|  | Relevant features of the vaccine trial | ||||||
---|---|---|---|---|---|---|---|---|
 |  | Trial design and endpoints | Logistics | |||||
 |  | Absence of a validated surrogate endpoint for efficacya | Efficacy outcome not assessed in real-timeb | No control arm with ‘standard’ strategy or placebo | Possibility to move more than one strategy to the next development stage | Safety and efficacy endpoints at different time pointsc | High early accrual dynamicsd | Randomised multi-arm multi-center trial |
Potential alternative frequentist designs | Â | Â | Â | Â | Â | Â | Â | |
Type | Example | Â | Â | Â | Â | Â | Â | Â |
A) Designs for both efficacy and toxicity evaluation | Â | Â | Â | Â | Â | Â | Â | |
Non-comparative bivariate two-stage designs | Bryant and Day design [53] | Â | No | Â | Â | No | No | Â |
Seamless phase I/II design | Design proposed by Messer et al. (including a 3 + 3 design for the integrated phase I evaluation) [54] |  |  |  |  |  | No | No |
B) Toxicity stopping rules integrated in efficacy designs | Â | Â | Â | Â | Â | Â | Â | |
Non-comparative stopping rule based on continuous toxicity monitoring per serious adverse event | Continuous monitoring proposed by Kramar et al. [55] | Â | Â | Â | Â | Â | No | Â |
Non-comparative stopping rule based on continuous toxicity monitoring per participant | Continuous monitoring proposed by Ivanova et al. [56] | Â | Â | Â | Â | Â | No | Â |
Non-comparative stopping rule based on group-sequential approach | Probabilistic approach proposed by Yu et al. [57] | Â | Â | Â | Â | Â | No | Â |
C) Designs for efficacy evaluation, considered in combination with toxicity stopping rules in B) | Â | Â | Â | Â | Â | Â | Â | |
Non-comparative two-stage or multi-stage designs | Â | No | Â | Â | Â | No | Â | |
Non-comparative treatment selection design | Ranking design by Simon [35] | No | Â | Â | No | Â | Â | Â |
Comparative multi-arm designs | Comparative phase II designs; screening designs [60] | No | Â | No | Â | Â | Â | Â |
 | Group sequential designs; adaptive designs with comparative decision rule [61] | No | No |  |  |  | No |  |