Implementation of risk based monitoring into academic led clinical trials in Ireland

Introduction: In November 2016, the International Conference on Harmonsation (ICH) published a requirement for sponsors to develop a systematic, prioritised, risk-based approach to monitoring clinical trials. This process is more commonly known as Risk Based Monitoring (RBM). However, evidence suggested that a gold standard validated approach to RBM did not exist and it was unclear how sponsors would introduce RBM into their clinical trials units (CTUs). In 2014, Ireland, unlike countries such as Switzerland and the UK, did not have a national strategy to support the introduction of RBM into its publicly funded, academic-led CTUs. The absence of a national strategy and gold standard RBM approach meant it was not clear how RBM would be implemented in CTUs. Therefore, the overarching aim of this thesis was to develop, implement and evaluate a quality improvement intervention to support the introduction of RBM into academic-led clinical trials in Ireland. Methods: This thesis employed a multi-method research strategy directed by the Knowledge to Action (KTA) framework over four years from October 2014 to October 2018. The KTA framework is a conceptual framework to assist the translation of knowledge into sustainable, evidence-based interventions. This thesis used a range of research methods, implemented in four separate sequential phases, to address different components of the KTA framework which primarily involve knowledge creation and knowledge translations. The four phases first involved systematically reviewing the existing evidence of RBM methods. Then, in a mixed method study, I explored the attitudes, and perceived barriers and facilitators to the implementation of RBM in academic-led clinical trials in Ireland. Next, I did a document analysis study to examine the experience of monitoring in a clinical trial. Finally, I developed the quality improvement study by combining the results of the three earlier phases to identify the most appropriate quality improvement intervention to support RBM use in academic led clinical trials in Ireland. Results: The systematic review showed several tools exist to support the implementation of RBM. The mixed methods study showed a need for training and regulatory endorsed guidelines to support the implementation of RBM in academic-led clinical trials. The document analysis showed that on-site and centralised monitoring can be used simultaneously to fulfil ICH GCP’s seventeen monitoring requirements. The findings of these three studies were combined and a brief, face-to-face, interactive education workshop was identified as an effective way to encourage RBM tool usage among clinical researchers working in academic-led clinical trials in Ireland. Conclusion: Applying the KTA framework to empirical data has led to an intervention that is implementable in clinical practice and has the potential to positively change monitoring practices of clinical researchers. This thesis provides critical evidence on the complexities associated with implementing RBM in academic-led clinical trials. It provides practical recommendations to guide clinical researchers who wish to perform RBM

Participants’ perspectives and preferences on clinical trial result dissemination: The TRUST Thyroid Trial experience

Background: While there is an increasing consensus that clinical trial results should be shared with trial participants, there is a lack of evidence on the most appropriate methods. The aim of this study is to use a patient and public involvement (PPI) approach to identify, develop and evaluate a patient-preferred method of receiving results of the Thyroid Hormone Replacement for Subclinical Hypo-Thyroidism Trial (TRUST). Methods: This is a mixed methods study with three consecutive phases. Phase 1 iteratively developed a patient-preferred result method using semi-structured focus groups and a consensus-orientated-decision model, a PPI group to refine the method and adult literacy review for plain English assessment. Phase 2 was a single-blind parallel group trial. Irish TRUST participants were randomised to the intervention (patient-preferred method) and control group (standard method developed by lead study site). Phase 3 used a patient understanding questionnaire to compare patient understanding of results between the two methods. Results: Patients want to receive results of clinical trials, with qualitative findings indicating three key themes including ‘acknowledgement of individual contribution’, ‘contributing for a collective benefit’ and ‘receiving accessible and easy to understand results’. Building on these findings, a patient-preferred method of receiving results was developed as described above. TRUST participants (n=101) were randomised to the intervention. The questionnaire response rate was 74% for the intervention group and 62% for the control group. There were no differences in patient understanding between the two methods. Conclusions: We have demonstrated that it is feasible to conduct PPI with regard to the dissemination of results. The study identified and developed a patient-preferred method of receiving clinical trial results for older adults over 65 years. Although, in this study PPI did not influence patients’ final understanding of results, it provides a record of the process of conducting PPI within the clinical trial setting

Perceived barriers and facilitators to Risk Based Monitoring in academic-led clinical trials: a mixed methods study.

BACKGROUND: In November 2016, the ICH published a requirement for sponsors to develop a systematic, prioritised, risk-based approach to monitoring clinical trials. This approach is more commonly known as risk-based monitoring (RBM). However, recent evidence suggests that a 'gold standard', validated approach to RBM does not exist and it is unclear how sponsors will introduce RBM into their organisations. A first step needed to inform the implementation of RBM is to explore academic trialists' readiness and ability to perform RBM. The aim of this paper is to identify the attitudes and perceived barriers and facilitators to the implementation of RBM in academic-led clinical trials in Ireland. METHODS: This is a mixed-methods, explanatory sequential design, with quantitative survey followed by semistructured interviews. Academic clinical researchers (N = 132) working in Ireland were surveyed to examine their use and perceptions of RBM. A purposive sample of survey participants (n = 22) were then interviewed to gain greater insight into the quantitative findings. The survey and interview data were merged to generate a list of perceived barriers and facilitators to RBM implementation, with suggestions for, and solutions to, these issues. RESULTS: Survey response rate was 49% (132/273). Thirteen percent (n = 18) of responders were not familiar with the term risk-based monitoring and less than a quarter of respondents (21%, n = 28) had performed RBM in a clinical trial. Barriers to RBM implementation included lack of RBM knowledge/training, increased costs caused by greater IT demands, increased workload for trial staff and lack of evidence to support RBM as an effective monitoring approach. Facilitators included participants' legal obligation to perform RBM under the new ICH-GCP guidelines, availability of RBM guidance and perception of cost savings by performing RBM in future trials. CONCLUSION: The results of this study demonstrate a need for training and regulatory-endorsed guidelines to support the implementation of RBM in academic-led clinical trials. The study provides valuable insights to inform interventions and strategies by policy-makers and clinical trial regulators to improve RBM uptake

Going beyond richness: Modelling the BEF relationship using species identity, evenness, richness and species interactions via the DImodels R package, and a comparison with traditional approaches

BEF studies aim at understanding how ecosystems respond to a gradient of species diversity. Diversity-Interactions models are suitable for analysing the BEF relationship. These models relate an ecosystem function response of a community to the identity of the species in the community, their evenness (proportions) and interactions. The no. of species in the community (richness) is also implicitly modelled through this approach. It is common in BEF studies to model an ecosystem function as a function of richness; while this can uncover trends in the BEF relationship, by definition, species diversity is much broader than richness alone, and important patterns in the BEF relationship may remain hidden. We compare DI models to traditional modelling approaches to highlight the advantages of using a multi-dimensional definition of species diversity. DI models can capture variation due to species identities, species proportions and species interactions, in addition to richness effects. We also introduce the DImodels R package for implementing DI models. Through worked examples, we show that using DI models can lead to considerably improved model fit over other methods. Collapsing the multiple dimensions of species diversity to a single dimension (such as richness) can result in valuable ecological information being lost. Predicting from a DI model is not limited to the study design points, the model can extrapolate to predict for any species composition and proportions. Overall, DI models lead to enhanced inference compared to other approaches. Expressing the BEF relationship as a function of richness alone can be useful to capture overall trends, however, there are multiple ways to quantify the species diversity of a community. DI modelling provides a framework to test the multiple aspects of species diversity and facilitates uncovering a deeper ecological understanding of the BEF relationship

Burden, screening, and treatment of depressive and anxious symptoms among women referred to cardiac rehabilitation: a prospective study

Background Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality among women. Women with CVD experience a greater burden of psychosocial distress than men, and practice guidelines promote screening in cardiac patients, especially women. The objectives herein were to describe the burden of psychosocial distress, extent of screening, forms of treatment, and whether receipt of treatment was related to psychosocial distress symptom severity at follow-up, among women. Methods Within a multi-center trial of women randomized to cardiac rehabilitation models, consenting participants were asked to complete surveys upon consent and 6 months later. Clinical data were extracted from charts. This study presents a secondary analysis of the surveys, including investigator-generated items assessing screening and treatment, the Beck Depression Inventory-II, the Hospital Anxiety and Depression Scale, and Patient Health Questionnaire-2. Results Of the 128 (67.0%) participants with valid baseline and follow-up survey results, 48 (40.3%) self-reported that they recalled being screened, and of these, 10 (21.3%) recalled discussing the results with a health care professional. Fifty-six (43.8%) retained participants had elevated symptoms of psychosocial distress at baseline, of which 25 (44.6%) were receiving treatment. Regression analyses showed that treatment of psychosocial distress was not significantly associated with follow-up depressive symptoms, but was significantly associated with greater follow-up anxiety. Conclusions Findings reiterate the great burden of psychosocial distress among women with CVD. Less than half of patients with elevated symptoms were treated, and the treatment approaches appeared to insufficiently achieve symptom relief.This research was funded by the Heart and Stroke Foundation of Ontario (HSFO), Grant-in-Aid #NA 6682

Study within a trial (SWAT) protocol. Participants' perspectives and preferences on clinical trial result dissemination: The TRUST Thyroid Trial experience.

INTRODUCTION: Dissemination of results of randomised controlled trials is traditionally limited to academic and professional groups rather than clinical trial participants. While there is increasing consensus that results should be communicated to trial participants, there is a lack of evidence on the most appropriate methods of dissemination. This study within a trial (SWAT) aims to address this gap by using a public and patient involvement (PPI) approach to identify, develop and evaluate a patient-preferred method of receiving trial results of the Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial (TRUST). METHODS: An experimental (intervention) study will be conducted using mixed methods to inform the development of and evaluation of a patient-preferred method of communication of trial results. The study will involve three consecutive phases. In the first phase, focus groups of trial participants will be conducted to identify a patient-preferred method of receiving trial results. The method will be developed and then assessed and refined by a patient and public expert group. In the second phase participants will be randomly assigned to the intervention (patient-preferred method) and comparison groups (standard dissemination method as developed by the lead study site in Glasgow, Scotland). In the third phase, a quantitative questionnaire will be used to measure and compare patient understanding of trial results between the two groups. DISCUSSION: This protocol provides a template for other trialists who wish to enhance patient and public involvement and additionally, will provide empirical evidence on how trialists should best disseminate study results to their participants

Participants' perspectives and preferences on clinical trial result dissemination: The TRUST Thyroid Trial experience.

Background: While there is an increasing consensus that clinical trial results should be shared with trial participants, there is a lack of evidence on the most appropriate methods. The aim of this study is to use a patient and public involvement (PPI) approach to identify, develop and evaluate a patient-preferred method of receiving results of the Thyroid Hormone Replacement for Subclinical Hypo-Thyroidism Trial (TRUST). Methods: This is a mixed methods study with three consecutive phases. Phase 1 iteratively developed a patient-preferred result method using semi-structured focus groups and a consensus-orientated-decision model, a PPI group to refine the method and adult literacy review for plain English assessment. Phase 2 was a single-blind parallel group trial. Irish TRUST participants were randomised to the intervention (patient-preferred method) and control group (standard method developed by lead study site). Phase 3 used a patient understanding questionnaire to compare patient understanding of results between the two methods. Results: Patients want to receive results of clinical trials, with qualitative findings indicating three key themes including 'acknowledgement of individual contribution', 'contributing for a collective benefit' and 'receiving accessible and easy to understand results'. Building on these findings, a patient-preferred method of receiving results was developed as described above. TRUST participants (n=101) were randomised to the intervention. The questionnaire response rate was 74% for the intervention group and 62% for the control group.  There were no differences in patient understanding between the two methods.  Conclusions: We have demonstrated that it is feasible to conduct PPI with regard to the dissemination of results. The study identified and developed a patient-preferred method of receiving clinical trial results for older adults over 65 years. Although, in this study PPI did not influence patients' final understanding of results, it provides a record of the process of conducting PPI within the clinical trial setting

Study protocol; thyroid hormone replacement for untreated older adults with subclinical hypothyroidism - a randomised placebo controlled trial (TRUST)

Background: Subclinical hypothyroidism (SCH) is a common condition in elderly people, defined as elevated serum thyroid-stimulating hormone (TSH) with normal circulating free thyroxine (fT4). Evidence is lacking about the effect of thyroid hormone treatment. We describe the protocol of a large randomised controlled trial (RCT) of Levothyroxine treatment for SCH. Methods: Participants are community-dwelling subjects aged ≥65 years with SCH, diagnosed by elevated TSH levels (≥4.6 and ≤19.9 mU/L) on a minimum of two measures ≥ three months apart, with fT4 levels within laboratory reference range. The study is a randomised double-blind placebo-controlled parallel group trial, starting with levothyroxine 50 micrograms daily (25 micrograms in subjects <50Kg body weight or known coronary heart disease) with titration of dose in the active treatment group according to TSH level, and a mock titration in the placebo group. The primary outcomes are changes in two domains (hypothyroid symptoms and fatigue / vitality) on the thyroid-related quality of life questionnaire (ThyPRO) at one year. The study has 80% power (at p = 0.025, 2-tailed) to detect a change with levothyroxine treatment of 3.0% on the hypothyroid scale and 4.1% on the fatigue / vitality scale with a total target sample size of 750 patients. Secondary outcomes include general health-related quality of life (EuroQol), fatal and non-fatal cardiovascular events, handgrip strength, executive cognitive function (Letter Digit Coding Test), basic and instrumental activities of daily living, haemoglobin, blood pressure, weight, body mass index and waist circumference. Patients are monitored for specific adverse events of interest including incident atrial fibrillation, heart failure and bone fracture. Discussion: This large multicentre RCT of levothyroxine treatment of subclinical hypothyroidism is powered to detect clinically relevant change in symptoms / quality of life and is likely to be highly influential in guiding treatment of this common condition. Trial registration: Clinicaltrials.gov NCT01660126; registered 8th June 2012

Radially Extended Kinematics in the S0 Galaxy NGC 2768 from Planetary Nebulae, Globular Clusters and Starlight

There are only a few tracers available to probe the kinematics of individual early-type galaxies beyond one effective radius. Here we directly compare a sample of planetary nebulae (PNe), globular clusters (GCs) and galaxy starlight velocities out to ~4 effective radii, in the S0 galaxy NGC 2768. Using a bulge-to-disk decomposition of a K-band image we assign PNe and starlight to either the disk or the bulge. We show that the bulge PNe and bulge starlight follow the same radial density distribution as the red subpopulation of GCs, whereas the disk PNe and disk starlight are distinct components. We find good kinematic agreement between the three tracers to several effective radii (and with stellar data in the inner regions). Further support for the distinct nature of the two galaxy components come from our kinematic analysis. After separating the tracers into bulge and disk components we find the bulge to be a slowly rotating pressure-supported system, whereas the disk reveals a rapidly rising rotation curve with a declining velocity dispersion profile. The resulting V/sigma ratio for the disk resembles that of a spiral galaxy and hints at an origin for NGC 2768 as a transformed late-type galaxy. A two-component kinematic analysis for a sample of S0s will help to elucidate the nature of this class of galaxy.Comment: 10 pages, 5 figures, accepted for publication in MRA

The impact of COVID-19 on farmers’ mental health: a case study of the UK

Objectives In this paper, we use a UK case study to explore how the COVID-19 pandemic affected the mental health (emotional, psychological, social wellbeing) of farmers. We outline the drivers of poor farming mental health, the manifold impacts of the pandemic at a time of policy and environmental change, and identify lessons that can be learned to develop resilience in farming communities against future shocks. Methods We undertook a survey answered by 207 farmers across the UK, focusing on drivers of poor mental health and the effect of the COVID-19 pandemic. We also conducted 22 in-depth interviews with individuals in England, Scotland and Wales who provide mental health support to farmers. These explored how and why the COVID-19 pandemic affected the mental health of farmers. These interviews were supplemented by 93 survey responses from a similar group of support providers (UK-wide). Results We found that the pandemic exacerbated underlying drivers of poor mental health and wellbeing in farming communities. 67% of farmers surveyed reported feeling more stressed, 63% felt more anxious, 38% felt more depressed, and 12% felt more suicidal. The primary drivers of poor mental health identified by farmers during the pandemic included decreased social contact and loneliness, issues with the general public on private land, and moving online for social events. Support providers also highlighted relationship and financial issues, illness, and government inspections as drivers of poor mental health. Some farmers, conversely, outlined positive impacts of the pandemic. Conclusion The COVID-19 pandemic is just one of many potential stressors associated with poor farming mental health and its impacts are likely to be long-lasting and delayed. Multiple stressors affecting farmers at the same time can create a tipping point. Therefore, there is a need for long-term support and ongoing evaluation of the drivers of poor mental health in farming families