RWR Insights | Regulatory Considerations for Non-Interventional Study Protocols
Real-world evidence (RWE) study protocols and clinical trial protocols both outline the design and conduct of a study. However, they are distinctly different in several ways given the differences in objectives, methodologies, settings, and populations involved in clinical trials versus RWE studies.
[1] Objectives: The main objective of a clinical trial is to evaluate the efficacy and safety of a medical intervention in a controlled environment, usually by comparing it to a placebo or standard treatment. On the other hand, RWE studies typically aim to understand how an intervention works in routine clinical practice, often focusing on outcomes such as long-term effectiveness, side-effects, quality of life, and cost-effectiveness.
[2] Study Design and Methodology: Clinical trials, especially phase III, are predominantly randomized controlled trials (RCTs) where subjects are randomly assigned to the intervention or control group to minimise bias. They follow a pre-specified protocol and are conducted under tightly controlled conditions. RWE studies, on the other hand, are typically observational in nature and analyse data from sources like electronic health records (EHRs), claims databases, or patient registries.
[3] Setting: Clinical trials are conducted in specific, controlled environments and follow a strict protocol. RWE studies are conducted in routine clinical practice settings, making them more representative of ‘real-world’ conditions.
[4] Population: Clinical trials often have strict inclusion and exclusion criteria, resulting in a relatively homogeneous group of participants. This can limit the generalisability of the results. RWE studies, in contrast, involve broader, more diverse populations (including those often excluded from trials like the elderly, people with multiple co-morbidities, etc.), making the findings more generalisable to everyday practice.
[5] Data Collection: In clinical trials, data collection is rigorous, detailed, and specific to the trial endpoints. Adverse events are actively sought and documented. RWE studies primarily rely on existing data sources such as EHRs, patient registries, or insurance claims data. This can potentially lead to incomplete or inaccurate data.
[6] Intervention: In clinical trials, the intervention (dosage, frequency, duration, etc.) is pre-specified and strictly monitored. In RWE studies, interventions reflect routine clinical practice and may vary widely.
[7] Follow-up: Clinical trials have a defined follow-up period while RWE studies can often provide information on long-term outcomes, given they use data from routine clinical practice over longer periods.
Despite these differences, both RWE and clinical trials play critical roles in healthcare research. While clinical trials provide the highest level of evidence for determining a treatment’s efficacy, RWE studies complement this by providing evidence on real-world effectiveness and long-term safety.
HARPER PROTOCOL TEMPLATE
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 [1]. 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
Link: https://onlinelibrary.wiley.com/doi/10.1002/pds.5507
Four protocol templates were identified for RWE studies:
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- The European Medicines Agency’s (EMA) Guideline on Good Pharmacovigilance Practices (GVP) Module VIII – post-authorisations safety studies (PASS) template,
- ISPE’s guidelines for good pharmacoepidemiology practice (ISPE GPP) section on protocol development,
- The National Evaluation System for health Technology (NEST) protocol guidance, and
- The Structured Template and Reporting Tool for Real World Evidence (STaRT-RWE).
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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.
References
1. 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; 32( 1): 44- 55. doi:10.1002/pds.5507
