Redefining Regulatory Proof: The End of the Two‐Trial Paradigm
Abstract
The recent decision to establish a single pivotal trial as the default evidentiary standard for Food and Drug Administration (FDA) approval marks a substantive shift in the architecture of regulatory proof. This marks a shift from replication‐based validation to a coherence‐based model of sufficiency, beyond a procedural adjustment. Because FDA standards likely influence global development strategies, this change will likely extend beyond the United States. Although accelerating access and reducing development costs are legitimate objectives, the reform raises methodological and epistemological concerns. The statistical rationale does not fully incorporate the contextual factors that influence false‐positive risk, including prior plausibility and statistical power. Prior plausibility remains informal, and post‐marketing evidence seldom restores the epistemic security provided by independent replication. Replication is not merely a statistical redundancy but rather a structural safeguard of robustness and external validity. Without explicit safeguards, increased regulatory flexibility may generate heterogeneity in evidentiary thresholds and progressively weaken the discriminative function of health technology assessment.
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BibTeX
@article{lega2026redefining,
title = {{Redefining Regulatory Proof: The End of the Two‐Trial Paradigm}},
author = {Jean‐christophe Lega and Steeve Provencher and Bruno Falissard and Clara Locher and Matthieu Roustit and Arthur Gougeon and Rémy Boussageon and Sylvie Chevret},
journal = {Fundamental \& Clinical Pharmacology},
year = {2026},
month = sep,
doi = {10.1111/fcp.70110},
url = {https://hal.science/hal-05743396v1},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Redefining Regulatory Proof: The End of the Two‐Trial Paradigm
AU - Jean‐christophe Lega
AU - Steeve Provencher
AU - Bruno Falissard
AU - Clara Locher
AU - Matthieu Roustit
AU - Arthur Gougeon
AU - Rémy Boussageon
AU - Sylvie Chevret
PY - 2026
DA - 2026/09/09
JO - Fundamental & Clinical Pharmacology
DO - 10.1111/fcp.70110
UR - https://hal.science/hal-05743396v1
AB - The recent decision to establish a single pivotal trial as the default evidentiary standard for Food and Drug Administration (FDA) approval marks a substantive shift in the architecture of regulatory proof. This marks a shift from replication‐based validation to a coherence‐based model of sufficiency, beyond a procedural adjustment. Because FDA standards likely influence global development strategies, this change will likely extend beyond the United States. Although accelerating access and reducing development costs are legitimate objectives, the reform raises methodological and epistemological concerns. The statistical rationale does not fully incorporate the contextual factors that influence false‐positive risk, including prior plausibility and statistical power. Prior plausibility remains informal, and post‐marketing evidence seldom restores the epistemic security provided by independent replication. Replication is not merely a statistical redundancy but rather a structural safeguard of robustness and external validity. Without explicit safeguards, increased regulatory flexibility may generate heterogeneity in evidentiary thresholds and progressively weaken the discriminative function of health technology assessment.
SN - 0767-3981
SN - 1472-8206
ER -