Integrating selection and confirmation phases into a single trial can expedite the development of new treatments and allows to use all accumulated data in the decision process. In this paper we review adaptive treatment selection based on combination tests and propose overall adjusted p-values and simultaneous confidence intervals. Also point estimation in adaptive trials is considered. The methodology is illustrated in a detailed example based on an actual planned study.

Background: It has been proposed that treatments for irritable bowel syndrome with constipation (IBS-C) should provide rapid symptomatic relief, be intermittent, and effective upon repeated use. Aims: To evaluate the efficacy and safety of tegaserod on IBS symptoms, and its impact on quality of life and health economic measures. Patients: Women (>18 years of age) with IBS-C according to the Rome II criteria. Methods: Prospective, double blind, placebo controlled, randomised trial. Women with IBS-C either received tegaserod 6 mg twice daily or placebo for one month. Patients with at least a partial response entered a treatment free interval. Upon symptom recurrence, tegaserod treated patients were re-randomised to tegaserod or placebo for an additional month. Primary efficacy variables were response (overall IBS symptoms and abdominal discomfort/pain) to first and repeated treatment. Analysis was by intention to treat. Results: 2660 patients and 1191 patients were randomised for first and repeated treatment respectively. Tegaserod was superior to placebo for each primary efficacy variable (first treatment: 33.7% v 24.2% responders respectively for relief of IBS symptoms and 31.3% v 22.1% for relief of abdominal discomfort/ pain; repeated treatment: 44.9% v 28.7%, and 42.4% v 27.1%, all p,0.0001). Tegaserod was superior to placebo for every secondary efficacy variable (relief of abdominal discomfort/pain, bloating and constipation; stool frequency and consistency). A response to tegaserod was observed within the first treatment week. Tegaserod produced greater satisfaction, work productivity, and improved quality of life than placebo (p,0.05). Conclusion: Tegaserod provides rapid and sustained relief of IBS-C symptoms both during first and repeated treatment.

LUMINOUS study confirms the effectiveness of ranibizumab for the treatment of neovascular age-related macular degeneration in real-world clinical practice. Visual acuity gains were higher among patients receiving a greater number of ranibizumab injections, particularly with three loading doses and lower BLVA levels. No new safety signals with ranibizumab were identified. Supplemental Digital Content is Available in the Text.

Purpose: Recent years have seen a change in the way that clinical trials are being conducted. There has been a rise of designs more flexible than traditional adaptive and group sequential trials which allow the investigation of multiple substudies with possibly different objectives, interventions, and subgroups conducted within an overall trial structure, summarized by the term master protocol. This review aims to identify existing master protocol studies and summarize their characteristics. The review also identifies articles relevant to the design of master protocol trials, such as proposed trial designs and related methods. Methods: We conducted a comprehensive systematic search to review current literature on master protocol trials from a design and analysis perspective, focusing on platform trials and considering basket and umbrella trials. Articles were included regardless of statistical complexity and classified as reviews related to planned or conducted trials, trial designs, or statistical methods. The results of the literature search are reported, and some features of the identified articles are summarized. Findings: Most of the trials using master protocols were designed as single-arm (n ¼ 29/50), Phase II trials (n ¼ 32/50) in oncology (n ¼ 42/50) using a binary endpoint (n ¼ 26/50) and frequentist decision rules (n ¼ 37/50). We observed an exponential increase in publications in this domain during the last few years in both planned and conducted trials, as well as relevant methods, which we assume has not yet reached its peak. Although many operational and statistical challenges associated with such trials remain, the general consensus seems to be that master protocols provide potentially enormous advantages in efficiency and flexibility of clinical drug development. Implications: Master protocol trials and especially platform trials have the potential to revolutionize clinical drug development if the methodologic and operational challenges can be overcome.

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