Getting our ducks in a row: The need for data utility comparisons of healthcare systems data for clinical trials.

BACKGROUND: Better use of healthcare systems data, collected as part of interactions between patients and the healthcare system, could transform planning and conduct of randomised controlled trials. Multiple challenges to widespread use include whether healthcare systems data captures sufficiently well the data traditionally captured on case report forms. "Data Utility Comparison Studies" (DUCkS) assess the utility of healthcare systems data for RCTs by comparison to data collected by the trial. Despite their importance, there are few published UK examples of DUCkS. METHODS-AND-RESULTS: Building from ongoing and selected recent examples of UK-led DUCkS in the literature, we set out experience-based considerations for the conduct of future DUCkS. Developed through informal iterative discussions in many forums, considerations are offered for planning, protocol development, data, analysis and reporting, with comparisons at "patient-level" or "trial-level", depending on the item of interest and trial status. DISCUSSION: DUCkS could be a valuable tool in assessing where healthcare systems data can be used for trials and in which trial teams can play a leading role. There is a pressing need for trials to be more efficient in their delivery and research waste must be reduced. Trials have been making inconsistent use of healthcare systems data, not least because of an absence of evidence of utility. DUCkS can also help to identify challenges in using healthcare systems data, such as linkage (access and timing) and data quality. We encourage trial teams to incorporate and report DUCkS in trials and funders and data providers to support them.

Participant experiences of guided self-help Acceptance and Commitment Therapy for improving quality of life in muscle disease: a nested qualitative study within the ACTMus randomized controlled trial.

Introduction: In adults, muscle disease (MD) is typically a chronic long-term condition that can lead to a reduced quality of life (QoL). Previous research suggests that a psychological intervention, in particular Acceptance and Commitment Therapy (ACT), may help improve QoL for individuals living with chronic conditions such as MD. Methods: This nested qualitative study was incorporated within a randomized controlled trial which evaluated a guided self-help ACT intervention for people living with MD to explore their experiences of the intervention. Semi-structured interviews (n = 20) were conducted with those who had received ACT. Data were analyzed via thematic analysis. Results: There were four overarching themes. (1) Views on whether therapy sessions would help with a medical condition: participants' expectations regarding ACT varied. Some participants were skeptical about mindfulness. (2) I was able to look at things in a different way: participants described increased meaningful activity, greater awareness of thoughts and emotions and acceptance or adaptation to mobility problems. Some described improvement in the quality of relationships and a sense of feeling free. (3) Treating the body and the mind together: following the intervention participants noted that a holistic approach to healthcare is beneficial. (4) Intervention delivery: The remote delivery was generally seen as helpful for practical reasons and allowed participants to speak openly. Participants voiced a need for follow-up sessions. Discussion: Overall, the intervention was experienced as acceptable. Suggested improvements included de-emphasizing the role of mindfulness and adding follow-up sessions.

Monitoring metrics over time: Why clinical trialists need to systematically collect site performance metrics.

Background: Over the last decade, there has been an increasing interest in risk-based monitoring (RBM) in clinical trials, resulting in a number of guidelines from regulators and its inclusion in ICH GCP. However, there is a lack of detail on how to approach RBM from a practical perspective, and insufficient understanding of best practice. Purpose: We present a method for clinical trials units to track their metrics within clinical trials using descriptive statistics and visualisations. Research Design: We suggest descriptive statistics and visualisations within a SWAT methodology. Study Sample: We illustrate this method using the metrics from TEMPER, a monitoring study carried out in three trials at the MRC Clinical Trials Unit at UCL. Data Collection: The data collection for TEMPER is described in DOI: 10.1177/1740774518793379. Results: We show the results and discuss a protocol for a Study-Within-A-Trial (SWAT 167) for those wishing to use the method. Conclusions: The potential benefits metric tracking brings to clinical trials include enhanced assessment of sites for potential corrective action, improved evaluation and contextualisation of the influence of metrics and their thresholds, and the establishment of best practice in RBM. The standardisation of the collection of such monitoring data would benefit both individual trials and the clinical trials community.

Early Human Pathophysiological Responses to Exertional Hypobaric Decompression Stress.

INTRODUCTION: Consistent blood biomarkers of hypobaric (altitude) decompression stress remain elusive. Recent laboratory investigation of decompression sickness risk at 25,000 ft (7620 m) enabled evaluation of early pathophysiological responses to exertional decompression stress.METHODS: In this study, 15 healthy men, aged 20-50 yr, undertook 2 consecutive (same-day) ascents to 25,000 ft (7620 m) for 60 and 90 min, breathing 100% oxygen, each following 1 h of prior denitrogenation. Venous blood was sampled at baseline (T0), immediately after the second ascent (T8), and next morning (T24). Analyses encompassed whole blood hematology, endothelial microparticles, and soluble markers of cytokine response, endothelial function, inflammation, coagulopathy, oxidative stress, and brain insult, plus cortisol and creatine kinase.RESULTS: Acute hematological effects on neutrophils (mean 72% increase), eosinophils (40% decrease), monocytes (37% increase), and platelets (7% increase) normalized by T24. Consistent elevation (mean five-fold) of the cytokine interleukin-6 (IL-6) at T8 was proinflammatory and associated with venous gas emboli (microbubble) load. Levels of C-reactive protein and complement peptide C5a were persistently elevated at T24, the former by 100% over baseline. Additionally, glial fibrillary acidic protein, a sensitive marker of traumatic brain injury, increased by a mean 10% at T24.CONCLUSIONS: This complex composite environmental stress, comprising the triad of hyperoxia, decompression, and moderate exertion at altitude, provoked pathophysiological changes consistent with an IL-6 cytokine-mediated inflammatory response. Multiple persistent biomarker disturbances at T24 imply incomplete recovery the day after exposure. The elevation of glial fibrillary acidic protein similarly implies incomplete resolution following recent neurological insult.Connolly DM, Madden LA, Edwards VC, D'Oyly TJ, Harridge SDR, Smith TG, Lee VM. Early human pathophysiological responses to exertional hypobaric decompression stress. Aerosp Med Hum Perform. 2023; 94(10):738-749.

The effect of sex and protein supplementation on bone metabolism during a 36-h military field exercise in energy deficit.

This study investigated sex differences in, and the effect of protein supplementation on, bone metabolism during a 36-h military field exercise. Forty-four British Army Officer cadets (14 women) completed a 36-h field exercise. Participants consumed either their habitual diet [n = 14 women (Women) and n = 15 men (Men Controls)] or the habitual diet with an additional 46.6 g·day-1 of protein for men [n = 15 men (Men Protein)]. Women and Men Protein were compared with Men Controls to examine the effect of sex and protein supplementation. Circulating markers of bone metabolism were measured before, 24 h after (postexercise), and 96 h after (recovery) the field exercise. Beta C-telopeptide cross links of type 1 collagen and cortisol were not different between time points or Women and Men Controls (P ≥ 0.094). Procollagen type I N-terminal propeptide decreased from baseline to postexercise (P < 0.001) and recovery (P < 0.001) in Women and Men Controls. Parathyroid hormone (PTH) increased from baseline to post-exercise (P = 0.006) and decreased from postexercise to recovery (P = 0.047) in Women and Men Controls. Total 25(OH)D increased from baseline to postexercise (P = 0.038) and recovery (P < 0.001) in Women and Men Controls. Testosterone decreased from baseline to post-exercise (P < 0.001) and recovery (P = 0.007) in Men Controls, but did not change for Women (all P = 1.000). Protein supplementation in men had no effect on any marker. Men and women experience similar changes to bone metabolism-decreased bone formation and increased PTH-following a short-field exercise. Protein had no protective effect likely because of the energy deficit.NEW & NOTEWORTHY Energy deficits are common in arduous military training and can cause disturbances to bone metabolism. This study provides first evidence that short periods of severe energy deficit and arduous exercise-in the form of a 36-h military field exercise-can suppress bone formation for at least 96 h, and the suppression in bone formation was not different between men and women. Protein feeding does not offset decreases in bone formation during severe energy deficits.

Do they really care? Specificity of social support issues in hoarding disorder and obsessive-compulsive disorder.

OBJECTIVES: Unmet interpersonal needs may play a role in excessive emotional attachments to objects for people with hoarding disorder (HD). Previous research indicates that social support (but not attachment difficulties) may be specific to HD. The study aimed to evaluate social networks and support in HD relative to clinical controls with obsessive-compulsive disorder (OCD) and healthy controls (HC). The secondary aim was to explore the extent of loneliness and thwarted belongingness. Potential mechanisms for deficits in social support were also considered. DESIGN: A cross-sectional between-groups design was used to compare scores on measures in those with HD (n = 37); OCD (n = 31); and HCs (n = 45). METHODS: Participants completed a structured clinical interview by telephone (to assign diagnostic categories) followed by online questionnaires. RESULTS: Whilst individuals with HD and OCD both report smaller social networks than HC, lower levels of perceived social support appear to be specific to HD. The HD group also showed higher levels of loneliness and thwarted belonging compared to OCD and HC. No differences were found between groups for perceived criticism or trauma. CONCLUSIONS: The results support previous findings of lower levels of self-reported social support within HD. Loneliness and thwarted belongingness also appear significantly elevated within HD compared with OCD and HC. Further research is required to explore the nature of felt support and belonging, direction of effect and to identify potential mechanisms. Clinical implications include advocating and promoting support systems (both personal supporters and professionals) for individuals with HD.

Association between external training loads and injury incidence during 44 weeks of military training.

Military training is physically arduous and associated with high injury incidence. Unlike in high-performance sport, the interaction between training load and injury has not been extensively researched in military personnel. Sixty-three (43 men, 20 women; age 24 ± 2 years; stature 1.76 ± 0.09 m; body mass 79.1 ± 10.8 kg) British Army Officer Cadets undergoing 44 weeks of training at the Royal Military Academy Sandhurst volunteered to participate. Weekly training load (cumulative 7-day moderate-vigorous physical activity [MVPA], vigorous PA [VPA], and the ratio between MVPA and sedentary-light PA [SLPA; MVPA:SLPA]) was monitored using a wrist-worn accelerometer (GENEActiv, UK). Self-report injury data were collected and combined with musculoskeletal injuries recorded at the Academy medical center. Training loads were divided into quartiles with the lowest load group used as the reference to enable comparisons using odds ratios (OR) and 95% confidence intervals (95% CI). Overall injury incidence was 60% with the most common injury sites being the ankle (22%) and knee (18%). High (load; OR; 95% CI [>2327 mins; 3.44; 1.80-6.56]) weekly cumulative MVPA exposure significantly increased odds of injury. Similarly, likelihood of injury significantly increased when exposed to low-moderate (0.42-0.47; 2.45 [1.19-5.04]), high-moderate (0.48-0.51; 2.48 [1.21-5.10]), and high MVPA:SLPA loads (>0.51; 3.60 [1.80-7.21]). High MVPA and high-moderate MVPA:SLPA increased odds of injury by ~2.0 to 3.5 fold, suggesting that the ratio of workload to recovery is important for mitigating injury occurrence.

Lack of transparent reporting of trial monitoring approaches in randomised controlled trials: A systematic review of contemporary protocol papers.

BACKGROUND: Monitoring is essential to ensure patient safety and data integrity in clinical trials as per Good Clinical Practice. The Standard Protocol Items: Recommendations for Interventional Trials Statement and its checklist guides authors to include monitoring in their protocols. We investigated how well monitoring was reported in published 'protocol papers' for contemporary randomised controlled trials. METHODS: A systematic search was conducted in PubMed to identify eligible protocol papers published in selected journals between 1 January 2020 and 31 May 2020. Protocol papers were classified by whether they reported monitoring and, if so, by the details of monitoring. Data were summarised descriptively. RESULTS: Of 811 protocol papers for randomised controlled trials, 386 (48%; 95% CI: 44%-51%) explicitly reported some monitoring information. Of these, 20% (77/386) reported monitoring information consistent with an on-site monitoring approach, and 39% (152/386) with central monitoring, 26% (101/386) with a mixed approach, while 14% (54/386) did not provide sufficient information to specify an approach. Only 8% (30/386) of randomised controlled trials reported complete details about all of scope, frequency and organisation of monitoring; frequency of monitoring was the least reported. However, 6% (25/386) of papers used the term 'audit' to describe 'monitoring'. DISCUSSION: Monitoring information was reported in only approximately half of the protocol papers. Suboptimal reporting of monitoring hinders the clinical community from having the full information on which to judge the validity of a trial and jeopardises the value of protocol papers and the credibility of the trial itself. Greater efforts are needed to promote the transparent reporting of monitoring to journal editors and authors.

A randomised controlled trial of acceptance and commitment therapy for improving quality of life in people with muscle diseases.

Abstract. BACKGROUND: Chronic muscle diseases (MD) are progressive and cause wasting and weakness in muscles and are associated with reduced quality of life (QoL). The ACTMuS trial examined whether Acceptance and Commitment Therapy (ACT) as an adjunct to usual care improved QoL for such patients as compared to usual care alone. METHODS: This two-arm, randomised, multicentre, parallel design recruited 155 patients with MD (Hospital and Depression Scale ⩾ 8 for depression or ⩾ 8 for anxiety and Montreal Cognitive Assessment ⩾ 21/30). Participants were randomised, using random block sizes, to one of two groups: standard medical care (SMC) (n = 78) or to ACT in addition to SMC (n = 77), and were followed up to 9 weeks. The primary outcome was QoL, assessed by the Individualised Neuromuscular Quality of Life Questionnaire (INQoL), the average of five subscales, at 9-weeks. Trial registration was NCT02810028. RESULTS: 138 people (89.0%) were followed up at 9-weeks. At all three time points, the adjusted group difference favoured the intervention group and was significant with moderate to large effect sizes. Secondary outcomes (mood, functional impairment, aspects of psychological flexibility) also showed significant differences between groups at week 9. CONCLUSIONS: ACT in addition to usual care was effective in improving QoL and other psychological and social outcomes in patients with MD. A 6 month follow up will determine the extent to which gains are maintained.

What is the purpose of clinical trial monitoring?

BACKGROUND: The sources of information on clinical trial monitoring do not give information in an accessible language and do not give detailed guidance. In order to enable communication and to build clinical trial monitoring tools on a strong easily communicated foundation, we identified the need to define monitoring in accessible language. METHODS: In a three-step process, the material from sources that describe clinical trial monitoring were synthesised into principles of monitoring. A poll regarding their applicability was run at a UK national academic clinical trials monitoring meeting. RESULTS: The process derived 5 key principles of monitoring: keeping participants safe and respecting their rights, having data we can trust, making sure the trial is being run as it was meant to be, improving the way the trial is run and preventing problems before they happen. CONCLUSION: From the many sources mentioning monitoring of clinical trials, the purpose of monitoring can be summarised simply as 5 principles. These principles, given in accessible language, should form a firm basis for discussion of monitoring of clinical trials.

Adherence to the 2015 and 2020 British Society of Paediatric Endocrinology and Diabetes guidelines and outcomes in critically ill children with diabetic ketoacidosis: a retrospective cohort study.

OBJECTIVES: To compare clinical management and key outcomes of critically ill children with diabetic ketoacidosis (DKA) in two cohorts (2015 cohort: managed according to the 2015 British Society of Paediatric Endocrinology and Diabetes (BSPED) guidelines; 2020 cohort: managed according to the 2020 BSPED guidelines). DESIGN: Retrospective cohort study using prospectively collected data. SETTING: A critical care advice and transport service based in London, and referring hospitals within the critical care network. PATIENTS: All children 0-17 years referred for advice and/or critical care transport with a clinical diagnosis of DKA over a 30-month period (from September 2018 to March 2021). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Admission to intensive care unit (ICU), clinically diagnosed cerebral oedema and death. RESULTS: There were significant differences in fluid and insulin administration practices between the 2015 and 2020 cohorts (fluid bolus >20 mL/kg: 3% vs 30%, p<0.001; median total fluid given in the first 24 hours: 84 mL/kg vs 117 mL/kg, p<0.01; starting insulin infusion rate 0.1 U/kg/hour: 54% vs 31%, p<0.01). However, these differences were consistent with guideline recommendations (initial fluid infusion rate within 5% of guideline-recommended rate: 80% in the 2015 group vs 84% in the 2020 group). There were no significant differences in outcomes (ICU admission: 26% vs 35%, p=0.2; cerebral oedema: 21% vs 23%, p=0.8). CONCLUSIONS: Our study findings indicate that changes to fluid and insulin administration occurred after the 2020 BSPED guideline publication, with strong adherence to the guideline, but these changes were not associated with changes in key outcomes.

Nutrition and Physical Activity During British Army Officer Cadet Training: Part 1-Energy Balance and Energy Availability.

Military training is characterized by high daily energy expenditures which are difficult to match with energy intake, potentially resulting in negative energy balance (EB) and low energy availability (EA). The aim of this study was to quantify EB and EA during British Army Officer Cadet training. Thirteen (seven women) Officer Cadets (mean ± SD: age 24 ± 3 years) volunteered to participate. EB and EA were estimated from energy intake (weighing of food and food diaries) and energy expenditure (doubly labeled water) measured in three periods of training: 9 days on-camp (CAMP), a 5-day field exercise (FEX), and a 9-day mixture of both CAMP and field-based training (MIX). Variables were compared by condition and gender with a repeated-measures analysis of variance. Negative EB was greatest during FEX (-2,197 ± 455 kcal/day) compared with CAMP (-692 ± 506 kcal/day; p < .001) and MIX (-1,280 ± 309 kcal/day; p < .001). EA was greatest in CAMP (23 ± 10 kcal·kg free-fat mass [FFM]-1·day-1) compared with FEX (1 ± 16 kcal·kg FFM-1·day-1; p = .002) and MIX (10 ± 7 kcal·kg FFM-1·day-1; p = .003), with no apparent difference between FEX and MIX (p = .071). Irrespective of condition, there were no apparent differences between gender in EB (p = .375) or EA (p = .385). These data can be used to inform evidenced-based strategies to manage EA and EB during military training, and enhance the health and performance of military personnel.

Nutrition and Physical Activity in British Army Officer Cadet Training Part 2-Daily Distribution of Energy and Macronutrient Intake.

Dietary intake and physical activity impact performance and adaptation during training. The aims of this study were to compare energy and macronutrient intake during British Army Officer Cadet training with dietary guidelines and describe daily distribution of energy and macronutrient intake and estimated energy expenditure. Thirteen participants (seven women) were monitored during three discrete periods of military training for 9 days on-camp, 5 days of field exercise, and 9 days of a mixture of the two. Dietary intake was measured using researcher-led food weighing and food diaries, and energy expenditure was estimated from wrist-worn accelerometers. Energy intake was below guidelines for men (4,600 kcal/day) and women (3,500 kcal/day) during on-camp training (men = -16% and women = -9%), field exercise (men = -33% and women = -42%), and combined camp and field training (men and women both -34%). Carbohydrate intake of men and women were below guidelines (6 g·kg-1·day-1) during field exercise (men = -18% and women = -37%) and combined camp and field training (men = -33% and women = -39%), respectively. Protein intake was above guidelines (1.2 kcal·kg-1·day-1) for men and women during on-camp training (men = 48% and women = 39%) and was below guidelines during field exercise for women only (-27%). Energy and macronutrient intake during on-camp training centered around mealtimes with a discernible sleep/wake cycle for energy expenditure. During field exercise, energy and macronutrient intake were individually variable, and energy expenditure was high throughout the day and night. These findings could be used to inform evidenced-based interventions to change the amount and timing of energy and macronutrient intake around physical activity to optimize performance and adaptations during military training.

Managing Hypertension, Diabetes, and Cardiovascular Disease Risk via Short-Term Medical Trips: A Retrospective Longitudinal Study in Santo Domingo.

BACKGROUND: Short-term medical trips (STMTs) from high-resource countries frequently provide care in low and middle-income countries. Little existing literature objectively tracks the long-term outcomes of these interventions on the receiving populations over time to assess potential benefits and to ensure no harm is being done. OBJECTIVES: The purpose of this study was to objectively analyze the outcomes of a biannual STMT to Santo Domingo, Dominican Republic on hypertension (HTN), diabetes mellitus type 2 (DM2), and cardiovascular disease (CVD) risk over a five-year period (2015-2019). METHODS: Data from 1655 patients was extracted from the electronic medical record. In patients who received treatment and had more than one visit, a linear mixed model was used to analyze effects on systolic blood pressure (SBP) and hemoglobin A1C (HbA1C) values over time. In patients with high CVD risk based on a non-laboratory-based assessment, provider compliance with prescribing an aspirin and statin was calculated and tracked over time. RESULTS: In patients with HTN who received treatment, average SBP was 148.83 mmHg (SD = 23.96) at initial visit and demonstrated no change over time (Estimate: 0.68 mmHg/year increase, p = 0.46). HbA1C data was insufficient for analysis. Treatment for patients with high CVD risk with an aspirin and statin improved from 41.46% in 2015 to 70.51% in 2019. CONCLUSION: SBP in patients with HTN treated by this STMT demonstrated no significant change over time. Possible contributing factors included patient education, access and adherence to medications, and documentation of data. Provider compliance with appropriate prescribing was high for patients with HTN and DM2 and improved over time for patients with high CVD risk, serving as an indirect measure for potential long-term benefits on these populations. All STMTs should objectively track outcomes of their interventions to assess risks and benefits to the communities being served.

Use of routinely collected health data in randomised clinical trials: comparison of trial-specific death data in the BOSS trial with NHS Digital data.

BACKGROUND: A promising approach to reduce the increasing costs of clinical trials is the use of routinely collected health data as participant data. However, the quality of this data could limit its usability as trial participant data. METHODS: The BOSS trial is a randomised controlled trial comparing regular endoscopies versus endoscopies at need in patients with Barrett's oesophagus with primary endpoint death. Data on death and cancer collected every 2 years after randomisation (trial-specific data) were compared to data received annually (all patients on one date) from the routinely collected health data source National Health Service (NHS) Digital. We investigated completeness, agreement and timeliness and looked at the implications for the primary trial outcome. Completeness and agreement were assessed by evaluating the number of reported and missing cases and any disparities between reported dates. Timeliness was considered by graphing the year a death was first reported in the trial-specific data against that for NHS Digital data. Implications on the primary trial outcome, overall survival, of using one of the data sources alone were investigated using Kaplan-Meier graphs. To assess the utility of cause of death and cancer diagnoses, oesophageal cancer cases were compared. RESULTS: NHS Digital datasets included more deaths and often reported them sooner than the trial-specific data. The number reported as being from oesophageal cancer was similar in both datasets. Due to time lag in reporting and missing cases, the event rate appeared higher using the NHS Digital data. CONCLUSION: NHS Digital death data is useful for calculating overall survival where trial-specific follow-up is only every 2 years from randomisation and the follow-up requires patient response. The cancer data was not a large enough sample to assess usability. We suggest that this assessment of registry data is done for more phase III RCTs and for more registry data to get a more complete picture of when RCHD would be useful in phase III RCT. TRIAL REGISTRATION: ISRCTN54190466 (BOSS) 1 Oct 2009.

Critical transition for colliding swarms.

Swarming patterns that emerge from the interaction of many mobile agents are a subject of great interest in fields ranging from biology to physics and robotics. In some application areas, multiple swarms effectively interact and collide, producing complex spatiotemporal patterns. Recent studies have begun to address swarm-on-swarm dynamics, and in particular the scattering of two large, colliding swarms with nonlinear interactions. To build on early numerical insights, we develop a self-propelled, rigid-body approximation that can be used to predict the parameters under which colliding swarms are expected to form a milling state. Our analytical method relies on the assumption that, upon collision, two swarms oscillate near a limit cycle, where each swarm rotates around the other while maintaining an approximately constant and uniform density. Using this approach we are able to predict the critical swarm-on-swarm interaction coupling, below which two colliding swarms merely scatter, as a function of physical swarm parameters. We show that the critical coupling gives a lower bound for all impact parameters, including head-on collision, and corresponds to a saddle-node bifurcation of a stable limit cycle in the uniform, constant density approximation. Our results are tested and found to agree with both small and large multiagent simulations.

Swarm shedding in networks of self-propelled agents.

Understanding swarm pattern formation is of great interest because it occurs naturally in many physical and biological systems, and has artificial applications in robotics. In both natural and engineered swarms, agent communication is typically local and sparse. This is because, over a limited sensing or communication range, the number of interactions an agent has is much smaller than the total possible number. A central question for self-organizing swarms interacting through sparse networks is whether or not collective motion states can emerge where all agents have coherent and stable dynamics. In this work we introduce the phenomenon of swarm shedding in which weakly-connected agents are ejected from stable milling patterns in self-propelled swarming networks with finite-range interactions. We show that swarm shedding can be localized around a few agents, or delocalized, and entail a simultaneous ejection of all agents in a network. Despite the complexity of milling motion in complex networks, we successfully build mean-field theory that accurately predicts both milling state dynamics and shedding transitions. The latter are described in terms of saddle-node bifurcations that depend on the range of communication, the inter-agent interaction strength, and the network topology.

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.

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.