Real World Evidence (RWE) is generated as a result of the real-world usage of drugs, and thus can complement the RCT (randomized controlled trial) evidence that is generated in controlled settings. RWE uses real-world data (RWD) including patient health status, health care, and outcomes routinely collected from various, usually unstructured, sources such as electronic health records (EHRs), insurance claims databases, patient registries, pharmacy data, laboratory data, data from wearables, and so on. Therefore, it represents a broader and more varied distribution of patients, and for the same reason, regulators consider RWE as a crucial part of the evidence used in regulatory and Health Technology Assessment (HTA) decisions. However, because of this varied and unstructured nature of RWD, the resulting RWE is also found to be quite varying in terms of design, structure, flow, and content, all of which culminates to a low level of reproducibility of RWE studies.(1, 2)
Recognizing this issue, the Professional Society for Health Economics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) convened a joint task force including members from both societies and international stakeholder groups to develop a uniform template to help collect RWD and conduct RWE studies. The result was the publication of the Harmonized Protocol Template to Enhance Reproducibility (HARPER) in 2022. This template provides a set of core recommendations for clear and reproducible RWE studies, and is intended to be used throughout the research process from designing a study, registration, its implementation and reporting on those implementations.(3)
The template builds upon prior efforts to increase transparency on the design and conduct of studies using RWD (such as the EMA PASS template, STaRT-RWE template, and NEST protocol). It considers current insights on the degree of detail required to ensure study reproducibility. The joint task force’s core committee examined each section heading in the mapped table of the existing protocol templates to develop HARPER.(4-7)
The development process of this template harbored an assessment of its internal and external validity. Five subteams evaluated internal validity by testing and developing example use cases with various designs and data sources. External validity was assessed by comparing existing protocol templates or guidance developed by international multi-stakeholder groups to ensure compatibility with agreed-upon scientific principles. These efforts resulted in a standard template with integrated advice and detailed instructions for each heading.
The headers of the template are mostly similar to those of the EMA PASS template. There are nine main sections, each with structured free text, tables, or figures. Users are encouraged to provide context and rationale for the investigations and decisions in structured free text. Users can also provide details about how the study was carried out using free-text and organized tables. Further, to improve understanding and usability of the template, the authors have also provided sample protocols for various use cases to show how to utilize the template.(3)
Alongside the benefits mentioned above of this template, the creators have highlighted various limitations. For example, some complex study designs may be wholly reasonable but may not fit within the HARPER structure. Moreover, HARPER does not cover every aspect of transparency over the lifecycle of a research study, which may involve sharing protocol, code, data, and results.(3)
As this template is relatively recently launched, its acceptability by different organizations and stakeholders is yet to be gauged. The pilot studies conducted as a part of internal validation of this template provides suitable examples for its implementation in various study designs. It is possible that with time and with feedback from various stakeholders, the HARPER template may see further revisions to accommodate the evolution of new methods. The end users may be better able to assess the quality of RWE studies and, consequently, their usefulness for decision-making if significant difficulties in protocol registration are addressed.
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1. Chodankar D. Introduction to real-world evidence studies. Perspect Clin Res. 2021 Jul-Sep;12(3):171-174.
2. Kim HS, Lee S, Kim JH. Real-world Evidence versus Randomized Controlled Trial: Clinical Research Based on Electronic Medical Records. J Korean Med Sci. 2018 Jun 26;33(34):e213.
3. Wang SV, Pottegård A, Crown W, et al. HARmonized Protocol Template to Enhance Reproducibility of hypothesis evaluating real-world evidence studies on treatment effects: A good practices report of a joint ISPE/ISPOR task force. Pharmacoepidemiol Drug Saf. 2023 Jan;32(1):44-55.
4. Guideline on good pharmacovigilance practices (GVP) Module VIII: post‐authorisation safety studies (rev 3) section VIII.B.2. Study registration. European Medicines Agency; 2017.
5. European Medicines Agency. Guidance for the format and content of the protocol of non‐interventional post‐authorisation safety studies.
6. Wang SV, Pinheiro S, Hua W, et al. STaRT-RWE: structured template for planning and reporting on the implementation of real world evidence studies. BMJ. 2021 Jan 12;372:m4856.
7. National Evaluation System for health Technology Coordinating Center (NESTcc) Methods Framework A Report of the Methods Subcommittee of the NEST Coordinating Center: An initiative of MDIC. 2020.