Abstract
The power of a large clinical trial can be adversely affected by low recruitment, follow-up, and adherence rates. External pilot trials estimate these rates and use them, via prespecified decision rules, to determine if the definitive trial is feasible and should go ahead. There is little methodological research underpinning how these decision rules, or the sample size of the pilot, should be chosen. In this article we propose a hypothesis test of the feasibility of a definitive trial, to be applied to the external pilot data and used to make progression decisions. We quantify feasibility by the power of the planned trial, as a function of recruitment, follow-up, and adherence rates. We use this measure to define hypotheses to test in the pilot, propose a test statistic, and show how the error rates of this test can be calculated for the common scenario of a two-arm parallel group definitive trial with a single normally distributed primary endpoint. We use our method to redesign TIGA-CUB, an external pilot trial comparing a psychotherapy with treatment as usual for children with conduct disorders. We then extend our formulation to include using the pilot data to estimate the standard deviation of the primary endpoint and incorporate this into the progression decision.
Highlights
Randomised Controlled Trials (RCTs) often fail to recruit to target [1], leading to an analysis with less power than intended
We have considered how recruitment, follow-up and adherence rates all affect the power of the definitive trial, and have shown how these can be assessed in an external pilot trial as part of a hypothesis test
We have described how the test can be extended to include the common pilot objective of estimating an unknown standard deviation nuisance parameter, and found that for this to be incorporated the sample size of the pilot trial will have to be increased if operating characteristics are to be maintained
Summary
Randomised Controlled Trials (RCTs) often fail to recruit to target [1], leading to an analysis with less power than intended. A common approach to anticipate these problems is to run a small version of the intended trial, known as an external pilot, to obtain estimates of the relevant parameters and decide if, and how, the definitive trial should be conducted [4, 5]. This decision is typically made with reference to so-called Progression Criteria (PCs), a set of conditions which must be satisfied for the definitive trial to be considered feasible [6]. A recent workshop identified that recruitment, follow-up, and intervention adherence have emerged as common targets of progression criteria [6]
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