Simulation studies of phase III clinical trials to test the efficacy of a candidate HIV-1 vaccine

One question of particular importance in phase III HIV vaccine trials is th e choice of efficacy measure (EM) to validly and precisely estimate the tru e vaccinal efficacy. Traditional EMs, based on hazard rate ratio (HRR) or c umulative incidence ratio (CIR) are time-sensitive to mode of vaccine actio n and population heterogeneities. Through Monte-Carlo simulation, the perfo rmance of HRR and CIR based EMs are examined across different trial designs and vaccine and population characteristics. A new EM based on log-spline h azard regression (HARE) is proposed. Given that vaccinal properties (mode o f action, time-lag, waning) are unknown a priori, appropriate selection of EM is problematic, and HRR and CIR can be unreliable to estimate the true m aximum efficacy of candidate products. Non-random sexual mixing can exacerb ate biases in HRR and CIR. HARE can offer valid estimation across different modes of vaccine action and in presence of frailty effects, contrary to it s traditional counterparts. Our simulation studies highlight the weaknesses of widely used EMs while offering guidelines for trial design and suggesti ng new avenues for statistical analysis.