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Table 3 Frequentist early-stage designs described in the literature and requirements for the vaccine trial design

From: Accelerating clinical development of HIV vaccine strategies: methodological challenges and considerations in constructing an optimised multi-arm phase I/II trial design

  

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

       

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

 
  1. Non-exhaustive list of trial features and alternative frequentist designs. Only main features of vaccine trial leading to incompatibility with alternative designs are indicated.
  2. No: characteristic of the vaccine trial not compatible with alternative design.
  3. The term ‘non-comparative’ is used to indicate that no inter-arm comparison is required.
  4. 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.
  5. bImmunogenicity measurements done in batch on frozen samples at the end of the trial.
  6. cSafety evaluation at week 2; Efficacy evaluation at week 30.
  7. dHigh early accrual dynamics expected after a single call for volunteers in the media.