U.S. Food and Drug Administration Webinar on the RCT-DUPLICATE Initiative

Why It Matters

The work demonstrates that high‑quality RWE can reliably supplement or replace traditional trials, offering faster, cheaper pathways for drug approvals while maintaining regulatory confidence.

Key Takeaways

• Rigorous real‑world evidence can match RCT outcomes when designs align.
• Emulation challenges, like missing inpatient data, cause result divergence.
• A three‑step benchmark‑calibrate framework guides supplemental indication submissions.
• Pre‑specified protocols and data checks improve transparency and reproducibility.
• High correlation (0.94) observed for trials with close design emulation.

Summary

The FDA’s RCT‑DUPLICATE webinar presented a systematic effort to assess when real‑world evidence (RWE) can stand in for randomized clinical trials (RCTs). The initiative benchmarks observational database studies against completed trials, then extends the methodology to predict outcomes of ongoing studies and to support supplemental indication submissions.

Early results show that rigorously designed, prespecified RWE studies can reach conclusions comparable to their RCT counterparts, especially when key trial design elements—population, exposure, comparator, outcomes—are closely emulated. Divergences arise from practical limitations such as the inability to capture inpatient medication use or to replicate a placebo arm, which can introduce bias or chance effects.

A notable outcome is the three‑step “benchmark‑expand‑calibrate” framework: first emulate a reference trial, then design a database study for a new indication, and finally adjust results based on observed calibration differences. Across more than 30 trial emulations, the overall correlation between RWE and RCT effect estimates was 0.94 for the subset with high design fidelity, illustrating the potential of RWE when methodological rigor is maintained.

The findings underscore that RWE, when transparent, reproducible, and aligned with trial design, can inform regulatory decision‑making, accelerate supplemental indication approvals, and reduce reliance on costly prospective trials. However, developers must anticipate and mitigate design‑emulation gaps to preserve validity.

Original Description

U.S. Food and Drug Administration Webinar on the RCT-DUPLICATE Initiative: Emulating Randomized Clinical Trials with Non-Randomized Real-World Data Studies

On Wednesday, April 29, 2026, the FDA is hosted a free public webinar to provide updates on RCT-DUPLICATE, one of FDA’s demonstration projects addressing key methodological challenges in studies using real-world data (RWD).

This webinar highlights how the RCT-DUPLICATE initiative evaluates when and how non-randomized healthcare database studies have generated valid causal inferences, using randomized controlled trial findings as a benchmark. The initiative has demonstrated that results have been strongly concordant when those studies closely emulated trial designs and has helped clarify when and why divergence may occur.

Building on these findings, the project has also predicted the results of seven randomized controlled trials that were ongoing at the time the database study was conducted and is developing a structured approach that may increase confidence in using RWE to support potential indication expansions.

Event Agenda

Welcome & Introduction:

Marie Bradley, U.S. Food and Drug Administration

Presentation on RCT-DUPLICATE Initiative:

Shirley Wang, Brigham & Women’s Hospital and Harvard Medical School

Sebastian Schneeweiss, Brigham & Women’s Hospital and Harvard Medical School

This event is supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award U01FD008451 totaling $1,399,999 with 100 percent funded by FDA/HHS. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government.