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<p>The U.S. Food and Drug Administration’s proposal to adopt a single randomized controlled trial (RCT) as the default evidentiary standard for drug approval marks a substantial change in regulatory philosophy. Although advances in mechanistic science, biomarkers, and statistical methods may justify this approach for conditions with significant, biologically coherent treatment effects, applying it to chronic obstructive pulmonary disease (COPD) raises substantial concerns. COPD is a heterogeneous, multifactorial syndrome with variable disease trajectories, modest treatment effects, and limited validated biomarkers. In this context, reliance on a single trial increases inferential fragility, risks type I error, and limits generalizability due to restrictive eligibility criteria and contextual variability. Although biomarker- and trait-based strategies are promising, they remain insufficiently validated to ensure robust estimation of treatment effects across populations. Similarly, the modest effect sizes and endpoint variability in COPD trials amplify the risk of false-positive or context-specific findings. Replication across independent studies primarily serves to test the consistency and robustness of observed effects under varying conditions, rather than to increase statistical power. We discuss a conceptual regulatory framework in which a single RCT may be acceptable only if it meets strict criteria, including large effect sizes, strong biological plausibility, a low risk of bias, and consistent subgroup effects. However, for highly heterogeneous conditions such as COPD, at least two independent studies remain preferable. Alternatively, if a single robust RCT is conducted, equivalent post-marketing validation is required. Ultimately, regulatory standards should be calibrated to biological and methodological uncertainty, balancing timely patient access with evidentiary reliability.</p>

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From Signal to Certainty: Why COPD Needs More Than One Trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月31日

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  • Mario Cazzola,
  • Daiana Stolz,
  • Don D. Sin,
  • Maria Gabriella Matera,
  • Paola Rogliani

摘要

The U.S. Food and Drug Administration’s proposal to adopt a single randomized controlled trial (RCT) as the default evidentiary standard for drug approval marks a substantial change in regulatory philosophy. Although advances in mechanistic science, biomarkers, and statistical methods may justify this approach for conditions with significant, biologically coherent treatment effects, applying it to chronic obstructive pulmonary disease (COPD) raises substantial concerns. COPD is a heterogeneous, multifactorial syndrome with variable disease trajectories, modest treatment effects, and limited validated biomarkers. In this context, reliance on a single trial increases inferential fragility, risks type I error, and limits generalizability due to restrictive eligibility criteria and contextual variability. Although biomarker- and trait-based strategies are promising, they remain insufficiently validated to ensure robust estimation of treatment effects across populations. Similarly, the modest effect sizes and endpoint variability in COPD trials amplify the risk of false-positive or context-specific findings. Replication across independent studies primarily serves to test the consistency and robustness of observed effects under varying conditions, rather than to increase statistical power. We discuss a conceptual regulatory framework in which a single RCT may be acceptable only if it meets strict criteria, including large effect sizes, strong biological plausibility, a low risk of bias, and consistent subgroup effects. However, for highly heterogeneous conditions such as COPD, at least two independent studies remain preferable. Alternatively, if a single robust RCT is conducted, equivalent post-marketing validation is required. Ultimately, regulatory standards should be calibrated to biological and methodological uncertainty, balancing timely patient access with evidentiary reliability.