Table 1

Examples of core categories

Core categoryStudy design exampleStudy design definitionStudy design methodology
Master protocolsPlatform‘A platform trial is a single histology randomized phase II clinical trial involving multiple biomarkers and multiple drugs. Rather than assuming that we know which drug is appropriate for which biomarker stratum, randomization among drugs is used in the platform trial.’43 ‘Initially the treatments are randomized with equal weights to the patients of a stratum. As data accumulates, the randomization weights change to favour assignment of drugs with higher within-stratum response rates. The endpoint used must be observed early enough to enable adaption of randomization weights.’ 43
Randomise-allBiomarker-positive and overall strategies with fall-back analysis‘It evaluates both the treatment effect in the overall study population and in the biomarker-positive subgroup sequentially.’14 ‘In the fall-back design, we first test the overall population using the reduced significance level Embedded Image and if the test is significant, we consider that the novel treatment is effective in the overall population; however, if the result is not significant then we test the treatment effect in the biomarker-positive subgroup using the level of significance Embedded Image ,where α is the overall significance level (Type I error rate). The significance levels α can be considered as one-sided or two-sided significance levels.’14
Biomarker strategyBiomarker-strategy design with treatment randomisation in the control arm‘The biomarker-strategy design with treatment randomization in the control treatment is able to inform us about whether the biomarker-based strategy is better than not only the standard treatment but also better than the experimental treatment in the overall population.’ 14 ‘Patients are first randomly assigned to either the biomarker-based strategy arm or to the non-biomarker-based strategy arm. Next, patients who are allocated to the non-biomarker-based strategy are again randomized either to the experimental treatment arm or to the standard treatment arm irrespective of their biomarker status. Patients who are allocated to the biomarker-based strategy and who are biomarker-positive are given the experimental treatment and patients who are biomarker-negative are given the control treatment.’ 14
EnrichmentAdaptive threshold sample-enrichment design‘It is a two-stage design in a Phase III setting(…) to adaptively modify accrual in order to broaden the targeted patient population.’ 15 ‘At the interim analysis stage, the treatment effect of a sample of patients (Embedded Image ) from the biomarker-positive subset is estimated. If an improvement is seen in the experimental treatment arm which is greater than a pre-specified threshold value (ie, the estimated treatment difference between the novel treatment arm and the control treatment arm for this subpopulation is greater than a threshold value c divided by the square root of the aforementioned sample size Embedded Image ) the trial continues with accrual of patients from the entire biomarker-positive subgroup and additional patients are also accrued from the biomarker-negative subpopulation; otherwise the trial is stopped for futility. At the end of the trial, the treatment effect is estimated for all subpopulations. Researchers should choose the sample size Embedded Image so that a persuasive result can be reached when the first stage of the trial is completed.’ 15