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INTRODUCTION: Although oncology has seen large scientific and clinical advances over the last decade, it also has one of the lowest success rates for novel agents across therapeutic areas. Adaptive clinical trial design has been a popular option for increasing clinical trial efficiency and the chances of trial success. Seamless clinical trial design are studies in which two or more clinical trial phases are combined into a single study with a pre-specified transition between stages. This integration of phases may enhance efficiency. METHODS: To understand the precedent for the use of seamless designs, this working group was formed to conduct a comprehensive literature search on seamless clinical trials conducted with confirmatory intent in oncology. Trial design features were extracted into a database and analyzed with descriptive statistics. RESULTS: A literature search identified 68 clinical trials meeting inclusion and exclusion criteria. The most common design feature was a gate on treatment efficacy, where the trial would only proceed to the second stage if sufficient efficacy was observed in the first. The next most common feature was a selection of a dose or treatment regimen. Inferentially and operationally seamless designs were approximately equally represented. DISCUSSION: Key statistical considerations for seamless phase II/III designs include optimizing design choices by evaluating and comparing operating characteristics across design alternatives as well as showing control of overall Type I error rates. Executing the transition between phases should be evaluated for issues related to accrual, drug production, and procedures to maintain trial integrity. CONCLUSIONS: While there are unique statistical, regulatory, and operational considerations for seamless designs they are also uniquely suited to many development settings. These include, for example, addressing dose selection under FDA's Project Optimus and addressing the growing use of biomarkers and personalized medicine approaches in cancer treatment.
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BACKGROUND AND OBJECTIVES: The aim of this study was to examine the diurnal links between average and changes in average levels of prospectively rated mood, sleep, energy, and stress as predictors of incident headache in a community-based sample. METHODS: This observational study included structured clinical diagnostic assessment of both headache syndromes and mental disorders and electronic diaries that were administered 4 times per day for 2 weeks yielding a total of 4,974 assessments. The chief outcomes were incident morning (am) and later-day (pm) headaches. Generalized linear mixed-effects models were used to evaluate the average and lagged values of predictors including subjectively rated mood, anxiety, energy, stress, and sleep quality and objectively measured sleep duration and efficiency on incident am and pm headaches. RESULTS: The sample included 477 participants (61% female), aged 7 through 84 years. After adjusting for demographic and clinical covariates and emotional states, incident am headache was associated with lower average (ß = -0.206*; confidence intervals: -0.397 to -0.017) and a decrease in average sleep quality on the prior day (ß = -0.172*; confidence interval: -0.305, -0.039). Average stress and changes in subjective energy levels on the prior day were associated with incident headaches but with different valence for am (decrease) (ß = -0.145* confidence interval: -0.286, -0.005) and pm (increase) (ß = 0.157*; confidence interval: 0.032, 0.281) headache. Mood and anxiety disorders were not significantly associated with incident headache after controlling for history of a diagnosis of migraine. DISCUSSION: Both persistent and acute changes in arousal states manifest by subjective sleep quality and energy are salient precursors of incident headaches. Whereas poorer sleep quality and decreased energy on the prior day were associated with incident morning headache, an increase in energy and greater average stress were associated with headache onsets later in the day. Different patterns of predictors of morning and later-day incident headache highlight the role of circadian rhythms in the manifestations of headache. These findings may provide insight into the pathophysiologic processes underlying migraine and inform clinical intervention and prevention. Tracking these systems in real time with mobile technology provides a valuable ancillary tool to traditional clinical assessments.