RWD May Not Be Ready for Prime-Time Postapproval Confirmatory Clinical Trials of Therapeutic Agents

In November 2021, Joshua D. Wallach, PhD, MS and six other researchers, published a research letter in JAMA Network Open discussing the feasibility of using real-world data (RWD) to emulate post-approval confirmatory clinical trials of therapeutic agents granted accelerated approval by the United States Food and Drug Administration (FDA).

According to Wallach and his co-authors, RWD are not yet robust enough to confirm the benefit of drugs that have been awarded accelerated approval based on surrogate endpoints. The research letter notes, “The findings of this cross-sectional study suggest that none of the 50 FDA-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 EHR [electronic health record] data.”

Supporting Findings

Wallach and his coauthors provided supporting statistics, including that between 2009 and 2018, the FDA approved 41 new therapeutic agents through the accelerated approval pathway, requiring a total of 50 postapproval confirmatory trials. Twenty of those fifty postapproval confirmatory trials (40%) were ongoing at the time of accelerated approval.

The authors noted that among the 50 postapproval confirmatory trials, 12 had a clinical indication that “could be routinely ascertained from claims and/or structured EHR data” while the other 38 required “non-routinely ascertainable disease severity or treatment-related qualifiers.”

Additionally, of the 46 trials for which clinical inclusion and exclusion criteria were available on ClinicalTrials.gov, two had at least 80% of their criteria that could be routinely ascertained. Of the 41 trials with a comparator arm, 22 used active comparators, all of which could be ascertained using RWD. Of the 49 trials for which primary end point information was available, 20 had at least one end point that could be routinely ascertained from RWD.

Wallach and his coauthors noted that none of the FDA-required postapproval confirmatory trials had all four of the following: (1) a clinical indication, (2) at least 80% of the clinical inclusion and exclusion criteria, (3) a comparator, and (4) at least 1 primary end point that could be routinely ascertained from RWD.

Wallach and his coauthors also note that while the FDA has written guidance on how to use evidence drawn from RWD to fulfill requirements for post-approval studies there are many limitations of using RWD-based studies instead of postapproval clinical trials, including difficulty pulling data from EHRs, billing, and claims data. They also noted problems in determining which interventions are being used for which indications and in identifying inclusion and exclusion criteria.

Future Potential?

It wasn’t all doom and gloom from Wallach and his co-researchers, though, as they noted that the idea of creating a RWD-based postapproval study are attractive, “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.”

Wallach and his coauthors concluded by suggesting that to use RWD for regulatory evaluations, steps are needed to “standardize data elements across different facilities, clinicians, and EHRs.”