Modernizing Regulatory Evidence with Trials and Real-World Studies

Abstract

We are taught that randomized controlled trials (RCTs) are the gold standard for evaluating whether a treatment can achieve its intended benefit because they are designed to isolate treatment effects while essentially balancing all other factors, known and unknown. While an elegant tool, the results from RCTs are not always generalizable to less idealized settings and more diverse patients. Real-world evidence (RWE), conducted alongside or as an extension of clinical trials, can play an important role in completing the picture of how well a therapy works, for which patients, and under what conditions. Such evidence has long been used for treatment and reimbursement decisions; the question at hand is whether, when and how RWE should contribute to regulatory decision-making and be considered credible enough to be counted as 'substantial evidence of effectiveness.' Among numerous efforts to evaluate RWE suitability for regulatory use, a recent Friends of Cancer Research (Friends) study provides valuable lessons for RCT and RWE zealots alike. Here, we review the complementary nature of RCTs and RWE, discuss the key learnings from the Friends project, and reinforce the call for continued examination of methods and data sources to guide reliable regulatory use of RWE for evaluating therapies.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Replication of randomized clinical trial results using real-world data: paving the way for effectiveness decisions

“…However, careful review and interpretation of the results will be critical, particularly if there are discrepancies between the target RCT and the observational study. The conclusion should not be that the observational study was flawed or confounded [40]. The learning achieved through investigating the reasons for differences may improve our understanding of when trustworthy causal inferences can be made from observational data but may also provide insights on how better to design RCTs to improve their generalizability and usefulness in decision-making.…”

Real World Evidence in Medical Cannabis Research

“…Research has therefore focused on compounds under patent as opposed to generic CBMPs where research outcomes fail to provide a similar return on investment for licensed producers and pharmaceutical companies. Historically, clinical trials on CBMPs were funded privately, which may be associated with potential reporting biases [ 19 ].…”

Comparing Findings From a Friends of Cancer Research Exploratory Analysis of Real-World End Points With the Cancer Analysis System in England

“…There can be differences in the results of RWD and RCTs; however, considering the complexities in health care systems and high degree of variation in treatment response in the real world, RWD may differ from RCTs but still be valid. 14 …”

“…Extension of initiatives such as Friends to multicountry settings will further support the development of best practices for the generation and evaluation of RWE to supplement RCTs in regulatory decision making and inform the development of future regulatory guidance. 14 RWE can support regulatory decision making about new or expanded medication indications in a number of ways, from the more established use of external controls for single-arm trials, which have also been used as the basis of US Food and Drug Administration–accelerated approvals, to the growing interest in the use of pragmatic trials and nonrandomized RWE from health care databases, particularly in situations where real-world outcomes and clinical practice patterns differ significantly from the tightly controlled RCT settings. 6 , 19 Studies similar to ours that establish research processes and evaluate the strengths, limitations, and validity of specific RWD for addressing defined clinical questions can support development of guidelines on fit-for-purpose RWD and defining standards for RWE studies intended to inform regulatory decisions.…”