Purpose: There is a need to develop hybrid trial methodology combining the best parts of traditional randomized controlled trials (RCTs) and observational study designs to produce real‐world evidence (RWE) that provides adequate scientific evidence for regulatory decision‐making.Methods: This review explores how hybrid study designs that include features of RCTs and studies with real‐world data (RWD) can combine the advantages of both to generate RWE that is fit for regulatory purposes.Results: Some hybrid designs include randomization and use pragmatic outcomes; other designs use single‐arm trial data supplemented with external comparators derived from RWD or leverage novel data collection approaches to capture long‐term outcomes in a real‐world setting. Some of these approaches have already been successfully used in regulatory decisions, raising the possibility that studies using RWD could increasingly be used to augment or replace traditional RCTs for the demonstration of drug effectiveness in certain contexts. These changes come against a background of long reliance on RCTs for regulatory decision‐making, which are labor‐intensive, costly, and produce data that can have limited applicability in real‐world clinical practice.Conclusions: While RWE from observational studies is well accepted for satisfying postapproval safety monitoring requirements, it has not commonly been used to demonstrate drug effectiveness for regulatory purposes. However, this position is changing as regulatory opinions, guidance frameworks, and RWD methodologies are evolving, with growing recognition of the value of using RWE that is acceptable for regulatory decision‐making.

BACKGROUND: Recognizing the growing need for robust evidence about treatment effectiveness in real-world populations, the Good Research for Comparative Effectiveness (GRACE) guidelines have been developed for noninterventional studies of comparative effectiveness to determine which studies are sufficiently rigorous to be reliable enough for use in health technology assessments. OBJECTIVE: To evaluate which aspects of the GRACE Checklist contribute most strongly to recognition of quality. METHODS: We assembled 28 observational comparative effectiveness articles published from 2001 to 2010 that compared treatment effectiveness and/or safety of drugs, medical devices, and medical procedures. Twenty-two volunteers from academia, pharmaceutical companies, and government agencies applied the GRACE Checklist to those articles, providing 56 assessments. Ten senior academic and industry experts provided assessments of overall article quality for the purpose of decision support. We also rated each article based on ...

There is growing interest in regulatory use of randomized pragmatic trials and noninterventional real-world (RW) studies of effectiveness and safety, but t

BACKGROUND: While there is growing demand for information about comparative effectiveness (CE), there is substantial debate about whether and when observational studies have sufficient quality to support decision making. OBJECTIVE: To develop and test an item checklist that can be used to qualify those observational CE studies sufficiently rigorous in design and execution to contribute meaningfully to the evidence base for decision support. METHODS: An 11-item checklist about data and methods (the GRACE checklist) was developed through literature review and consultation with experts from professional societies, payer groups, the private sector, and academia. Since no single gold standard exists for validation, checklist item responses were compared with 3 different types of external quality ratings (N=88 articles). The articles compared treatment effectiveness and/or safety of drugs, medical devices, and medical procedures. We validated checklist item responses 3 ways against external quality ratings, usi...