Objectives：MID-NET^® has contributed to post-marketing drug safety assessment through various pharmacoepidemiological studies. To further promote an appropriate use of MID-NET^®, this paper describes points to consider in conducting studies utilizing MID-NET^® based on results from the two MID-NET^® studies.

Study design：Cohort study based on the secondary utilization of medical information database

Methods：In the first study, the incidence of decreased liver function in patients prescribed drugs for pulmonary arterial hypertension was compared with the results from all-case surveillance (primary data collection). In the second study, real world utilization of biosimilar (hereinafter referred to as “BS”) was investigated to understand characteristics of BS prescription in clinical practice.

Results：Although the incidence of decreased liver function varied depending on outcome definitions, the proportion on the definition identifying severe cases was similar to that in the all-case surveillance. It suggests that use of multiple outcomes including a definition taking into consideration a degree of severity is important to evaluate study results with robustness appropriately. In the second study, increased trends of BS prescriptions and various patterns of switching (from original biopharmaceutical to BS or from BS to original biopharmaceutical) depending on age and other factors were confirmed. It indicates that considerations about real world utilization of original biopharmaceutical and BS are necessary for future studies targeting BS.

Conclusion：These studies further expanded an understanding and knowledge about data characteristics of MID-NET^® and provide useful points to consider for promoting appropriate data utilization in future MID-NET^® studies.

Problem： Ambiguity in communication of key study parameters limits the utility of real-world evidence （RWE） studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of bias.

What We Did： The International Society for Pharmacoepidemiology (ISPE) and ISPOR―The Professional Society for Health Economics and Outcomes Research (ISPOR) convened a joint task force, including representation from key international stakeholders, to create a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making. The template builds on existing efforts to improve transparency and incorporates recent insights regarding the level of detail needed to enable RWE study reproducibility. The overarching principle was to reach for sufficient clarity regarding data, design, analysis, and implementation to achieve 3 main goals. One, to help investigators thoroughly consider then document their choices and rationale for key study parameters that define the causal question (e.g., target estimand), two, to facilitate decision-making by enabling reviewers to readily assess potential for biases related to these choices, and three, to facilitate reproducibility.

Strategies to Disseminate and Facilitate Use： Recognizing that the impact of this harmonized template relies on uptake, we have outlined a plan to introduce and pilot the template with key international stakeholders over the next 2 years.

Conclusion： The HARmonized Protocol Template to Enhance Reproducibility (HARPER) helps to create a shared understanding of intended scientific decisions through a common text, tabular and visual structure. The template provides a set of core recommendations for clear and reproducible RWE study protocols and is intended to be used as a backbone throughout the research process from developing a valid study protocol, to registration, through implementation and reporting on those implementation decisions