Harmonized protocol model for enhancing reproducibility (Harper) – Healthcare economist





Clinical trials contain detailed study protocols and are registered at ClinicalTrials.gov. What level of detail is required for real-world data (RWD) analytics aimed at estimating treatment effects? In Europe, the European Medicines Agency (EMA) requires many study protocols to be registered using a form for post-licensing safety studies (PASS) conducted by marketing authorization holders. Other efforts include the ISPE’s Good Pharmaceutical Epidemiology Practice (GPP) Guidelines on Protocol Development, the National Health Technology Evaluation System (NEST) Protocol Guidelines, and the Structured Template and Real Global Evidence Reporting Tool (STaRT-RWE).

The International Society for Pharmacoepidemiology (ISPE) and the International Society for Pharmacoeconomics and Outcome Research (ISPOR) have formed a joint task force to provide standards for RWD protocols. They have developed a harmonized protocol model for enhancing reproducibility (Harper). The table below compares HARPER vs. PASS, GPP, NEST, and STaRT-RWE.

The authors wisely note some of Harper’s limitations.

  • Organization vs. Flexibility. HARPER’s structured approach promotes clarity for stakeholders and consistency across studies. However, some complex study designs may be perfectly reasonable, but may not fit into HARPER’s structure. However, many sections contain free text sections.
  • Minimum, not maximum transparency. HARPER does not cover every aspect of transparency over the lifecycle of a research study, which may include sharing protocol, code, data, as well as results. Thus, HARPER should be seen as a minimum requirement for study protocol transparency.
  • Data evolution. As data collection evolves and new methods are developed, HARPER’s approach may need to adapt over time.

HARPER’s full table of contents is listed below.

  • 1. Title page
  • 2. Abstract
  • 3. Modifications and Updates
  • 4. Schedule
    • Table 1 Milestones and schedule
  • 5. Rationale and background
  • 6. Research question and objectives
    • Table 2 Primary, secondary and objective research questions
  • 7. Research methods
    • 7.1 Study design
    • 7.2 Study design outline
    • 7.3. Adjust
      • 7.3.1 Context and rationale for defining time 0 (and other primary time determinants) for entry into the study population
        • Table 3 Operational definition of time 0 (index date) and other base time stabilizers
      • 7.3.2 Context and Rationale for Study Inclusion Criteria:
        • Table 4. Operational definitions of the inclusion criteria
      • 7.3.3 Context and rationale for the study exclusion criteria
        • Table 5. Operational definitions of exclusion criteria
    • 7.4. variants
      • 7.4.1 The context and rationale for the exposure(s) of interest
        • Table 6. Operational definitions of exposure
      • 7.4.2 The context and rationale for the outcome(s) of interest
        • Table 7. Operational definitions of results
      • 7.4.3 Context and rationale for follow-up
        • Table 8. Operational tariffs to follow
      • 7.4.4 Context and rationale for covariates (confounding variables and effect modifiers, such as risk factors, comorbidities, and comedians)
        • Table 9. Operational definitions of covariates
    • 7.5 Data Analysis
      • 7.5.1 Context and rationale for the analysis plan
        • Table 10. Primary, secondary and sub-analysis specification
        • Table 11. Sensitivity analytics – rationale, strengths and limitations
    • 7.6. Data sources
      • 7.6.1 Context 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. force and sample size
  • 8. Reducing methods
  • 9. Human protection
  • 10. Reporting of adverse events
  • 11. References
  • 12. Appendices

You can read more details about Harper’s approach over here And at the Open Science Foundation over here.



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