Chauhan Weighted Trajectory Analysis of combined efficacy and safety outcomes for risk-benefit analysis

Analyzing and effectively communicating the efficacy and toxicity of treatment is the basis of risk benefit analysis (RBA). More efficient and objective tools are needed. We apply Chauhan Weighted Trajectory Analysis (CWTA) to perform RBA with superior objectivity, power, and clarity. We used CWTA to perform 1000-fold simulations of RCTs using ordinal endpoints for both treatment efficacy and toxicity. RCTs were simulated with 1:1 allocation at defined sample sizes and hazard ratios. We studied the simplest case of 3 levels each of toxicity and efficacy and the general case of the advanced cancer trial, with efficacy graded by five RECIST 1.1 health statuses and toxicity by the six-point CTCAE scale (6 x 5 matrix). The latter model was applied to a real-world dose escalation phase I trial in advanced cancer. Simulations in both the 3 x 3 and the 6 x 5 advanced cancer matrix confirmed that drugs with both superior efficacy and toxicity profiles synergize for greater statistical power with CWTA-RBA. The CWTA-RBA 6 x 5 matrix reduced sample size requirements over CWTA efficacy-only analysis. Application to the dose finding phase I clinical trial provided objective, statistically significant validation for the selected dose. CWTA-RBA, by incorporating both drug efficacy and toxicity, provides a single test statistic and plot that analyzes and effectively communicates therapeutic risks and benefits. CWTA-RBA requires fewer patients than CWTA efficacy-only analysis when the experimental drug is both more effective and less toxic. CWTA-RBA facilitates the objective and efficient assessment of new therapies throughout the drug development pathway. Furthermore, several advantages over competing tests in communicating risk-benefit will assist regulatory review, clinical adoption, and understanding of therapeutic risks and benefits by clinicians and patients alike.