Impact of retrospective data verification to prepare the ICON6 trial for use in a marketing authorization application.

BACKGROUND: The ICON6 trial (ISRCTN68510403) is a phase III academic-led, international, randomized, three-arm, double-blind, placebo-controlled trial of the addition of cediranib to chemotherapy in recurrent ovarian cancer. It investigated the use of placebo during chemotherapy and maintenance (arm A), cediranib alongside chemotherapy followed by placebo maintenance (arm B) and cediranib throughout both periods (arm C). Results of the primary comparison showed a meaningful gain in progression-free survival (time to progression or death from any cause) when comparing arm A (placebo) with arm C (cediranib). As a consequence of the positive results, AstraZeneca was engaged with the Medical Research Council trials unit to discuss regulatory submission using ICON6 as the single pivotal trial. METHODS: A relatively limited level of on-site monitoring, single data entry and investigator's local evaluation of progression were used on trial. In order to submit a license application, it was decided that (a) extensive retrospective source data verification of medical records against case report forms should be performed, (b) further quality control checks for accuracy of data entry should be performed and (c) blinded independent central review of images used to define progression should be undertaken. To assess the value of these extra activities, we summarize the impact on both efficacy and safety outcomes. RESULTS: Data point changes were minimal; those key to the primary results had a 0.47% error rate (36/7686), and supporting data points had a 0.18% error rate (109/59,261). The impact of the source data verification and quality control processes were analyzed jointly. The conclusion drawn for the primary outcome measure of progression-free survival between arm A and arm C was unchanged. The log-rank test p-value changed only at the sixth decimal place, the hazard ratio does not change from 0.57 with the exception of a marginal change in its upper bound (0.74-0.73) and the median progression-free survival benefit from arm C remained at 2.4 months. Separately, the blinded independent central review of progression scans was performed as a sensitivity analysis. Estimates and p values varied slightly but overall demonstrated a difference in arms, which is consistent with the initial result. Some increases in toxicity were observed, though these were generally minor, with the exception of hypertension. However, none of these increases were systematically biased toward one arm. CONCLUSION: The conduct of this pragmatic, academic-sponsored trial was sufficient given the robustness of the results, shown by the results remaining largely unchanged following retrospective verification despite not being designed for use in a marketing authorization. The burden of such comprehensive retrospective effort required to ensure the results of ICON6 were acceptable to regulators is difficult to justify.

Direct thermal desorption gas chromatographic determination of toxicologically relevant concentrations of ethylene glycol in whole blood.

A simple and rapid method involving thermal desorption gas chromatography (TD-GC) with flame ionisation detection has been successfully developed for the determination of ethylene glycol in whole blood. No sample extraction or derivatization steps were required. The conditions required for the direct determination of ethylene glycol in whole blood were optimised and require only the addition of the internal standard, 1,2-butanediol, to the sample. A 1 µL aliquot of the sample was then introduced to the thermal desorption unit, dried, and thermally desorbed directly to the gas chromatograph. A calibration curve was constructed over the concentration range of 1.0 to 200 mM and was found to be linear over the range investigated with an R2 value of 0.9997. The theoretical limit of detection based on 3σ was calculated to be 50.2 µM (3.11 mg L-1). No issues with carryover were recorded. No interferences were recorded from endogenous blood components or a number of commonly occurring alcohols. The proposed method was evaluated by carrying out replicate ethylene glycol determinations on fortified whole blood samples at the levels of 12.5 mM, 20.0 mM, 31.2 mM, 100 mM and 200 mM comparable to commonly reported blood levels in intoxications. Mean recoveries of between 84.8% and 107% were obtained with coefficients of variation of between 1.7% and 5.8%. These data suggest that the method holds promise for applications in toxicology, where a rapid, reliable method to confirm ethylene glycol poisoning is required.

The golden ratio in baseball: the influence of historical eras on winning percentages in major league baseball.

Introduction: The golden section or golden ratio (61.8% or 0.618) is a mathematical phenomenon that appears in art, literature, music and nature with such ubiquity that it is thought to be a fundamental principle of aesthetic organisation. The golden ratio also manifests in sport, particularly as the proportion of wins to losses required to win a Major League Baseball championship. This study extends early work on the golden ratio in baseball by incorporating more than three decades of additional data. Methods: This study involved a historically contextualized examination of how winning percentages have changed across the seven historical eras of modern baseball, including analyses of the relative contribution of offensive and defensive statistics to championship winning teams. Data was extracted from Baseball Reference and included statistics for 398 championship winning teams from both the American and National Leagues between 1901 and 2019. Pearson correlation coefficients were computed for winning percentage with indicators of offensive and defensive performance during each era. Main and interaction effects of Era and League on winning percentage were examined using factorial ANOVA, with follow-up analyses examining whether the golden ratio was included in each factor's 95% confidence interval. Results: Our findings suggest that winning percentages for championship teams were closest to the golden ratio during eras where the relative contribution of offense and defense was most closely balanced: the Integration Era (1942-1960) and the Expansion Era (1961-1976). Discussion: Previous scholarship theorizes that the golden ratio represents an aesthetic ideal or a Gestalt archetype. If this aesthetic theory is applied to sporting competition, these results suggest that baseball may be most aesthetically appealing to fans when offense and defense is balanced in such a way as to ensure that championship teams win 61.8% of their games.

Practical guidance for running late-phase platform protocols for clinical trials: lessons from experienced UK clinical trials units.

BACKGROUND: Late-phase platform protocols (including basket, umbrella, multi-arm multi-stage (MAMS), and master protocols) are generally agreed to be more efficient than traditional two-arm clinical trial designs but are not extensively used. We have gathered the experience of running a number of successful platform protocols together to present some operational recommendations. METHODS: Representatives of six UK clinical trials units with experience in running late-phase platform protocols attended a 1-day meeting structured to discuss various practical aspects of running these trials. We report and give guidance on operational aspects which are either harder to implement compared to a traditional late-phase trial or are specific to platform protocols. RESULTS: We present a list of practical recommendations for trialists intending to design and conduct late-phase platform protocols. Our recommendations cover the entire life cycle of a platform trial: from protocol development, obtaining funding, and trial set-up, to a wide range of operational and regulatory aspects such as staffing, oversight, data handling, and data management, to the reporting of results, with a particular focus on communication with trial participants and stakeholders as well as public and patient involvement. DISCUSSION: Platform protocols enable many questions to be answered efficiently to the benefit of patients. Our practical lessons from running platform trials will support trial teams in learning how to run these trials more effectively and efficiently.

"'The Tragedy of the Punch Drunk': Reading Concussion in Australian Sporting Newspapers, 1843-1954".

Australian cultural attitudes toward sports related concussion (SRC) are understudied. Australia has a long history of valorising combat, collision, and contact sports, in which SRC is a common occurrence. It is therefore vital to understand how sociocultural and historical factors shape Australian attitudes toward SRC, in order to more critically evaluate the decisions made by athletes, parents, coaches, and others with regards to risk and brain injury in sport. This paper analyzed historical representations of SRC in Australian sporting newspapers between 1803 and 1954. Using distant reading, this analysis revealed four distinct periods of increased press discourse about "concussion," which were subject to interrogation via close reading. Close reading revealed that concussion was being reported in the Australian sporting press as early as 1859. Further analysis revealed critical and scientifically informed discussions about the delayed effects of concussion in 1901, systemic critiques of sporting organizations' response to concussion in 1906, and evidence of a limited concussion crisis in Australian boxing during the early 1930s. The findings of this research show that concussion was not only being reported in Australian newspapers throughout the late nineteenth and early twentieth centuries but it was subject to critical and informed commentary that has striking similarities with current debates about SRC. Despite this, widespread systematic changes to Australian sport did not occur until recently. This raises important questions about the political and institutional factors that prevented a major concussion crisis from developing in Australia during the early twentieth century, and prompts us to further consider the distinguishing features that facilitated the development of the current crisis.

Changing platforms without stopping the train: experiences of data management and data management systems when adapting platform protocols by adding and closing comparisons.

BACKGROUND: There is limited research and literature on the data management challenges encountered in multi-arm, multi-stage platform and umbrella protocols. These trial designs allow both (1) seamless addition of new research comparisons and (2) early stopping of accrual to individual comparisons that do not show sufficient activity. FOCUS4 (colorectal cancer) and STAMPEDE (prostate cancer), run from the Medical Research Council Clinical Trials Unit (CTU) at UCL, are two leading UK examples of clinical trials implementing adaptive platform protocol designs. To date, STAMPEDE has added five new research comparisons, closed two research comparisons following pre-planned interim analysis (lack of benefit), adapted the control arm following results from STAMPEDE and other relevant trials, and completed recruitment to six research comparisons. FOCUS4 has closed one research comparison following pre-planned interim analysis (lack of benefit) and added one new research comparison, with a number of further comparisons in the pipeline. We share our experiences from the operational aspects of running these adaptive trials, focusing on data management. METHODS: We held discussion groups with STAMPEDE and FOCUS4 CTU data management staff to identify data management challenges specific to adaptive platform protocols. We collated data on a number of case report form (CRF) changes, database amendments and database growth since each trial began. DISCUSSION: We found similar adaptive protocol-specific challenges in both trials. Adding comparisons to and removing them from open trials provides extra layers of complexity to CRF and database development. At the start of an adaptive trial, CRFs and databases must be designed to be flexible and scalable in order to cope with the continuous changes, ensuring future data requirements are considered where possible. When adding or stopping a comparison, the challenge is to incorporate new data requirements while ensuring data collection within ongoing comparisons is unaffected. Some changes may apply to all comparisons; others may be comparison-specific or applicable only to patients recruited during a specific time period. We discuss the advantages and disadvantages of the different approaches to CRF and database design we implemented in these trials, particularly in relation to use and maintenance of generic versus comparison-specific CRFs and databases. The work required to add or remove a comparison, including the development and testing of changes, updating of documentation, and training of sites, must be undertaken alongside data management of ongoing comparisons. Adequate resource is required for these competing data management tasks, especially in trials with long follow-up. A plan is needed for regular and pre-analysis data cleaning for multiple comparisons that could recruit at different rates and periods of time. Data-cleaning activities may need to be split and prioritised, especially if analyses for different comparisons overlap in time. CONCLUSIONS: Adaptive trials offer an efficient model to run randomised controlled trials, but setting up and conducting the data management activities in these trials can be operationally challenging. Trialists and funders must plan for scalability in data collection and the resource required to cope with additional competing data management tasks.

Publisher's Note: General scaling relations for locomotion in granular media [Phys. Rev. E 95, 052901 (2017)].

This corrects the article DOI: 10.1103/PhysRevE.95.052901.

General scaling relations for locomotion in granular media.

Inspired by dynamic similarity in fluid systems, we have derived a general dimensionless form for locomotion in granular materials, which is validated in experiments and discrete element method (DEM) simulations. The form instructs how to scale size, mass, and driving parameters in order to relate dynamic behaviors of different locomotors in the same granular media. The scaling can be derived by assuming intrusion forces arise from resistive force theory or equivalently by assuming the granular material behaves as a continuum obeying a frictional yield criterion. The scalings are experimentally confirmed using pairs of wheels of various shapes and sizes under many driving conditions in a common sand bed. We discuss why the two models provide such a robust set of scaling laws even though they neglect a number of the complexities of granular rheology. Motivated by potential extraplanetary applications, the dimensionless form also implies a way to predict wheel performance in one ambient gravity based on tests in a different ambient gravity. We confirm this using DEM simulations, which show that scaling relations are satisfied over an array of driving modes even when gravity differs between scaled tests.