Abstract
BackgroundIn a non-inferiority (NI) trial, analysis based on the intention-to-treat (ITT) principle is anti-conservative, so current guidelines recommend analysing on a per-protocol (PP) population in addition. However, PP analysis relies on the often implausible assumption of no confounders. Randomisation-based efficacy estimators (RBEEs) allow for treatment non-adherence while maintaining a comparison of randomised groups. Fischer et al. have developed an approach for estimating RBEEs in randomised trials with two active treatments, a common feature of NI trials. The aim of this paper was to demonstrate the use of RBEEs in NI trials using this approach, and to appraise the feasibility of these estimators as the primary analysis in NI trials.MethodsTwo NI trials were used. One comparing two different dosing regimens for the maintenance of remission in people with ulcerative colitis (CODA), and the other comparing an orally administered treatment to an intravenously administered treatment in preventing skeletal-related events in patients with bone metastases from breast cancer (ZICE). Variables that predicted adherence in each of the trial arms, and were also independent of outcome, were sought in each of the studies. Structural mean models (SMMs) were fitted that conditioned on these variables, and the point estimates and confidence intervals compared to that found in the corresponding ITT and PP analyses.ResultsIn the CODA study, no variables were found that differentially predicted treatment adherence while remaining independent of outcome. The SMM, using standard methodology, moved the point estimate closer to 0 (no difference between arms) compared to the ITT and PP analyses, but the confidence interval was still within the NI margin, indicating that the conclusions drawn would remain the same. In the ZICE study, cognitive functioning as measured by the corresponding domain of the QLQ-C30, and use of chemotherapy at baseline were both differentially associated with adherence while remaining independent of outcome. However, while the SMM again moved the point estimate closer to 0, the confidence interval was wide, overlapping with any NI margin that could be justified.ConclusionDeriving RBEEs in NI trials with two active treatments can provide a randomisation-respecting estimate of treatment efficacy that accounts for treatment adherence, is straightforward to implement, but requires thorough planning during the design stage of the study to ensure that strong baseline predictors of treatment are captured. Extension of the approach to handle nonlinear outcome variables is also required.Trial registrationThe CODA study: ClinicalTrials.gov, identifier: NCT00708656. Registered on 8 April 2008. The ZICE study trial: ClinicalTrials.gov, identifier: NCT00326820. Registered on 16 May 2006.
Highlights
In a non-inferiority (NI) trial, analysis based on the intention-to-treat (ITT) principle is anti-conservative, so current guidelines recommend analysing on a per-protocol (PP) population in addition
The aim of this paper is to demonstrate the use of Randomisation-based efficacy estimator (RBEE) in NI trials using the methods outlined by Fischer et al, and to appraise the feasibility of these estimators as the primary analysis in NI trials
As the lower limit of the 95% CI did not include −10%, and this was confirmed in the PP analysis, the findings confirmed the non-inferiority of the once daily dosing (OD) regimen compared to the times daily dosing (TDS) regimen
Summary
In a non-inferiority (NI) trial, analysis based on the intention-to-treat (ITT) principle is anti-conservative, so current guidelines recommend analysing on a per-protocol (PP) population in addition. In some instances, it can be sufficient to demonstrate that a treatment is no worse than another on some outcome of interest This is true where a standard treatment is already in place (a so-called ‘active control’), and the new treatment could offer substantial benefits on non-primary outcomes such as reduce side effects, reduced costs, simpler dosing regimen, etc. The ‘gold standard’ approach to analysis in a superiority trial is based on the intention-to-treat (ITT) principle, where participants are analysed in the groups to which they were originally randomised [3]. This approach is favoured as it preserves randomisation and, in the case of departures from randomised treatment, makes treatment groups appear more similar; producing a conservative estimate of treatment effect. The ideal analytical method would be based on participants who received the treatment to which they were allocated, while maintaining a comparison of groups as randomised (and not prone to the selection biases that are common with a PP analysis)
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