Applying a Risk-benefit Analysis to Outcomes in Tuberculosis Clinical Trials

Abstract

Although it is common to analyze efficacy and safety separately in clinical trials, this could yield a misleading study conclusion if an increase in efficacy is accompanied by a decrease in safety. A risk-benefit analysis is a systematic approach to examine safety and efficacy jointly. Both the "rank-based" and "partial-credit" methods described in this paper allow researchers to create a single, composite outcome incorporating efficacy, safety, and other factors. The first approach compares the distribution of rankings between arms. In the second approach, a score can be assigned to each outcome category, considering its severity and comparing the mean or median scores of arms. The methods were applied to the A5279/Brief Rifapentine-Isoniazid Efficacy for TB Prevention study, and design considerations for future clinical trials are discussed, including the challenge of arriving at a consensus on rankings/scorings. If well designed, a risk-benefit analysis may allow for a superiority comparison and, therefore, avoid setting a noninferiority margin. Clinical Trials Registration. NCT01404312 (A5279).

Keywords: TB; clinical trials; composite outcome ranking; risk-benefit analysis.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Example for Motivation #2: efficacy result from a noninferiority tuberculosis treatment shortening trial. Abbreviations: EXP, experimental arm; SOC, standard of care/control arm; NI, noninferiority margin.

Figure 2.

Example for Motivation #2: safety result from a noninferiority tuberculosis treatment shortening trial. Abbreviations: EXP, experimental arm; SOC, standard of care/control arm.