Search

A noninferiority study is often used to investigate whether a treatment's efficacy or safety profile is acceptable compared with an alternative therapy regarding the time to a clinical event. The empirical quantification of the treatment difference for such a study is routinely based on the hazard ratio (HR) estimate. The HR, which is not a relative risk, may be difficult to interpret clinically, especially when the underlying proportional hazards assumption is violated. The precision of the HR estimate depends primarily on the number of observed events but not directly on exposure times or sample size of the study population. If the event rate is low, the study may require an impractically large number of events to ensure that the prespecified noninferiority criterion for the HR is attainable. This article discusses deficiencies in the current approach for the design and analysis of a noninferiority study. Alternative procedures are provided, which do not depend on any model assumption, to compare 2 treatments. For a noninferiority safety study, the patients' exposure times are more clinically important than the observed number of events. If the patients' exposure times are long enough to evaluate safety reliably, then these alternative procedures can effectively provide clinically interpretable evidence on safety, even with relatively few observed events. These procedures are illustrated with data from 2 studies. One explores the cardiovascular safety of a pain medicine; the second examines the cardiovascular safety of a new treatment for diabetes. These alternative strategies to evaluate safety or efficacy of an intervention lead to more meaningful interpretations of the analysis results than the conventional strategy that uses the HR estimate.

Background: When clinical practice is governed by evidence-based guidelines and there is consensus about their validity, practice variation should be minimal. For areas in which evidence gaps exist, greater variation is expected., Objective: To systematically assess interinstitutional variation in management decisions for 4 common types of cancer., Design: Multi-institutional, observational cohort study of patients with cancer diagnosed between July 2006 through May 2011 and observed through 31 December 2011., Setting: 18 cancer centers participating in the formulation of treatment guidelines and systematic outcomes assessment through the National Comprehensive Cancer Network., Patients: 25 589 patients with incident breast cancer, colorectal cancer, lung cancer, or non-Hodgkin lymphoma., Measurements: Interinstitutional variation for 171 binary management decisions with varying levels of supporting evidence. For each decision, variation was characterized by the median absolute deviation of the center-specific proportions., Results: Interinstitutional variation was high (median absolute deviation >10%) for 35 of 171 (20%) oncology management decisions, including 9 of 22 (41%) decisions for non-Hodgkin lymphoma, 16 of 76 (21%) for breast cancer, 7 of 47 (15%) for lung cancer, and 3 of 26 (12%) for colorectal cancer. Forty-six percent of high-variance decisions involved imaging or diagnostic procedures and 37% involved choice of chemotherapy regimen. The evidence grade underpinning the 35 high-variance decisions was category 1 for 0%, 2A for 49%, and 2B/other for 51%., Limitation: Physician identifiers were unavailable, and results may not generalize outside of major cancer centers., Conclusion: The substantial variation in institutional practice manifest among cancer centers reveals a lack of consensus about optimal management for common clinical scenarios. For clinicians, awareness of management decisions with high variation should prompt attention to patient preferences. For health systems, high variation can be used to prioritize comparative effectiveness research, patient-provider education, or pathway development., Primary Funding Source: National Cancer Institute and National Comprehensive Cancer Network.

Source Citation: Schrag D, Uno H, Rosovsky R, et al; CANVAS Investigators. Direct oral anticoagulants vs low-molecular-weight heparin and recurrent VTE in patients with cancer: a randomized clinical trial. JAMA. 2023;329:1924-1933. 37266947 Clinical Impact Ratings: GIM/FP/GP: Hospitalists: Oncology: Hematology: [ABSTRACT FROM AUTHOR]