Real-World by Design: Considerations for Designing Clinical Trials that Include Real-World Evidence
It just got real. While randomized and non-randomized clinical trials are the mainstay for clinical data collection, real-world data are any data that are collected during care delivery in the real-world (in-home care, clinical practices, hospitals, emergency rooms, etc.). Unlike controlled clinical trials, which are designed specifically to limit variability, real-world data are gathered in a comparatively less controlled setting, and is therefore considered a representation of how a drug or device might impact health outcomes in the real world.
Real-world evidence (synthesized using real-world data) is changing health care by generating real-world information for healthcare providers and payers. Sources of real-world data include electronic health records and case report forms, patient-generated data from surveys and wearable technology, cost and utilization data from claims and public databases and public health data from government-funded data sources, to name a few. Real-world evidence is adding value to healthcare by bridging the gap between expectation and reality.
This article explores some key considerations for incorporating real-world evidence when designing non-randomized trials and observational studies. Opportunities for collecting real-world data are described, important criteria are highlighted and some limitations of collecting real-world data are explained.
The following article was published in the June 2021 edition of Medical Writing (Volume 30, Number 2), a journal of the European Medical Writers Association.
The complexity of modern-day clinical trials has propelled trial design from being a consideration to now becoming what some experts believe is a science in and of itself. The United States Food and Drug Administration (FDA) sees immense potential in utilizing real-world data in designing clinical trials. This article introduces real-world data and presents a few considerations for designing non-randomized single-arm clinical trials and observational studies that include this design element.¹,²
The FDA’s Food, Drug and Cosmetics Act defines real-world data as data relating to patient health status and/or the delivery of healthcare routinely collected from a variety of sources, including data derived from electronic health records, medical claims and billing data, data from product and disease registries, patient-generated data, data from in-home-use settings and data gathered from mobile devices.²
In a non-randomized, single-arm trial setting, the following are some opportunities for the incorporation of real-world data:
1. External controls for studies wherein the disease evaluation criteria is well established;
2. Historical records of vital signs, either as a pooled dataset or stratified according to any prespecified participant characteristic, collected from trial participants residing in different geographies; and
3. Comparison datasets for those trials wherein a placebo or non-treatment arm is either not ethical or feasible.²⁻⁴
In an observational study setting, the following are some opportunities for the incorporation of real-world data:
1. Because certain types of real-world data such as data from mobile health monitoring and wearable devices are captured in a noninterventional, purely observational, uncontrolled and ‘natural’ setting, they may be utilized to test hypotheses based on physical activity, caffeine consumption and a variety of other lifestyle characteristics; and
2. Postmarketing surveillance data and real-world data derived from medical claims, administrative claims and electronic health records may be used not only to gain a deeper understanding of treatment-emergent adverse events in the long term, but also to validate safety and efficacy claims from randomized controlled trials.³,⁴
Despite the value that real-world data can offer, it may not be applicable to all types of trial designs. As a design element, the incorporation of real-world data in a clinical study often begins with a multifaceted discussion focusing on many considerations, including the following:
1. Whether the treatment methodology is routine enough and the therapeutic area is established enough to gather sufficient real-world data before study initiation;
2. Whether the available real-world data is of sufficient quality to lend itself to statistical comparisons against data gathered in a more traditional longitudinal study;
3. In trials focused on rare and ultra-rare diseases, whether the volume of available real-world data is sufficient for its utilization as a trial design element; and
4. In cases where historical controls are being used as real-world evidence, whether clinical practice guidelines and data collection methods have remained consistent for the data to be useable as an accurate comparator dataset.²
In conclusion, the incorporation of real-world data as a design element in clinical trials can broaden our perspective, allow us to see the invisible and potentially improve regulatory decision-making.
References
1. Food and Drug Administration. Use of real-world evidence to support regulatory decision-making for medical devices. 2017 [cited 2021 Feb 25]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-real-world-evidence- support-regulatory-decision-making-medical-devices
2. Food and Drug Administration. Framework for FDA’s real-world evidence program. 2018 [cited 2021 Feb 25]. Available from: www.fda.gov/media/120060/download.
3. Suvarna, VR. Real world evidence (RWE) – Are we (RWE) ready? Perspect Clin Res. 2018;9(2):61–3.
4. Franklin JM, Patorno E, Desai RJ, Glynn RJ, Martin D, Quinto K, et al. Emulating randomized clinical trials with nonrandomized real-world evidence studies: First results from the RCT DUPLICATE Initiative. Circulation. [Cited 2020 Dec 17 (online ahead of print)].
