Abstract
BackgroundExternal pilot or feasibility studies can be used to estimate key unknown parameters to inform the design of the definitive randomised controlled trial (RCT). However, there is little consensus on how large pilot studies need to be, and some suggest inflating estimates to adjust for the lack of precision when planning the definitive RCT.MethodsWe use a simulation approach to illustrate the sampling distribution of the standard deviation for continuous outcomes and the event rate for binary outcomes. We present the impact of increasing the pilot sample size on the precision and bias of these estimates, and predicted power under three realistic scenarios. We also illustrate the consequences of using a confidence interval argument to inflate estimates so the required power is achieved with a pre-specified level of confidence. We limit our attention to external pilot and feasibility studies prior to a two-parallel-balanced-group superiority RCT.ResultsFor normally distributed outcomes, the relative gain in precision of the pooled standard deviation (SDp) is less than 10% (for each five subjects added per group) once the total sample size is 70. For true proportions between 0.1 and 0.5, we find the gain in precision for each five subjects added to the pilot sample is less than 5% once the sample size is 60. Adjusting the required sample sizes for the imprecision in the pilot study estimates can result in excessively large definitive RCTs and also requires a pilot sample size of 60 to 90 for the true effect sizes considered here.ConclusionsWe recommend that an external pilot study has at least 70 measured subjects (35 per group) when estimating the SDp for a continuous outcome. If the event rate in an intervention group needs to be estimated by the pilot then a total of 60 to 100 subjects is required. Hence if the primary outcome is binary a total of at least 120 subjects (60 in each group) may be required in the pilot trial. It is very much more efficient to use a larger pilot study, than to guard against the lack of precision by using inflated estimates.
Highlights
External pilot or feasibility studies can be used to estimate key unknown parameters to inform the design of the definitive randomised controlled trial (RCT)
When we examine the relative percentage gain in precision by adding more subjects to the sample, our data suggest that a total of at least 70 may be necessary for estimating the standard deviation of a normally distributed variable with good precision, and 60 to 100 subjects in a single group for estimating an event rate seems reasonable
On average when the definitive RCT is planned using an estimate from a pilot study there will be a tendency for the planned study to be underpowered
Summary
External pilot or feasibility studies can be used to estimate key unknown parameters to inform the design of the definitive randomised controlled trial (RCT). A substantial proportion of these research grants were randomised controlled trials (RCTs) to assess the clinical effectiveness and costeffectiveness of new health technologies. RCTs aim to provide precise estimates of treatment effects and need to be well designed to have good power to answer specific clinically important questions. Both overpowered and underpowered trials are undesirable and each poses different ethical, statistical and practical problems. If the outcome is well established, these key population or control parameters can be estimated from previous studies (RCTs or cohort studies) or through meta-analyses. In some cases finding robust estimates can pose quite a challenge if reliable data, for the proposed trial population under investigation, do not already exist
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