The U.S. Food and Drug Administration’s newly formalized pivot toward accepting one adequate and well controlled trial—supported by confirmatory evidence—as the default basis for drug approval marks a profound shift in how evidence is generated, evaluated, and trusted.
“Instead of prioritizing finite reviewer time reading and assessing two or more pivotal trials, we will focus our energies on ensuring that the one clinical trial we require provides the most up-to-date and useful information for American patients,” FDA officials Dr. Marty Makary and Dr. Vinay Prasad wrote in the New England Journal of Medicine.
While the statutory requirement for “substantial evidence” has not changed, the evidentiary framework has been recalibrated: rigor now matters more than redundancy. This shift places a new spotlight on the role of high quality real world data (RWD) and real-world evidence (RWE) in ensuring reproducibility—particularly when manufacturers no longer have a second pivotal trial to fall back on.
Why this policy change elevates real-world data quality
Historically, running two pivotal trials provided a safeguard against Type I errors and variability. But FDA leadership now argues that quantity alone is no guarantee of scientific truth. As Makary and Prasad noted, “Without examination of the quality of a study, two trials may even provide a false assurance.”
This is important because if trial redundancy decreases, the burden on RWD for verification increases. With only one trial, sponsors may need more real-world analyses—before, during, and after approval—to support decision-making around:
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Protocol optimization and design refinement
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Population representativeness
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Signal detection and safety surveillance
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Subgroup performance and outliers
This aligns with broader expert expectations that fewer preapproval trials may necessitate stronger postmarketing surveillance and more intensive real-world evidence generation.
In short: RWD quality is no longer a downstream “nice to have”—it’s upstream risk mitigation.
The quality vs. quantity story: What matters now
The FDA’s shift mirrors a broader realization: one high-quality trial plus strong corroborating evidence can outperform two mediocre studies. Regulatory Affairs Professional Society (RAPS) notes that the FDA will now scrutinize controls, endpoints, effect size, and statistical rigor with greater intensity as part of this updated paradigm.
This new standard has three big implications for RWD/RWE:
1. Reproducibility moves from trial design into evidence synthesis
By not needing two trials to show reproducibility, RWE generation for retrospective data can now be utilized.
In other words, reproducibility becomes:
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Retrospective rather than prospective
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Continuous rather than discrete
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Data driven rather than trial driven
A single trial provides the signal. RWD validates whether that signal persists across populations, practice patterns, and real-world clinical complexities.
2. Trial optimization will increasingly depend on RWD
With only one trial, research teams may do more RWD evaluations to really use a RWD-driven approach to optimizing their trial and protocol.
RWD can inform inclusion/exclusion criteria, endpoint selection, and expected event rates. Additionally, it can inform power calculations and comparator arm appropriateness.
The FDA also emphasized heightened attention to these same parameters—controls, endpoints, effect size, statistical rigor—within the single trial paradigm.
That alignment signals a new era: real-world analytics and regulatory expectations are converging.
3. Post approval evidence requirements will grow
With one trial instead of two, there’s a greater risk of missing safety or representativeness signals. There is the potential that signals are missed or that all types of people are inadvertently not included in a trial. This suggests a stronger need for RWD on the back end of studies.
FDA watchers agree: The single trial model is expected to intensify the need for robust real-world confirmatory support and postmarketing evidence generation.
Utilizing quality, complete RWD from MarketScan
MarketScan’s extensive, high-quality closed claims and integrated clinical data provides the representativeness, longitudinality, and interoperability required to meet evolving regulatory and research needs. Remember, the FDA is not asking for more RWD, but instead is asking for:
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Verifiable, reproducible, transparent RWD
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RWE methods that can withstand regulatory scrutiny
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Evidence that closes the gap left by the removed second trial
The FDA’s shift to a one trial standard is not a relaxation of rigor—it is a redistribution of where rigor must occur. The bar has not been lowered. It’s been moved.
With one pivotal trial at the center, RWD fills the evidentiary ecosystem around it. It guides smarter designs during development, provides confirmatory support at submission, and ensures reproducibility and safety at post-approval.
This is precisely why MarketScan data—and the analytical frameworks built around it—matter more today than ever before. We’re ready for the continued evolution of RWD needs. Connect with us today to see how we can help your research.
