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Are large randomised controlled trials in severe sepsis and septic shock statistically disadvantaged by repeated inadvertent underestimates of required sample size?
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    Further response from a reviewer: Are large randomised controlled trials in severe sepsis and septic shock statistically disadvantaged by repeated inadvertent underestimates of required sample size?

    In their manuscript, Wong et al. discuss an important aspect of randomized control trial (RCT) design: sample size determination. Although their focus is on RCTs for sepsis with the primary outcome of mortality, their review is generalizable to RCTs with binary primary outcomes (i.e. the presence or absence of an event of interest) and thus, may influence the design of RCTs in many patient populations. Therefore, it is important to address one of the primary conclusions of the manuscript.

    Wong et al. reviewed the sample size calculations for 13 RCTs for sepsis where the average treatment effect was defined as the absolute difference in the mortality rate comparing the control arm to the intervention arm. We will subsequently refer to this average treatment effect as AD. To determine the required sample size needed per arm for the RCT, it is required to specify both the anticipated mortality rate in the control arm and the AD. For the 13 RCTs, Wong et al. extracted and compared, via meta-analysis, the anticipated mortality rate in the control arm and AD used in the sample size calculation to the respective values obtained from the completed RCTs. They found that for both the control arm mortality rate and the AD, the anticipated values were, on average, greater than the values from the completed RCTs. The third paragraph of their discussion states “The consistent overestimation of control arm event rate (or lower than anticipated actual control arm event rate...

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    Conflict of Interest:
    I reviewed the paper for BMJ Open.