Table 3.
Frequentist early-stage designs described in the literature and requirements for the vaccine trial design
| |
|
Relevant features of the vaccine trial |
||||||
|---|---|---|---|---|---|---|---|---|
| |
|
Trial design and endpoints |
Logistics |
|||||
| |
|
Absence of a validated surrogate endpoint for efficacy
a
|
Efficacy outcome not assessed in real-time
b
|
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 points
c
|
High early accrual dynamics
d
|
Randomised multi-arm multi-center trial |
|
Potential alternative frequentist designs |
|
|
|
|
|
|
|
|
| Type | Example | |||||||
|
A) Designs for both efficacy and toxicity evaluation |
|
|
|
|
|
|
|
|
| Non-comparative bivariate two-stage designs |
Bryant and Day design [53] |
|
No |
|
|
No |
No |
|
| 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 |
|
|
|
|
|
|
|
|
| Non-comparative stopping rule based on continuous toxicity monitoring per serious adverse event |
Continuous monitoring proposed by Kramar et al. [55] |
|
|
|
|
|
No |
|
| Non-comparative stopping rule based on continuous toxicity monitoring per participant |
Continuous monitoring proposed by Ivanova et al. [56] |
|
|
|
|
|
No |
|
| Non-comparative stopping rule based on group-sequential approach |
Probabilistic approach proposed by Yu et al. [57] |
|
|
|
|
|
No |
|
|
C) Designs for efficacy evaluation, considered in combination with toxicity stopping rules in B) |
|
|
|
|
|
|
|
|
| Non-comparative two-stage or multi-stage designs |
Gehan’s, Simon’s or Fleming’s design [48,58,59] |
|
No |
|
|
|
No |
|
| Non-comparative treatment selection design |
Ranking design by Simon [35] |
No |
|
|
No |
|
|
|
| Comparative multi-arm designs |
Comparative phase II designs; screening designs [60] |
No |
|
No |
|
|
|
|
| Group sequential designs; adaptive designs with comparative decision rule [61] | No | No | No | |||||
Non-exhaustive list of trial features and alternative frequentist designs. Only main features of vaccine trial leading to incompatibility with alternative designs are indicated.
No: characteristic of the vaccine trial not compatible with alternative design.
The term ‘non-comparative’ is used to indicate that no inter-arm comparison is required.
aNo single validated endpoint in HIV vaccine immunogenicity trial, since correlates of vaccine protection are unknown. Currently, multiple different immunogenicity measurements are of interest without any definite hierarchical order in their relevance (multidimensional data) and no obvious definition of a composite endpoint. In the present vaccine trial, the primary immunogenicity endpoint is only used as a screening assay to discard out non-immunogenic strategies.
bImmunogenicity measurements done in batch on frozen samples at the end of the trial.
cSafety evaluation at week 2; Efficacy evaluation at week 30.
dHigh early accrual dynamics expected after a single call for volunteers in the media.