Assessing the potential for prevention or earlier detection of on-site monitoring findings from randomised controlled trials: Further analyses of findings from the prospective TEMPER triggered monitoring study

BACKGROUND/AIMS: Clinical trials should be designed and managed to minimise important errors with potential to compromise patient safety or data integrity, employ monitoring practices that detect and correct important errors quickly, and take robust action to prevent repetition. Regulators highlight the use of risk-based monitoring, making greater use of centralised monitoring and reducing reliance on centre visits. The TEMPER study was a prospective evaluation of triggered monitoring (a risk-based monitoring method), whereby centres are prioritised for visits based on central monitoring results. Conducted in three UK-based randomised cancer treatment trials of investigational medicine products with time-to-event outcomes, it found high levels of serious findings at triggered centre visits but also at visits to matched control centres that, based on central monitoring, were not of concern. Here, we report a detailed review of the serious findings from TEMPER centre visits. We sought to identify feasible, centralised processes which might detect or prevent these findings without a centre visit. METHODS: The primary outcome of this study was the proportion of all 'major' and 'critical' TEMPER centre visit findings theoretically detectable or preventable through a feasible, centralised process. To devise processes, we considered a representative example of each finding type through an internal consensus exercise. This involved (a) agreeing the potential, by some described process, for each finding type to be centrally detected or prevented and (b) agreeing a proposed feasibility score for each proposed process. To further assess feasibility, we ran a consultation exercise, whereby the proposed processes were reviewed and rated for feasibility by invited external trialists. RESULTS: In TEMPER, 312 major or critical findings were identified at 94 visits. These findings comprised 120 distinct issues, for which we proposed 56 different centralised processes. Following independent review of the feasibility of the proposed processes by 87 consultation respondents across eight different trial stakeholder groups, we conclude that 306/312 (98%) findings could theoretically be prevented or identified centrally. Of the processes deemed feasible, those relating to informed consent could have the most impact. Of processes not currently deemed feasible, those involving use of electronic health records are among those with the largest potential benefit. CONCLUSIONS: This work presents a best-case scenario, where a large majority of monitoring findings were deemed theoretically preventable or detectable by central processes. Caveats include the cost of applying all necessary methods, and the resource implications of enhanced central monitoring for both centre and trials unit staff. Our results will inform future monitoring plans and emphasise the importance of continued critical review of monitoring processes and outcomes to ensure they remain appropriate

Dynamic methods for ongoing assessment of site-level risk in risk-based monitoring of clinical trials: A scoping review

BACKGROUND/AIMS: It is increasingly recognised that reliance on frequent site visits for monitoring clinical trials is inefficient. Regulators and trialists have recently encouraged more risk-based monitoring. Risk assessment should take place before a trial begins to define the overarching monitoring strategy. It can also be done on an ongoing basis, to target sites for monitoring activity. Various methods have been proposed for such prioritisation, often using terms like 'central statistical monitoring', 'triggered monitoring' or, as in the International Conference on Harmonization Good Clinical Practice guidance, 'targeted on-site monitoring'. We conducted a scoping review to identify such methods, to establish if any were supported by adequate evidence to allow wider implementation, and to guide future developments in this field of research. METHODS: We used seven publication databases, two sets of methodological conference abstracts and an Internet search engine to identify methods for using centrally held trial data to assess site conduct during a trial. We included only reports in English, and excluded reports published before 1996 or not directly relevant to our research question. We used reference and citation searches to find additional relevant reports. We extracted data using a predefined template. We contacted authors to request additional information about included reports. RESULTS: We included 30 reports in our final dataset, of which 21 were peer-reviewed publications. In all, 20 reports described central statistical monitoring methods (of which 7 focussed on detection of fraud or misconduct) and 9 described triggered monitoring methods; 21 reports included some assessment of their methods' effectiveness, typically exploring the methods' characteristics using real trial data without known integrity issues. Of the 21 with some effectiveness assessment, most contained limited information about whether or not concerns identified through central monitoring constituted meaningful problems. Several reports demonstrated good classification ability based on more than one classification statistic, but never without caveats of unclear reporting or other classification statistics being low or unavailable. Some reports commented on cost savings from reduced on-site monitoring, but none gave detailed costings for the development and maintenance of central monitoring methods themselves. CONCLUSION: Our review identified various proposed methods, some of which could be combined within the same trial. The apparent emphasis on fraud detection may not be proportionate in all trial settings. Despite some promising evidence and some self-justifying benefits for data cleaning activity, many proposed methods have limitations that may currently prevent their routine use for targeting trial monitoring activity. The implementation costs, or uncertainty about these, may also be a barrier. We make recommendations for how the evidence-base supporting these methods could be improved

A third trial oversight committee: Functions, benefits and issues

BACKGROUND/AIMS: Clinical trial oversight is central to the safety of participants and production of robust data. The United Kingdom Medical Research Council originally set out an oversight structure comprising three committees in 1998. The first committee, led by the trial team, is hands-on with trial conduct/operations (‘Trial Management Group’) and essential. The second committee (Data Monitoring Committee), usually completely independent of the trial, reviews accumulating trial evidence and is used by most later phase trials. The Independent Data Monitoring Committee makes recommendations to the third oversight committee. The third committee, (‘Trial Steering Committee’), facilitates in-depth interactions of independent and non-independent trial members and gives broader oversight (blinded to comparative analysis). We investigated the roles and functioning of the third oversight committee with multiple research methods. We reflect upon these findings to standardise the committee’s remit and operation and to potentially increase its usage. METHODS: We utilised findings from our recent published suite of research on the third oversight committee to inform guideline revision. In brief, we conducted a survey of 38 United Kingdom–registered Clinical Trials Units, reviewed a cohort of 264 published trials, observed 8 third oversight committee meetings and interviewed 52 trialists. We convened an expert panel to discuss third oversight committees. Subsequently, we interviewed nine patient/lay third committee members and eight committee Chairs. RESULTS: In the survey, most Clinical Trials Units required a third committee for all their trials (27/38, 71%) with independent members (ranging from 1 to 6). In the survey and interviews, the independence of the third committee was valued to make unbiased consideration of Independent Data Monitoring Committee recommendations and to advise on trial progress, protocol changes and recruitment issues in conjunction with the trial leadership. The third committee also advised funders and sponsors about trial continuation and represented patients and the public by including lay members. Of the cohort of 264 published trials, 144 reported a ‘steering’ committee (55%), but the independence of these members was not described so these may have been internal Trial Management Groups. Around two thirds of papers (60%) reported having an Independent Data Monitoring Committee and 26.9% neither a steering nor an Independent Data Monitoring Committee. However, before revising the third committee charter (Terms of Reference), greater standardisation is needed around defining member independence, composition, primacy of decision-making, interactions with other committees and the lifespan. CONCLUSION: A third oversight committee has benefits for trial oversight and conduct, and a revised charter will facilitate greater standardisation and wider adoption

Predictors of Gains During Inpatient Rehabilitation in Patients with Stroke- A Review.

Stroke remains a major cause of disability. The cost of stroke rehabilitation is substantial. Understanding the factors that predict response to inpatient stroke rehabilitation may be useful, for example, to best individualize the content of therapy, or to maximize the efficiency with which resources are directed. This review reviewed the literature and found that numerous variables were associated with outcome after inpatient stroke rehabilitation. The strongest evidence exists for factors such as age, stroke subtype, nutritional status, psychosocial factors such as living with family prior to stroke or presence of a caregiver. Functional status on admission, urinary incontinence, post-stroke infection, and aphasia each can also impact prognosis. Strengths and weaknesses of cited studies are considered in an attempt to inform design of future studies examining the factors that predict response to inpatient rehabilitation after stroke

Cross-modal interference-control is reduced in childhood but maintained in aging: a cohort study of stimulus-and response-interference in cross-modal and unimodal Stroop tasks

Interference-control is the ability to exclude distractions and focus on a specific task or stimulus. However, it is currently unclear whether the same interference-control mechanisms underlie the ability to ignore unimodal and cross-modal distractions. In two experiments we assessed whether unimodal and cross-modal interference follow similar trajectories in development and aging and occur at similar processing levels. In Experiment 1, 42 children(6-11 years), 31 younger adults (18-25 years) and 32 older adults (60-84 years) identified colour rectangles with either written (unimodal) or spoken (cross-modal) distractor-words. Stimuli could be congruent, incongruent but mapped to the same response (stimulus-incongruent), or incongruent and mapped to different responses (response-incongruent), thus separating interference occurring at early (sensory) and late (response) processing levels. Unimodal interference was worst in childhood and old age; however, older adults maintained the ability to ignore cross-modal distraction. Unimodal but not cross-modal response interference also reduced accuracy. In Experiment 2 we compared the effect of audition on vision and vice versa in 52 children (6-11 years), 30 young adults (22-33 years) and 30 older adults (60-84 years). As in Experiment 1, older adults maintained the ability to ignore cross-modal distraction arising from either modality and neither type of cross-modal distraction limited accuracy in adults. However cross-modal distraction still reduced accuracy in children and children were more slowed by stimulus-interference compared with adults. We conclude that; unimodal and cross-modal interference follow different lifespan trajectories and differences in stimulus- and response-interference may increase cross-modal distractibility in childhood

UV-B perceived by the UVR8 photoreceptor inhibits plant thermomorphogenesis

Small increases in ambient temperature can elicit striking effects on plant architecture, collectively termed thermomorphogenesis [1]. In Arabidopsis thaliana, these include marked stem elongation and leaf elevation, responses that have been predicted to enhance leaf cooling [ 2, 3, 4 and 5]. Thermomorphogenesis requires increased auxin biosynthesis, mediated by the bHLH transcription factor PHYTOCHROME-INTERACTING FACTOR 4 (PIF4) [ 6, 7 and 8], and enhanced stability of the auxin co-receptor TIR1, involving HEAT SHOCK PROTEIN 90 (HSP90) [9]. High-temperature-mediated hypocotyl elongation additionally involves localized changes in auxin metabolism, mediated by the indole-3-acetic acid (IAA)-amido synthetase Gretchen Hagen 3 (GH3).17 [10]. Here we show that ultraviolet-B light (UV-B) perceived by the photoreceptor UV RESISTANCE LOCUS 8 (UVR8) [11] strongly attenuates thermomorphogenesis via multiple mechanisms inhibiting PIF4 activity. Suppression of thermomorphogenesis involves UVR8 and CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1)-mediated repression of PIF4 transcript accumulation, reducing PIF4 abundance. UV-B also stabilizes the bHLH protein LONG HYPOCOTYL IN FAR RED (HFR1), which can bind to and inhibit PIF4 function. Collectively, our results demonstrate complex crosstalk between UV-B and high-temperature signaling. As plants grown in sunlight would most likely experience concomitant elevations in UV-B and ambient temperature, elucidating how these pathways are integrated is of key importance to the understanding of plant development in natural environments

VLBI study of maser kinematics in high-mass SFRs. II. G23.01-0.41

The present paper focuses on the high-mass star-forming region G23.01-0.41. Methods: Using the VLBA and the EVN arrays, we conducted phase-referenced observations of the three most powerful maser species in G23.01-0.41: H2O at 22.2 GHz (4 epochs), CH3OH at 6.7 GHz (3 epochs), and OH at 1.665 GHz (1 epoch). In addition, we performed high-resolution (> 0".1), high-sensitivity (< 0.1 mJy) VLA observations of the radio continuum emission from the HMC at 1.3 and 3.6 cm. Results: We have detected H2O, CH3OH, and OH maser emission clustered within 2000 AU from the center of a flattened HMC, oriented SE-NW, from which emerges a massive 12CO outflow, elongated NE-SW, extended up to the pc-scale. Although the three maser species show a clearly different spatial and velocity distribution and sample distinct environments around the massive YSO, the spatial symmetry and velocity field of each maser specie can be explained in terms of expansion from a common center, which possibly denotes the position of the YSO driving the maser motion. Water masers trace both a fast shock (up to 50 km/s) closer to the YSO, powered by a wide-angle wind, and a slower (20 km/s) bipolar jet, at the base of the large-scale outflow. Since the compact free-free emission is found offset from the putative location of the YSO along a direction consistent with that of the maser jet axis, we interpret the radio continuum in terms of a thermal jet. The velocity field of methanol masers can be explained in terms of a composition of slow (4 km/s in amplitude) motions of radial expansion and rotation about an axis approximately parallel to the maser jet. Finally, the distribution of line of sight velocities of the hydroxyl masers suggests that they can trace gas less dense (n(H2) < 10^6 cm^-3) and more distant from the YSO than that traced by the water and methanol masers, which is expanding toward the observer. (Abridged)Comment: 23 pages, 8 figures, 4 tables, accepted by Astronomy and Astrophysic

Refrigeration System for the ATLAS Experiment

The proposed ATLAS detector for the 27 km circumference LHC collider is of unprecedented size and complexity. The magnet configuration is based on an inner superconducting solenoid and large superconducting air-core toroids (barrel and two end-caps) each made of eight coils symmetrically arranged outside the calorimetry. The total cold mass approaches 600 tons and the stored energy is 1.7 GJ. The cryogenic infrastructure will include a 6 kW @ 4.5 K refrigerator, a precooling unit and distribution systems and permits flexible operation during cool-down, normal running and quench recovery. A dedicated LN2 refrigeration system is proposed for the three liquid argon calorimeters (84 m3 of LAr). Magnets and calorimeters will be individually tested prior to their definitive installation in a large scale cryogenic test area on the surface. The experiment is scheduled to be operational in 2005

A Search for 6.7 GHz Methanol Masers in M33

We report the negative results from a search for 6.7 GHz methanol masers in the nearby spiral galaxy M33. We observed 14 GMCs in the central 4 kpc of the Galaxy, and found 3 sigma upper limits to the flux density of ~9 mJy in spectral channels having a velocity width of 0.069 km/s. By velocity shifting and combining the spectra from the positions observed, we obtain an effective 3sigma upper limit on the average emission of ~1mJy in a 0.25 km/s channel. These limits lie significantly below what we would expect based on our estimates of the methanol maser luminosity function in the Milky Way. The most likely explanation for the absence of detectable methanol masers appears to be the metallicity of M33, which is modestly less than that of the Milky Way