Accelerate vaccine development using seamless phase 2/3 trial designs

Figures & data

Figure 1. Design flow chart.

*The conditional power is calculated based on information from the phase 2 stage.

^△The test statistic is calculated based on information from phase 2 and phase 3A stages.

Figure 2. Performance of seamless design compared to conventional design for case 1 in terms of (a) Overall power, (b) Average sample size and (c) Trial duration when the null hypothesis is false.

r, the ratio of simulated post-vaccination immunogenicity response values of the high dose group to the real values derived from the 9-valent HPV trial, r = Exp(μ_sim)/Exp(μ_real).

Figure 3. Performance of seamless design for Case 1 in terms of (a) Early stop percentages, (b) Correct dose selection when the null hypothesis is false.

r, the ratio of simulated post-vaccination immunogenicity response values of the high dose group to the real values derived from the 9-valent HPV trial, r = Exp(μ_sim)/Exp(μ_real).

Figure 4. Performance of seamless design compared to conventional design for Case 2 in terms of (a) Overall power, (b) Average sample size and (c) trial duration when the null hypothesis is false.

r, the ratio of simulated post-vaccination immunogenicity response values of the high dose group to the real values derived from the 9-valent HPV trial, r = Exp(μ_sim)/Exp(μ_real).

Figure 5. Performance of seamless design for Case 2 in terms of (a) Early stop percentages, (b) Correct dose selection when the null hypothesis is false.

r, the ratio of simulated post-vaccination immunogenicity response values of the high dose group to the real values derived from the 9-valent HPV trial, r = Exp(μ_sim)/Exp(μ_real).

Figure 6. Performance of seamless design compared to conventional design for case 3 in terms of (a) Overall power, (b) Average sample size, (c) Trial duration and (d) Early stop percentages when the null hypothesis is false.

r, the ratio of simulated post-vaccination immunogenicity response values of the high dose group to the real values derived from the 9-valent HPV trial, r = Exp(μ_sim)/Exp(μ_real).

Table 1. Performance of seamless and conventional designs for Case 1 when the null hypothesis is true.

Abbreviations: K, number of endpoints; $\mathit{\rho }$, common correlation coefficient among endpoints; PES, percentage of efficacy stop; PFS, percentage of futility stop.

^aAverage sample size = 4n₁ +2n₂, the light green, green, and dark green regions indicate 100, 500, and 1000 subjects fewer for seamless design than for conventional design respectively.

^bThe light green, green, and dark green regions indicate 5, 10, and 15 months fewer for seamless design than for conventional design respectively.

^cThe light green, green, and dark green regions indicate [30, 60), [60, 90) and [90, 100] of PFS for seamless design.

Table 2. Performance of seamless and conventional designs for Case 2 when the null hypothesis is true.

Abbreviations: K, number of endpoints; PTS, percentage of toxicity stop; PES, percentage of efficacy stop; PFS, percentage of futility stop.

^aAverage sample size = 4n₁ +2n₂, the green region indicate 500 subjects fewer for seamless design than for conventional design.

^bThe light green, green, and dark green regions indicate 5, 10, and 15 months fewer for seamless design than for conventional design respectively.

^cThe light green and green regions indicate [30, 60) and [60, 90) of PFS for seamless design.

Table 3. Performance of two-stage and conventional designs for Case 3 when the null hypothesis is true.

Abbreviations: K, number of endpoints; PES, percentage of efficacy stop; PFS, percentage of futility stop.

^aAverage sample size = $n_{\mathit{T}1}+n_{\mathit{C}1}+n_{\mathit{T}2}+n_{\mathit{C}2}$, denote the whole sample size used for the experimental and control groups, the light green region indicate 100 subjects fewer for two-stage design than for conventional design.

^bThe light green region indicate 5 months fewer for two-stage design than for conventional design.

^cThe light green and green regions indicate [30, 60) and [60, 90) of PFS for two-stage design.