Real World Evidence (RWE) 101 – HARPER


Regulatory agencies, health technology assessors, and payers are increasingly interested in studies that make use of real-world data to inform regulatory and other policy or clinical decision-making. However, concerns over the credibility of real-world evidence studies have led to calls for more transparency on the design and conduct of RWE studies.
A joint task force between ISPE and ISPOR created a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making. The HARPER template provides clarity, structure, and a common denominator regarding the level of operational detail, context, and rationale necessary in a protocol.
HARPER = HARmonized Protocol Template to Enhance Reproducibility of hypothesis evaluating real-world evidence studies on treatment effects
Four protocol templates were identified for RWE studies:
1. The European Medicines Agency’s (EMA) Guideline on Good Pharmacovigilance Practices (GVP) Module VIII – post-authorizations safety studies (PASS) template,
2. ISPE’s guidelines for good pharmacoepidemiology practice (ISPE GPP) section on protocol development,
3. The National Evaluation System for health Technology (NEST) protocol guidance, and
4. The Structured Template and Reporting Tool for Real World Evidence (STaRT-RWE).
The HARPER protocol contains nine sections, including a title page, abstract, and a table for amendments and updates. Each section includes structured free text, a structured table, or a figure, and a free-text section to lay out context and rationale for scientific choices.
The study design diagram shows the context and rationale for the study setting, time 0 (index date), inclusion criteria, exclusion criteria, variables, exposure, outcome, follow up, covariates, sensitivity analyses, data sources, metadata, and software used in the study.
The data sources section includes a free text component followed by a structured table for specifying data sources. The data sources section can also include a detailed evaluation of the fitness-for-purpose of data source options.
Overall, the HARPER framework is a valuable resource for researchers and clinicians who are planning or conducting RWE studies. The framework can help to ensure that protocols are well-designed and will produce high-quality evidence.

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