Maximizing the potential of real-world evidence: pre-, central to and post-regulatory approval
In this exclusive editorial, Brett Beaulieu-Jones (Harvard Medical School; MA, USA) discusses the relevance of real-world evidence to the various stages of the regulatory drug approval process and how it measures up against data from randomized controlled trials.
Brett Beaulieu-Jones is a Research Fellow within the Department of Biomedical Informatics at Harvard Medical School (MA, USA); in this position, Beaulieu-Jones is focused on expanding the use of machine learning-based methods to more precisely define phenotypes from large-scale biomedical data repositories – such as those contained in clinical records – to include large-scale data integration.
Beaulieu-Jones has two primary concentrations: 1) evaluating the safety and effectiveness of machine learning- and informatics-based interventions to guide model deployment, and 2) developing models to understand disease subtypes and identify patient subpopulations in heterogeneous neurological conditions.
Real-world evidence (RWE) should not replace randomized controlled trial data as the gold standard to evaluate the efficacy of an intervention, for example when primary regulatory approval is being sought. However, RWE offers great potential to help the regulatory process to be faster, more efficient, of higher quality and more representative. RWE should be used to identify areas of need (pre), accelerate and reduce cost of RCTs (central) and perform longitudinal follow-up (post) to assess both the real-world effectiveness and safety of a novel intervention.
There are a number of reasons why RWE should not replace RCTs. Many compelling reasons can be boiled down to a single issue: no methodological or statistical approach can match the gold standard of randomization, used in RCTs, in observational data. Because observational data are not primarily collected for comparative effectiveness research, clinical decisions about which interventions to use are frequently made for reasons that may not present in the data. These unobserved confounders prevent a fair comparison between different interventions.
While we cannot afford to lower the standard of evidence RCTs provide, there are major challenges to performing RCTs under the status quo. Two notable issues are: 1) RCTs have become exceedingly expensive to perform from both a financial and time perspective, and 2) it is not always clear to what extent efficacy within a narrow clinical trial population generalizes to an interventions’ effectiveness in real-world populations under routine clinical practice.
The high costs of RCTs  affect much more than regulatory approval for new therapeutics and devices from large life sciences companies where there is the potential for substantial return on investment. High costs make it difficult to perform reliable, non-regulatory comparative effectiveness studies of clinical practice. Attempts have been made to reduce the costs of clinical trials, particularly from a time perspective, with usage of surrogate endpoints as primary outcomes, and accelerated and breakthrough designations. These attempts add a third important issue concerning the way RCTs are currently performed: the reliability of RCTs may be reduced. Surrogate endpoints do not perfectly represent gold-standard endpoints – such as overall survival – but can often be measured sooner.
Given these issues it is important that we utilize RWE to supplement traditional RCTs. One way to do this is by performing randomized registry trials (RRTs), or trials that utilize registries to expedite the recruitment of trial participants and facilitate the tracking of longitudinal outcomes. Importantly, while RRTs use registries to recruit and follow patients, they still incorporate randomization so that confounding factors between treatment groups can be rigorously controlled for.
Perhaps the most compelling example of an RRT to date was the Thrombus Aspiration during ST-segment Elevation (TASTE) myocardial infarction trial [2, 3], which investigated whether thrombus aspiration, prior to primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction, reduced mortality. The study observed that thrombus aspiration did not statistically reduce all-cause mortality above the threshold for statistical significance, however, this trial is also notable because the incremental cost-per-patient was less than US$50 . In addition, the trial organizers were able to conduct follow-up analyses published as a subsequent report looking at participants’ longer-term outcomes .
How was a large (N=7244) cardiology randomized trial in the urgent care setting able to be conducted at a cost orders of magnitude lower than most RCTs? In 2009, the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated according to Recommended Therapies (SWEDEHEART)  national registry was created to support evidence-based practice in the treatment of coronary artery disease. Using this registry, the TASTE trial organizers were able to recruit participants faster and cheaper than traditional trials, while maintaining the ability to conduct additional follow-up for the cost of maintaining a registry and performing data analysis.
RRTs offer a compelling example for the ways RWE can be used to supplement, but not supplant, RCTs when seeking regulatory approval. While post-approval safety and surveillance studies currently leverage RWE, stronger evidence could be provided by following initial RWE-based analyses with RRTs, even in post-approval and post-marketing settings.
In addition, due to the reduced costs of RRTs, and the ease of including multiple treatment sites, it is possible to include a population more representative of the real-world population. This population is also ideal for performing post-approval, value-based cost or reimbursement analyses of drugs. Appropriate use of RWE offers the promise to accelerate regulatory approval of new interventions by reducing both the cost of drug development and the time it takes to execute clinical trials, while maintaining rigor.
 Pharmaceutical Research and Manufacturers of America. Biopharmaceutical industry-sponsored clinical trials: impact on state economies.
 Fröbert O, Lagerqvist B, Gudnason T et al. Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia (TASTE trial). A multicenter, prospective, randomized, controlled clinical registry trial based on the Swedish angiography and angioplasty registry (SCAAR) platform. Study design and rationale. Am Heart J. 160(6): 1042–1048; (2010);
 Fröbert O, Lagerqvist B, Olivecrona GK et al. Thrombus aspiration during ST-segment elevation myocardial infarction. N Engl J Med. 369(17): 1587–1597; (2013);
 Wachtell K, Lagerqvist B, Olivecrona GK, James SK, Fröbert O. Novel trial designs: lessons learned from Thrombus Aspiration during ST-segment Elevation myocardial infarction in Scandinavia (TASTE) trial. Curr Cardiol Rep. 18(1): 11; (2016);
 Lagerqvist B, Fröbert O, Olivecrona GK et al. Outcomes 1 year after thrombus aspiration for myocardial infarction. N Engl J Med. 371(12); 1111–1120; (2014);
 Jernberg T, Attebring MF, Hambraeus K et al. The Swedish Web-system for enhancement and development of evidence-based care in heart disease evaluated according to recommended therapies (SWEDEHEART). Heart. 96(20); 1617–1621; (2010).