Table of Contents
Design
What Is a Pragmatic Clinical Trial?
- Why Are We Talking About Pragmatic Trials?
- The Embedded Pragmatic Clinical Trial Ecosystem
- Differentiating Between Research and Quality Improvement Activities
- Pragmatic Elements: An Introduction to PRECIS-2
- PRECIS-2 Case Study
- Key Considerations for Pragmatic Trials
- Additional Resources
Decentralized Pragmatic Clinical Trials
- What Is a Decentralized Trial?
- What Decentralized Elements Are Used in Pragmatic Trials?
- Community Health Considerations for Decentralized Approaches
- Quality Assurance
Developing a Compelling Grant Application
- Introduction
- Find the Right Program Official and Study Section
- Find the Notice of Funding Opportunity
- Write a Strong Proposal That Addresses Review Criteria
- Special Considerations
- Review Criteria
- Award Status
- Additional Resources
Experimental Designs and Randomization Schemes
- Introduction
- Statistical Design Considerations
- Cluster Randomized Trials
- Alternative Cluster Randomized Designs
- Stepped-Wedge Designs
- Choosing Between Cluster and Individual Randomization
- Covariate-Constrained Randomization
- Pair Matching and Stratification With Cluster Designs
- Concealment and Masking
- Designing to Avoid Identification Bias
- Additional Resources
Endpoints and Outcomes
- Introduction
- Meaningful Endpoints
- Outcomes Measured via the Electronic Health Record
- Inpatient Endpoints in Pragmatic Clinical Trials
- Using Death as an Endpoint
- Outcomes Measured via Digital Health Technology
- Outcomes Measured via Direct Patient Report
Analysis Plan
- Introduction
- Intraclass Correlation
- Unequal Cluster Sizes
- Accounting for Residual Confounding in the Analysis
- Missing Data and Intention-to-Treat Analyses
- Electronic Health Record Data Extraction
- Unanticipated Changes
- Interim Reassessment of Sample Size in Cluster Randomized Trials
- Case Study: STOP CRC Trial
Using Electronic Health Record Data
- Introduction
- Interoperability
- Data as a Surrogate for Clinical Phenomena
- Developing and Refining the Research Questions
- Specific Uses for EHR Data in PCTs
- Estimating and Identifying the Study Population and Assessing Baseline Prognostic Characteristics
- Implementing and Monitoring the Delivery of an Intervention
- Assessing Outcomes
- The Research Question Drives the Data Requirements
- Additional Resources
Building Partnerships and Teams to Ensure a Successful Trial
- Introduction
- Engagement Across Settings and Populations
- Deciding Who to Engage
- Partner Engagement Throughout the PCT Life Cycle
- Advice From Healthcare System Leadership
- Embedded ePCT Team Composition
- Learning Health Systems and Embedded Clinical Trials
- Framework for Health Systems to Assess PCT Participation
- FAQ
Intervention Delivery and Complexity
- Introduction
- Definition of Intervention Complexity
- Intervention Delivery Complexity Tool
- Examples of Tool Output
Patient Engagement
Data, Tools & Conduct
Assessing Feasibility
- Introduction
- Developing the Trial Documentation
- Establishing Close Partnerships With Participating Healthcare System Leaders and Staff
- Delineating the Roles of All Interest Holders to Determine Training Needs
- Pilot Testing
- Feasibility Assessment Scenarios From the NIH Collaboratory Trials
- Spotlight on NIH Collaboratory Trials
- Additional Resources
Acquiring Real-World Data
- Introduction
- Common Real-World Data Sources
- Data Formats
- Acquiring Electronic Health Record Data
- Acquiring Claims Data and CMS Research-Identifiable Files
- Acquiring Patient-Reported Data
- Gaining Permission to Use Real-World Data
- Methods of Access
- Case Study: The IMPACT-AFib Trial
Assessing Fitness-for-Use of Real-World Data
- Introduction
- Defining Fitness for Use
- Evaluating Fitness for Use
- Data Quality Measures
- Use of Medicare Data in PCTs
- Data Source Accuracy: Case Study from TRANSLATE-ACS
- Data Provenance
- Operationalizing Fitness-for-Use Assessments
Study Startup
Participant Recruitment
- Introduction
- Questions to Consider
- Case Study: ICD-Pieces™
- Payments and Incentives
- Recruitment Highlights
- Clinician Recruitment Case Study: HERO
- Additional Resources
Monitoring Intervention Fidelity and Adaptations
- Introduction
- Anticipating Changes That May Affect Intervention Fidelity
- Identifying the Functions and Forms of an Intervention
- Frameworks for Characterizing Fidelity and Adaptations
- Intervention Adaptation Strategies and Examples
- Additional Resources
Patient-Reported Outcomes
- Introduction
- How Are PRO Measures Used?
- Best Practices for Collecting PRO Measures in Pragmatic Clinical Trials
- NIH HEAL, FDA, and Other Core Outcome Sets
- Choosing PRO Measures
- Cultural Adaptation and Linguistic Translation
- Case Study From Guiding Good Choices for Health
- Incorporating PRO Data Into the EHR
- Patient-Focused Drug Development
- Additional Resources
Clinical Decision Support
- Introduction
- Definitions and Uses
- Uses in PCTs: Experiences From the NIH Collaboratory Trials
- Designing and Building CDS Tools for Pragmatic Clinical Trials
- Evaluating CDS
- Disseminating and Sharing CDS
- Additional Resources
Mobile Health (mHealth)
- Introduction
- Opportunities in mHealth
- Advantages and Considerations for mHealth in Pragmatic Trials
- Case Example From the Nudge Study
Electronic Health Records–Based Phenotyping
- Introduction
- Definitions
- Finding Existing Phenotype Definitions
- Evaluating Phenotype Definitions
- Data Quality
- Using Phenotypes in PCTs—How Do I Get Started?
Navigating the Unknown
- Introduction
- Staff Turnover, Leadership Changes, and Health System Acquisition and Mergers
- Impact of Electronic Health Record Updates and Changes
- Impact of COVID-19
- Challenges Related to Recruitment and Implementation
- Responding to Guideline and Policy Changes That Affect Ongoing ePCTs
- Accounting for Quality Improvement During ePCTs
Dissemination & Implementation
Data Sharing and Embedded Research
- Introduction
- Data Sharing Concerns
- Data Sharing Solutions for Embedded Research
- Patient Perspectives on Data Sharing
- Data-sharing Policy at the NIH, Collaboratory, and HEAL
- Incentive Structure and Citations for Data Sets
- Preparing for Data Sharing
- Moving Forward
- Additional Resources
- FAQ
Implementation
- Introduction
- Factors Influencing Implementation of PCT Results
- Incorporating Implementation Research Into PCTs
- Implementation Frameworks
- How PCTs Prepare for Implementation
Dissemination Approaches for Different Audiences
- Introduction
- Reporting to the Scientific Community
- Case Study: Journal Reviews of NIH Collaboratory Trials
- ClinicalTrials.gov
- Dissemination to Patients
- Dissemination to Clinicians and Health Systems
- Dissemination Case Studies
- Additional Resources
End-of-Trial Decision-Making
Ethics & Regulatory
Privacy Considerations
- Introduction
- Current Federal Regulatory Framework: Common Rule, FDA, and HIPAA
- Additional Protections: Certificates of Confidentiality
- Individual Privacy
- Clinician and Institutional Privacy Considerations
Identifying Those Engaged in Research
- Introduction
- Human Subjects/Research Participants and Others Affected by the Research
- Identifying Those Involved in the Process of the Research
- Clinicians’ Duty to Participate in Pragmatic Research
- Case Studies From PRISM NIH Collaboratory Trials
Consent, Disclosure, and Non-Disclosure
- Introduction
- Regulatory Requirements for Informed Consent
- Waivers and Alterations
- Notification
- Findings on Approaches to Consent
Collateral Findings
Data and Safety Monitoring
- Introduction
- Which Pragmatic Trials Should Have a DSMB?
- Monitoring Protocol Adherence
- Data Issues With Monitoring Pragmatic Trials
- Monitoring for Serious Adverse Events
- Decisions About Early Termination
- Additional Resources
Ethical Considerations of Data Sharing in Pragmatic Clinical Trials
- Introduction
- The Human Subjects Research Regulations and Data Sharing
- Ongoing Challenges for Respecting the Autonomy of Participants and Sharing Data From PCTs
- Respect for Persons and Data Sharing
Ethics for AI and ML
- Introduction
- Institutional Review Board Approval
- Data Procurement and Consent
- Training Data Generation
- Conclusion
IRB Responsibilities and Procedures