institutes of Health Licenses
							National Institutes of Health Licensing Process—Overview
							After Signature—Royalty Management, Monitoring, and Enforcement
							Success
		Part Three: Technology Transfer Agreements
			Background: Hypothetical Scenario
			The First and Biggest Mistake: Signing the Agreements
				Contract Execution in General
				Scope of Actual Authority of Government Laboratories
			Agreements to Protect Confidentiality
				Background: Trade Secrets
				Secrets and the Government
				Anatomy of a Confidential Disclosure Agreement
			Agreements to Transfer Materials
				The Basic Material Transfer Agreement
					Background
					Anatomy of the Material Transfer Agreement
						Parties
						Materials
						Uses
						Confidentiality
						Rights in the Materials
						Termination
						Warranties and Indemnification
						Inventions: “Reach-Through” Rights
					The Uniform Biological Material Transfer Agreement
					The Clinical Trial Agreement
					Other Key Specialized Material Transfer Agreements
						Materials in Repositories
						Software Transfer Agreements
			Collaboration and Inventions: The Cooperative Research and Development Agreement
				Background
				Cooperative Research and Development Agreement Basics
					Selecting the Collaborator
					Negotiating the Agreement
					Modifications to the Cooperative Research and Development Agreement Language
					Appendix A: The Research Plan
					Financial and Material Contributions
					National Institutes of Health Review of the Agreement
					Execution by the Parties and the Effective Date
					Possibilities
		Conclusion
		Brief Glossary of Critical Terms in Patenting
		Review Questions
		References
	30. Data Management in Clinical Trials
		The Research Team
			Principal Investigator and Subinvestigators
			Research Director/Manager
			Clinical Trials Nurse
			Clinical Research Associate
			Database Administrator
			Statistician
		Data Management
			Data Elements
			Case Report Forms
			Choosing a Database System
			Data Collection
			Sources of Data
			Quality Control of Data
		Auditing
		Unanticipated Problems and Adverse Event Monitoring and Reporting
		Legal and Regulatory Issues Related to Data Reporting
		Follow-Up and Analysis
		Record Retention
		Conclusion
		Summary Questions
		References
	31. Clinical Research Data: Characteristics, Representation, Storage, and Retrieval
		Introduction
		Data as Surrogates
			The Indirect Nature of Clinical Research Data
			Objectivity and Subjectivity of Clinical Data
			Transparency, Rigor, and Reproducibility
			Metadata
		Types of Data
		Data Standards
		Data Capture, Storage, and Retrieval
			Clinical Trials Data Management Systems
			Clinical Data Repositories
		Responsible Stewardship of Data
		Cooperative Sharing Efforts
		Summary
		Summary Questions
		References
	32. Management of Patient Samples
		Introduction
		Successful Research Rests on a Foundation of Careful Planning
		The Role of Pre-analytic Variables in Research Using Patient Specimens
		Training and Accreditation
		The Importance of Good Record Keeping
		Specimen Tracking
		Specimen Collection
		Specimen Handling
		Specimen Transit
		Specimen Storage
		Access to Patient Samples
		Specimen Culling, Transfer of Collections, and Repository Closings
		Summary Questions
		References
	33. Evaluating a Protocol Budget
		Overview
		Institutional Review Board Fees
		Overhead or Indirect Cost
		Determining the Hourly Rate
		The “Per Patient” Budget
		Start-Up Cost and Invoiced Items
		Submitting Your Budget to the Sponsor for Approval
		Areas of Concern
		Walking Away
		Wrapping Up
	34. Getting the Funding You Need to Support Your Research: Navigating the National Institutes of Health Peer Review Process
		Overview of National Institutes of Health
			Mission and Organization of National Institutes of Health
			Responsibilities of National Institutes of Health Staff
			National Institutes of Health Extramural Funding Mechanisms
			National Institutes of Health Funding Announcements
				Funding Opportunity Announcements
				Requests for Applications and Program Announcements in the National Institutes of Health Guide
			Electronic Submission of Applications Through Grants.gov
			Multiple Principal Investigators
		The National Institutes of Health Peer Review Process for Grants
			The National Institutes of Health Dual-Review System
			National Institutes of Health Review “Cycles”
			Assignment of Applications to a Review Group and Funding Institute
			How Are Reviewers Selected?
			How Does the Review Proceed?
			Review Criteria for Research Project Grant Applications
				Core Review Criteria
				Additional Review Criteria
				Additional Review Considerations
			Research Project Grant Applications From New/Early-Stage Investigators
			Possible Scientific Review Group Actions
			Overall Impact/Priority Score and Percentiles
			The Summary Statement Tells You What the Reviewers Thought About Your Application
			Review by National Advisory Councils and Boards
			What Determines Which Applications Are Awarded?
			Confidentiality and Conflict of Interest
		Hints for Preparing Better Grant Applications
			Planning Your Application
				Allow Sufficient Time to Prepare the Application
				Get Help
			Follow the Instructions Closely—Submit a Complete and Carefully Prepared Application
			Hints and Suggestions for Preparing Each Part of Your Application
				SF424 (R&R) Project Summary/Abstract
				PHS 398 Specific Research Plan Component
					Specific Aims
					Research Strategy
				PHS 398 Specific Human Subjects Sections
					Protection of Human Subjects
					Data Safety Monitoring Plan
					Inclusion of Women and Minorities
					Inclusion of Children
				Vertebrate Animals
				Budget and Justification
				Senior/Key Personnel Profiles Component and Biosketches
				Facilities and Other Resources
				Appendix
		Recent Changes to Application Procedures for National Institutes of Health–Funded Clinical Trials—More to Come
		Revising Unsuccessful Applications
			How to Decide Whether to Revise Your Application
			How to Revise and Resubmit Your Application
			What if It Appears That the Study Section Was Inappropriate or Biased?
			What if It Appears That There Was a Procedural Error During Peer Review?
		National Institutes of Health Grant Programs for Clinical Researchers at Various Stages in Their Careers
			Individual Career Development (“K”) Awards
			Mentored Career Development Awards
				Mentored Clinical Scientist Development Award (K08)
				Mentored Patient-Oriented Research Career Development Award (K23)
			Career Transition Awards
				K99/R00 Pathway to Independence Award
				K22 Career Transition Awards
			Independent Scientist Awards
			Midcareer Investigator Award in Patient-Oriented Research
			Exploratory/Development Grant (R21) Applications
			Small Research Grant (R03) Applications
			Loan Repayment Program
		How to Stay Informed About National Institutes of Health Peer Review
			“About Grants” Page (https://grants.nih.gov/grants/about_grants.htm)
			National Institutes of Health Institute/Center Home Pages
			The Center for Scientific Review Home Page (www.csr.nih.gov)
	35. Philanthropy's Role in Advancing Biomedical Research
		Introduction
		Organization of the Philanthropic Sector and Terminology
			Foundations
			Public Charities
			Alliances and Umbrella Organizations Serving the Philanthropic Sector
		History of the Philanthropic Sector
			Private Foundations
			Public Charities and Patient-Oriented Organizations
		Areas of Contribution
			Philanthropic Sector: Areas of Contribution
			Developing Human Capital
			Building Knowledge and Expanding Scientific Disciplines
				Biomedical Imaging and Bioengineering
				Neuroinflammation
				Biomarkers
				Stem Cell Research
			Supporting Institutions
			Stimulating Innovation
			Translating Discoveries into Cures, Therapeutics, and Preventions of Disease
			Establishing Product Development Partnerships
			Fostering Dissemination of Information, Data Sharing, and Patient Engagement
			Advocating for Resources and Policy Changes
		Conclusions and Future Directions
		Summary Questions
		References
IV CLINICAL RESEARCH INFRASTRUCTURE
	36. Identifying, Understanding, and Managing Patient Safety and Clinical Risks in the Clinical Research Environment
		Identifying and Managing Clinical Risk in the Clinical Research Environment
		Building a Road map to Safe and High-Quality Care and Research Support: Applying the Principles of High Reliability in the  ...
		Leveraging Patient Safety and Quality Improvement Techniques in the Conduct of Clinical Research
		Proactively Assessing Clinical and Operational Risk
			Continually Monitoring the Clinical Research Environment for Risk
			Patient Safety and Clinical Event Reporting Systems
		Electronic Surveillance for Errors and System Failures
		Patient Safety and Clinical Quality Measures
		Assessing Clinical Research Participants' Perceptions of the Clinical Research Experience
		Conclusion
		Summary Questions
		References
	37. Clinical Pharmacology and Its Role in Pharmaceutical Development
		Clinical Pharmacology as a Translational Discipline
			Definition and Scope
		Overview of Drug Development
		Current State of Affairs in Drug Development
		Contribution of Clinical Pharmacology
			First in Human Study
				Starting Dose in First in Human Study
				Dose Escalation in First in Human Study
			Identification, Development, and Qualification of Biomarkers and Utilization of Functional Imaging Tools
				Qualifying New Biomarkers
				Safety Biomarkers
				Efficacy Biomarkers and Surrogate End Points
				Functional Imaging Tools Related to Phase 0
			Personalized Medicine
			Design and Conduct of Improved and Rigorous Phase I–II Studies With Adequate Exploration of the Exposure–Response Relationship
			Modeling and Simulation and Model-Based Drug Development
			Advent of Pharmacogenetics and Pharmacogenomics
		The Role of the Regulatory Agency
			FDA and Clinical Pharmacology
			FDA and Drug Safety
			FDA and the Special Populations
		Summary Questions
		References
	38. Career Paths in Clinical Research
		Background
		Student and Resident Training in Clinical Research
		Physician–Scientist Workforce
		Clinical Research Curriculum and Training
		NIH Clinical Center Core Curriculum
		Additional Educational Approaches and Support for Training
		Conclusions
		Summary/Discussion Questions
		References
	39. Clinical Research Nursing: A New Domain of Practice
		Introduction
		Clinical Research Nursing: An Evolving Practice Specialty
		Defining and Documenting the Specialty of Clinical Research Nursing
			Conceptual Framework: The Domain of Practice
			Practice Standards for Clinical Research Nursing
				Standards of Care
				Standards of Practice
			Job Descriptions
			Competency Assessment
			Defining a Core Curriculum
			What About Certification?
		Legal Scope of Practice Issues
			What Regulations Govern Practice and Liability in Clinical Research Settings?
		Tools to Assist a Principal Investigator in Staffing a Study
			Planning a Study in the Clinical Setting
			Assessing the Need for Nursing Support
			Creating the Staffing Plan
			The Concept of “Research Intensity”
		Future Considerations
			Career Potential for Nurses in Clinical Research
			Meeting the Need for Nurses to Fill Clinical Research Roles
			Nursing Role in Community-Based Research
			Supporting the Transition of Nurses Into Clinical Research From Clinical Practice
		Summary/Discussion Questions
		Acknowledgment
		References
	40. The Importance and Use of Electronic Health Records in Clinical Research
		Electronic Medical Record
		Electronic Health Record
		Electronic Health Record Architecture
			Example of an Electronic Health Record Architectural Diagram
			Electronic Health Record System Connectivity at the National Institutes of Health Clinical Center
		Clinical Research Information Systems
		Using an Electronic Health Record in Clinical Research
			Data Characteristics
			Clinical Decision Support Within Electronic Health Record
			Protocol Order Sets Within the Electronic Health Record
				Sample Protocol Map/Research Grid
		Secondary Use of the Electronic Health Record for Clinical Research
		Legislation and the Electronic Health Record
			Health Information Technology for Economic and Clinical Health Act
			Medicare Access and Children's Health Insurance Program Reauthorization Act of 2015
			U.S. Food and Drug Administration Guidance for Electronic Health Record in Clinical Research
		Summary
		Summary Questions
		Terms
		References
		Further Reading
	41. The Clinical Researcher and the Media
		What Makes News in Science and Medicine?
		Published Science—The Media's Bread and Butter
		Novelty
		The Unexpected
		Celebrity
		Controversy
		Impact
		Why Talk to Reporters?
		Why Reporters Want to Talk to You
		Why You Should Talk to Reporters
		Social Media: What to Keep in Mind
		Engaging the Media—The Process
		A Word About Email, the Web, and Social Media
		The Interview
		What if You Are Misquoted?
		What the Public Does Not Know About Science
		Unexpected Questions
		When the News Is Not Good
		A Word About Investigative Reporters
		The Freedom of Information Act
		Embargoes
			The Ingelfinger Rule
		When to Contact Your Communications Office
		Conclusion
		Summary Questions
	42. Information Resources for the Clinical Researcher
		Introduction
		Organization and Features of Information Resources
		Origin
		Content and Structure
		Search Capabilities
		Citation Searching
		Access and Business Models
		Familiarity and Currency
		Biomedical Databases
		Bioinformatics Resources
			Major Bioinformatics Organizations
			Bioinformatics Directories
			Browsers
			Commercial Software
		Data Management
		Data Integration and Precision Medicine
		Bibliometrics
		Bibliographic Managers
		Resource Selection and Search Strategy
		Educational Resources
		Final Notes
		Acknowledgments
		References
1 Answer Key to Summary Questions
	Chapter 1
	Chapter 2
	Chapter 3
	Chapter 4
	Chapter 5
	Chapter 6
	Chapter 8
	Chapter 9
	Chapter 10
	Chapter 12
	Chapter 13
	Chapter 15
	Chapter 17
	Chapter 18
	Chapter 20
	Chapter 21
	Chapter 22
	Chapter 23
	Chapter 24
	Chapter 26
	Chapter 27
	Chapter 28
	Chapter 29
	Chapter 30
	Chapter 31
	Chapter 32
	Chapter 35
	Chapter 36
	Chapter 37
	Chapter 38
	Chapter 39
	Chapter 41
2 Acronyms
	Part I—Ethical, Regulatory, and Legal Issues
	Part II—Study Design and Biostatistics
	Part III—Technology Transfer, Data Management, and Sources of Funding Support for Research
	Part IV—Clinical Research Infrastructure
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
	Y
	Z