An adaptive two-arm clinical trial using early endpoints to inform decision making: design for a study of sub-acromial spacers for repair of rotator cuff tendon tears.

BACKGROUND: There is widespread concern across the clinical and research communities that clinical trials, powered for patient-reported outcomes, testing new surgical procedures are often expensive and time-consuming, particularly when the new intervention is shown to be no better than the standard. Conventional (non-adaptive) randomised controlled trials (RCTs) are perceived as being particularly inefficient in this setting. Therefore, we have developed an adaptive group sequential design that allows early endpoints to inform decision making and show, through simulations and a worked example, that these designs are feasible and often preferable to conventional non-adaptive designs. The methodology is motivated by an ongoing clinical trial investigating a saline-filled balloon, inserted above the main joint of the shoulder at the end of arthroscopic debridement, for treatment of tears of rotor cuff tendons. This research question and setting is typical of many studies undertaken to assess new surgical procedures. METHODS: Test statistics are presented based on the setting of two early outcomes, and methods for estimation of sequential stopping boundaries are described. A framework for the implementation of simulations to evaluate design characteristics is also described. RESULTS: Simulations show that designs with one, two and three early looks are feasible and, with appropriately chosen futility stopping boundaries, have appealing design characteristics. A number of possible design options are described that have good power and a high probability of stopping for futility if there is no evidence of a treatment effect at early looks. A worked example, with code in R, provides a practical demonstration of how the design might work in a real study. CONCLUSIONS: In summary, we show that adaptive designs are feasible and could work in practice. We describe the operating characteristics of the designs and provide guidelines for appropriate values for the stopping boundaries for the START:REACTS (Sub-acromial spacer for Tears Affecting Rotator cuff Tendons: a Randomised, Efficient, Adaptive Clinical Trial in Surgery) study. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN17825590. Registered on 5 March 2018.

Adaptive designs in clinical trials: from scientific advice to marketing authorisation to the European Medicine Agency.

BACKGROUND: In recent years, experience on the application of adaptive designs in confirmatory clinical trials has accumulated. Although planning such trials comes at the cost of additional operational complexity, adaptive designs offer the benefit of flexibility to update trial design and objectives as data accrue. In 2007, the European Medicines Agency (EMA) provided guidance on confirmatory clinical trials with adaptive (or flexible) designs. In order to better understand how adaptive trials are implemented in practice and how they may impact medicine approval within the EMA centralised procedure, we followed on 59 medicines for which an adaptive clinical trial had been submitted to the EMA Scientific Advice (SA) and analysed previously in a dedicated EMA survey of scientific advice letters. We scrutinized in particular the submission of the corresponding medicines for a marketing authorisation application (MAA). We also discuss the current regulatory perspective as regards the implementation of adaptive designs in confirmatory clinical trials. METHODS: Using the internal EMA MAA database, the AdisInsight database and related trial registries, we analysed how many of these 59 trials actually started, the completion status, results, the time to trial start, the adaptive elements finally implemented after SA, their possible influence on the success of the trial and corresponding product approval. RESULTS: Overall 31 trials out of 59 (53%) were retrieved. Thirty of them (97%) have been started and 23 (74%) concluded. Nine of these trials (39% out of 23) demonstrated a significant treatment effect on their primary endpoint and 4 (17% out of 23) supported a marketing authorisation (MA). An additional two trials were stopped using pre-defined criteria for futility, efficiently identifying trials on which further resources should not be spent. Median time to trial start after SA letter was given by EMA was 5 months. In the investigated trial registries, at least 18 trial (58% of 31 retrieved trials) designs were implemented with adaptive elements, which were predominantly dose selection, sample size reassessment (SSR) and stopping for futility (SFF). Among the 11 completed trials including adaptive elements, 6 demonstrated a significant treatment effect on their primary endpoint (55%). CONCLUSIONS: Adaptive designs are now well established in the drug development landscape. If properly pre-planned, adaptations can play a key role in the success of some of these trials, for example to help successfully select the most promising dose regimens for phase II/III trials. Interim analyses can also enable stopping of trials for futility when they do not hold their promises. Type I error rate control, trial integrity and results consistency between the different stages of the analyses are fundamental aspects to be discussed thoroughly. Engaging early dialogue with regulators and implementing the scientific advice received is strongly recommended, since much experience in discussing adaptive designs and assessing their results has been accumulated.

Choice of futility boundaries for group sequential designs with two endpoints.

BACKGROUND: In clinical trials, the opportunity for an early stop during an interim analysis (either for efficacy or for futility) may relevantly save time and financial resources. This is especially important, if the planning assumptions required for power calculation are based on a low level of evidence. For example, when including two primary endpoints in the confirmatory analysis, the power of the trial depends on the effects of both endpoints and on their correlation. Assessing the feasibility of such a trial is therefore difficult, as the number of parameter assumptions to be correctly specified is large. For this reason, so-called 'group sequential designs' are of particular importance in this setting. Whereas the choice of adequate boundaries to stop a trial early for efficacy has been broadly discussed in the literature, the choice of optimal futility boundaries has not been investigated so far, although this may have serious consequences with respect to performance characteristics. METHODS: In this work, we propose a general method to construct 'optimal' futility boundaries according to predefined criteria. Further, we present three different group sequential designs for two endpoints applying these futility boundaries. Our methods are illustrated by a real clinical trial example and by Monte-Carlo simulations. RESULTS: By construction, the provided method of choosing futility boundaries maximizes the probability to correctly stop in case of small or opposite effects while limiting the power loss and the probability of stopping the study 'wrongly'. Our results clearly demonstrate the benefit of using such 'optimal' futility boundaries, especially compared to futility boundaries commonly applied in practice. CONCLUSIONS: As the properties of futility boundaries are often not considered in practice and unfavorably chosen futility boundaries may imply bad properties of the study design, we recommend assessing the performance of these boundaries according to the criteria proposed in here.