Study: RWD not ready for postapproval prime time

Regulatory NewsRegulatory News | 11 November 2021 |  By 

For drugs and biologics that receive accelerated approval, could information drawn from real-world data sources supplant traditional postapproval clinical trials to confirm that the therapies have benefit? Real-world data (RWD) are not yet robust enough to confirm the benefit of drugs awarded accelerated approval based on surrogate endpoints, answered the authors of a recent study.
“The findings of this cross-sectional study suggest that none of the 50 [Food and Drug Administration]-required postapproval confirmatory trials for therapeutic agents granted accelerated approval between 2009 and 2018 could have been feasibly emulated using currently available claims and/or structured [electronic health record] data,” wrote Yale’s Joshua Wallach and colleagues in a 9 November health policy research letter published in JAMA Network Open.
The US Food and Drug Administration (FDA) has written guidance on how to use evidence drawn from RWD to fulfill requirements for postapproval studies, meeting the mandates of the 21st Century Cures Act. However, Wallach and his research letter coauthors noted many limitations of using RWD-based studies in lieu of postapproval clinical trials, including difficulty in extracting data from electronic health records (EHRs), billing and claims data. The authors also cited problems in determining which interventions are being used for which indications, and in identifying inclusion and exclusion criteria.
Still, the potential advantages of constructing a RWD-based postapproval study are tantalizing: “A better understanding of the feasibility of emulating FDA-required postapproval trials conducted to verify clinical benefit is critical because these studies often face recruitment challenges, continue to focus on surrogate markers as end points, and are delayed for years after approval,” wrote Wallach, of Yale's Department of Environmental Health Sciences  in the school of public health, and coauthors.
The study followed Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines, examining all 50 postapproval confirmatory trials for the 41 new molecular entity drugs and biologics that received accelerated approval between 2009 and 2018.
For each drug or biologic that received accelerated approval, investigators looked at information available on as well as abstracts and study descriptions to determine whether RWD sources could provide data analogous to that obtained during a postapproval clinical trial. Specifically, Wallach and his coinvestigators measured the number of trials where the clinical indication, comparator, and primary endpoint could be “routinely ascertained from RWD.” At least 80% of inclusion and exclusion criteria also had to be available through RWD sources.
Only 12 of the 50 postapproval confirmatory trials the research team examined, or 24% of trials, had a clinical indication that could easily be gleaned from either claims or structured EHR data. Of the 46 trials whose inclusion and exclusion criteria were found on, just two trials had inclusion and exclusion criteria that could be found in this way.
The investigators did not turn up a single trial for which all the necessary data could be gleaned from RWD. “These characteristics were considered unlikely to be routinely ascertained from observational data if researchers would find it difficult to develop a computable phenotype using RWD sources,” they wrote. “Although RWD can be used to ascertain clinical outcomes for real-world populations receiving therapeutic agents, our findings suggest that current observational methods and RWD can complement, but are unlikely to replace, postapproval confirmatory trial requirements.”
Duration of postapproval trials
Another JAMA Network Open research letter looked at a separate aspect of postapproval trials. This study, also led by Wallach and involving many of the same coauthors, looked at the duration of postapproval trials compared with the duration of pivotal trials for the same set of drugs and biologics granted accelerated approval between 2009 and 2018. The investigators were able to ascertain trial duration for 31 agents that had been approved for 32 indications. Most of these agents (n=27; 84%) were approved for hematology or oncology indications, and two thirds of the total were drugs, while one third were biologics.
The investigators found that postapproval trial durations generally did not last much longer than the pivotal trials. Postapproval trials lasted a median 17 months, while pivotal trials lasted a median 10 months. However, the median elapsed time from accelerated approval to the “FDA-established postapproval trial results reporting deadlines” was 50 months. Wallach and his coauthors noted that this time span is a median of 30 months longer than postapproval trial duraitons.
“These findings raise questions about the use of the accelerated approval program for certain therapeutic agents, especially if postapproval confirmatory trials neither consistently evaluate clinical outcomes nor are much longer than pivotal trials using surrogate end points,” wrote Wallach and his coinvestigators.
JAMA Network Open research letter – RWD

JAMA Network Open research letter – Trial duration


© 2023 Regulatory Affairs Professionals Society.

Discover more of what matters to you