NEW YORK, Dec. 17, 2020 /PRNewswire/ — Real-world evidence (RWE) studies can offer comparable insights to randomized controlled trials (RCTs), particularly when the intent is to compare clinically meaningful treatment scenarios using rigorous study design and fit-for-purpose data, according to results from the RCT-DUPLICATE project published today in Circulation. Researchers from Brigham and Women’s Hospital (BWH) and Harvard Medical School, in close collaboration with the U.S. Food and Drug Administration (FDA) and Aetion, reported the findings from 10 RWE studies designed to emulate RCTs for cardiovascular outcomes of antidiabetic or antiplatelet medications.
Nine of the 10 RWE studies achieved at least two of three agreement metrics that researchers set at the outset. For each of these nine studies, the difference in results between the RWE and RCT was not statistically significant. Eight of the nine RWE findings achieved “estimate agreement,” which means they fell within the 95% confidence interval of the RCT results. Six of the nine studies achieved “regulatory agreement,” meaning that interpretation of the respective RWE and RCT results would lead to equivalent regulatory decisions. The tenth RWE trial emulation did not meet any of the three agreement metrics.
“These findings bring us one step closer in our effort to build empirical evidence that informs how RWE can support regulatory reviews across various treatment areas,” said Jessica Franklin, Ph.D., associate professor of medicine at Harvard Medical School, biostatistician at Brigham and Women’s Hospital, and co-lead of RCT-DUPLICATE. “The timing is critical: our hope is that these initial results will inform additional studies as global standards for regulatory use of RWE are refined and updated.”
The results indicate that in certain circumstances RWE studies can meaningfully supplement RCT evidence, or even replace some large-scale randomized safety trials. The RWE studies were particularly successful in emulating trials that themselves examined the real-life scenario of comparing a treatment to an alternative therapy. Findings confirmed the challenge of using RWE to emulate placebo-controlled trials, as placebos are not administered in everyday clinical practice and therefore are not observable in real-world data. Among the four emulations that did not achieve regulatory agreement, three were placebo-controlled. The difficulty arises in choosing a real-world treatment to stand in the place of the placebo, and the initiative’s preliminary findings shed useful light on how to refine that choice. Researchers will apply those learnings in the future, including with studies that go beyond the registered, pre-specified analysis plans applied in these 10 studies.
Launched in October 2018 in accordance with the 21st Century Cures Act, the RCT-DUPLICATE initiative seeks to inform when non-interventional RWE studies can support the same regulatory decisions as evidence generated from RCTs, and to contribute learnings to FDA’s forthcoming guidance on RWE. The demonstration project is funded by the FDA’s Center for Drug Evaluation and Research (CDER) and is led by the FDA’s Office of Medical Policy (OMP), as part of the Agency’s Real-World Evidence Program. All studies have been and will be conducted on the Aetion Evidence Platform®, which enables transparency among stakeholders, including regulator review of data and reanalysis to test assumptions. The project is ongoing; by fall 2021 researchers aim to complete a total of 30 RWE studies to emulate the results of completed RCTs, and will follow with an additional seven that predict the results of ongoing Phase IV trials.
“RCT-DUPLICATE exemplifies the FDA’s commitment to testing approaches in preparation for issuing guidance on RWE for regulatory decision-making in 2021,” said Carolyn Magill, CEO of Aetion. “Through this initiative, researchers have developed a standardized process for evidence generation, using the Aetion Evidence Platform to run RWE studies that are transparent, replicable, and scalable. We take seriously our responsibility to assess the uses, benefits, and limitations of real-world data as we partner with global regulators to advance standards.”
The FDA and other global regulatory agencies have increasingly adopted RWE as they work to efficiently assess the safety and effectiveness of COVID-19 interventions while reflecting populations often underrepresented in traditional trials. In May, Aetion announced a research collaboration agreement with the FDA to further understanding of and response to COVID-19. Aetion and BWH/Harvard Medical School are also active participants in the COVID-19 Evidence Accelerator, a collaboration organized by the Reagan-Udall Foundation for the FDA and Friends of Cancer Research, which seeks to advance RWE for COVID-19 decision-making.