Biomarker-Guided Non-Adaptive Trial Designs in Phase II and Phase III: A Methodological Review (vol 7, 1, 2017)

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Fixed and Adaptive Parallel Subgroup-Specific Design for Survival Outcomes: Power and Sample Size

Biomarker-guided clinical trial designs, which focus on testing the effectiveness of a biomarker-guided approach to treatment in improving patient health, have drawn considerable attention in the era of stratified medicine with many different designs being proposed in the literature. However, planning such trials to ensure they have sufficient power to test the relevant hypotheses can be challenging and the literature often lacks guidance in this regard. In this study, we focus on the parallel subgroup-specific design, which allows the evaluation of separate treatment effects in the biomarker-positive subgroup and biomarker-negative subgroup simultaneously. We also explore an adaptive version of the design, where an interim analysis is undertaken based on a fixed percentage of target events, with the option to stop each biomarker-defined subgroup early for futility or efficacy. We calculate the number of events and patients required to ensure sufficient power in each of the biomarker-defined subgroups under different scenarios when the primary outcome is time-to-event. For the adaptive version, stopping probabilities are also explored. Since multiple hypotheses are being tested simultaneously, and multiple interim analyses are undertaken, we also focus on controlling the overall type I error rate by way of multiplicity adjustment

Fixed and Adaptive Parallel Subgroup-Specific Design for Survival Outcomes: Power and Sample Size (vol 7, 19, 2017)

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Evidence to support inclusion of pharmacogenetic biomarkers in randomised controlled trials

Pharmacogenetics and biomarkers are becoming normalised as important technologies to improve drug efficacy rates, reduce the incidence of adverse drug reactions, and make informed choices for targeted therapies. However, their wider clinical implementation has been limited by a lack of robust evidence. Suitable evidence is required before a biomarker’s clinical use, and also before its use in a clinical trial. We have undertaken a review of five pharmacogenetic biomarker-guided randomised controlled trials (RCTs) and evaluated the evidence used by these trials to justify biomarker inclusion. We assessed and quantified the evidence cited in published rationale papers, or where these were not available, obtained protocols from trial authors. Very different levels of evidence were provided by the trials. We used these observations to write recommendations for future justifications of biomarker use in RCTs and encourage regulatory authorities to write clear guidelines

Joint Modelling of Multivariate Longitudinal Data and Time-to-Event Outcomes

Fits the joint model proposed by Henderson and colleagues (2000) (doi:10.1093/biostatistics/1.4.465), but extended to the case of multiple continuous longitudinal measures. The time-to-event data is modelled using a Cox proportional hazards regression model with time-varying covariates. The multiple longitudinal outcomes are modelled using a multivariate version of the Laird and Ware linear mixed model. The association is captured by a multivariate latent Gaussian process. The model is estimated using a Monte Carlo Expectation Maximization algorithm. This project is funded by the Medical Research Council (Grant number MR/M013227/1)

Development of corpus luteum susceptibility to an analog of prostaglandin F 2α, throughout the luteal phase in llamas (Lama glama)

The aim of the present study was to evaluate the susceptibility of the corpus luteum to d-cloprostenol (synthetic analog of PGF 2α) throughout the luteal phase in llamas. Female llamas (n=43) were induced to ovulate by GnRH injection in the presence of an ovulatory follicle and randomly assigned into one of six groups: control and treated with an injection of d-cloprostenol on Day 3, 4, 5, 6 or 8 post GnRH. Blood samples were collected to determine plasma progesterone concentrations. There was no effect of treatment on animals injected on Day 3 or 4 post-GnRH. In animals treated on Day 5, different responses were observed. No effect of treatment was recorded in 27% of the animals whereas 55% of the llamas showed a transitory decrease followed by a recovery in plasma progesterone concentrations after d-cloprostenol injection, indicative of a resurgence of the corpus luteum, extending the luteal phase a day more than in control animals. In the remaining 18% of the animals injected on Day 5, (corresponding to those exhibiting the greatest plasma progesterone concentrations at the day of injection), complete luteolysis was observed. Plasma progesterone concentrations decreased to below 1ngml -1 24h after d-cloprostenol in llamas injected on Day 6 or 8 post-GnRH. In conclusion, the corpus luteum of llamas is completely refractory to PGF 2α until Day 4 after induction of ovulation, being partially sensitive by Day 5 and fully responsive to PGF 2α, by Day 6 after induction of ovulation.Fil: Bianchi, Carolina Paula. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Endocrinología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; ArgentinaFil: Cavilla, María Verónica. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Endocrinología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; ArgentinaFil: Jorgensen, E.. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Endocrinología; ArgentinaFil: Benavente, Micaela Andrea. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Endocrinología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; ArgentinaFil: Aba, Marcelo Alfredo. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Endocrinología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentin