Harmonized Protocol Templates for Improved Repeatability (HARPER) – Healthcare Economist

Clinical trials have detailed research protocols and are registered with ClinicalTrials.gov. What level of detail is required for real-world data (RWD) analysis to estimate treatment effects? In Europe, the European Medicines Agency (EMA) requires the registration of many study protocols using the observational post-authorization safety study template (go through) by the marketing authorization holder.Other efforts include ISPE guidelines Good Pharmacoepidemiological Practice (GPP) Section on Protocol DevelopmentNational Health Technology Evaluation System (nest) protocol guidelines, as well as structured templates and reporting tools for real-world evidence (start-RWE).

The International Society for Pharmacoepidemiology (ISPE) and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) convened a joint working group to provide standards for RWD protocols. They developed the HARmonized Protocol Template to Enhance Reproducibility (HARPER). The table below compares HARPER with PASS, GPP, NEST and STaRT-RWE.

The authors wisely point out some limitations of HARPER.

• Structure and Flexibility. HARPER’s structured approach improves stakeholder clarity and consistency across studies. However, some complex study designs may be perfectly reasonable, but may not fit the HARPER structure. However, many sections contain free text sections.
• minimum rather than maximum transparency. HARPER does not cover all aspects of transparency in the research lifecycle, which may involve the sharing of protocols, codes, data and results. Therefore, HARPER should be considered a minimum requirement for transparency of research protocols.
• data evolution. Harper’s method may need to be adjusted over time as data collection evolves and new methods are developed.

The complete HARPER catalog is listed below.

• 1. Title page
• 2. Summary
• 3. Corrections and Updates
• 4. Schedule
  • Table 1 Milestones and Timeline
• 5. Rationale and background
• 6. Research Questions and Objectives
  • Table 2 Primary and secondary research questions and objectives
• 7. Research Methods
  • 7.1. Learning plan
  • 7.2. Study Design Diagram
  • 7.3. Environment
    • 7.3.1 Background and rationale for defining time 0 (and other major time anchors) for entry into the study population
      • table 3 Operational definitions for time 0 (index date) and other major time anchors
    • 7.3.2 Background and rationale for study inclusion criteria:
      • Table 4. Operational Definitions for Inclusion Criteria
    • 7.3.3 Background and rationale for study exclusion criteria
      • table 5. Operational Definition of Exclusion Criteria
  • 7.4. Variables
    • 7.4.1 Background and rationale for the exposure of interest
      • table 6. Expose the operational definition
    • 7.4.2 Background and rationale for relevant findings
      • table 7. The operation definition for the result
    • 7.4.3 Background and rationale for follow-up
      • table 8. Follow up action definition
    • 7.4.4 Background and rationale for covariates (confounding variables and effect modifiers, e.g. risk factors, comorbidities, medications)
      • table 9. Operational definition of covariates
  • 7.5. Data analysis
    • 7.5.1 Background and rationale for the analysis plan
      • Table 10. Primary, Secondary and Subgroup Analysis Specifications
      • Table 11. Sensitivity Analysis – Rationale, Strengths and Limitations
  • 7.6. Data sources
    • 7.6.1 Background and rationale for data sources
      • Table 12. Metadata about data sources and software
  • 7.7. Data Management
  • 7.8. Quality control
  • 7.9. Study size and feasibility
    • Table 13. Power and sample size
• 8. Limitations of the method
• 9. Protection of human subjects
• 10. Adverse event reporting
• 11. References
• 12. Appendix

You can read more details about the HARPER method here at the Open Science Foundation here.