Date: December 4, 2025 Guest Skeptic: Dr. Jestin Carlson – Long-time listener, second-time guest. Reference: Reinaud et al. Reporting of Noninferiority Margins on ClinicalTrials.gov: A Systematic Review. JAMA Netw Open. 2025 Case: You are working with a resident who asks you about a new thrombolytic they heard about on the SGEM for acute ischemic stroke. This new treatment was found not to be inferior to the existing thrombolytic, but they are not sure how the paper reached that conclusion. You start to discuss noninferiority margins when the resident asks you, “Are the noninferiority margins reported on ClinicalTrials.gov consistent with the final publications?” Background: A non-inferiority (NI) trial asks whether a new strategy is “not unacceptably worse” than an established, effective strategy by more than a pre-specified amount. The non-inferiority margin (Δ) or delta is the largest loss of effectiveness we would tolerate in exchange for another advantage (lower cost, easier logistics, fewer adverse effects). Regulators and methods groups emphasize that Δ must be clinically justified, pre-specified, and not chosen after seeing the data. The Δ is then tested using a one-sided hypothesis procedure or, equivalently, by checking whether the confidence interval for the treatment difference stays within Δ. For example, a new medicine to treat hypertension lowers patients’ systolic blood pressure by 1 point more than the standard treatment but causes gastrointestinal (GI) upset in 50% of patients. That difference may be statistically significant, but clinically it doesn’t result in a net benefit for the patients since so many of them get GI upset. Ideally, the noninferiority margins should be set up before the trial is conducted to minimize bias. Many modern ED trials rely on NI logic (TNK vs tPA for stroke, non-operative treatment of appendicitis, Simple Aspiration versus Drainage for Complete Pneumothorax, etc). However, prior work suggested poor reporting of noninferiority margins with reporting rates as low as 2.6% for studies published between 2012 and 2014. That was over 10 years ago...hopefully we have improved since then. Clinical Question: What proportion of registered noninferiority randomized trials report the noninferiority margin at registration, and how consistent are margins between ClinicalTrials.gov and corresponding publications? Reference: Reinaud et al. Reporting of Noninferiority Margins on ClinicalTrials.gov: A Systematic Review. JAMA Netw Open. 2025 Population: All registered non‑inferiority trials on ClinicalTrials.gov with primary completion 2010–2015 (Stage 1) and all first‑posted 2022–2023 (Stage 2). Excluded: Nonrandomized, single-arm, phase 1–2/2–3, diagnostic/screening trials where noninferiority was only a secondary outcome. Exposure: Presence of a prespecified noninferiority margin reported on ClinicalTrials.gov (at registration / during enrollment / after primary completion / in posted results). Comparison: Descriptive contrasts across timepoints and between the registry and corresponding publications (consistency). Outcome: Primary Outcome: Proportion reporting the noninferiority margin at registration on ClinicalTrials.gov. Secondary Outcomes: Timing of first reporting (registration, during enrollment, after completion, or in posted results); proportion reporting margin in posted results; proportion reporting margin in the corresponding publication; justification of margin; consistency between registry and publication; reporting of primary analysis population and Type I Error. Type of Study: A systematic review of registered randomized trials’ methods reporting. Authors’ Conclusions: “Reporting of the noninferiority margin on ClinicalTrials.gov was low (3.0% in 2010–2015 sample, 9.2% in 2022-2023 sample). Because margins are central to design and interpretation, mandatory reporting of trial design and the noninferiority margin at registration would improve transparency and reliability of noninferiority trial results.” Quality Checklist for Systematic Review: Was the main question clearly stated? Yes Was the search detailed and exhaustive? Yes Were the inclusion criteria appropriate? Yes Included studies sufficiently valid? Yes Results similar from study to study? Yes Any financial conflicts of interest? Authors do not report any financial conflicts of interest. Results: In the 2010 to 2015 cohort (n=266), 60% were industry‑funded; most evaluated drugs/biologics (~67%); parallel‑arm designs predominated (94%); open‑label was common (49%); adults‑only accounted for 74%; and the median planned sample size was 304 (IQR 63 to 545). The 2022 to 2023 cohort (n=327) showed similar patterns with more adult-only studies (83%) and a median planned sample size 228 (IQR 50 to 406). Key Result: Very few trials pre-specified a Δ at registration, a super majority reported a Δ in their publication and registry‑to‑publication consistency could only be evaluated in a handful of studies. 2010 t
