Change in Patient Enrollment After Site Principal Investigator Turnover in Surgical Clinical Trials.

This cohort study examines the association of principal investigator (PI) turnover with patient enrollment in surgical clinical trials.

Access to robotic assisted kidney transplant for recipients: a systematic review and call for reporting standards.

Robot-assisted kidney transplantation (RAKT) is a relatively novel, minimally invasive option for kidney transplantation. However, clarity on recipient selection in the published literature is lacking thereby significantly limiting interpretation of safety and other outcomes. This systematic review aimed to identify and synthesize the data on selection of RAKT recipients, compare the synthesized data to kidney transplant recipients across the USA, and explore geographical clusters of availability of RAKT. Systematic literature review, in accordance with PRISMA, via OVID MEDLINE, Embase, and Web of science from inception to March 5, 2023. All data entry double blinded and quality via Newcastle Ottawa Scale. 44 full-text articles included, encompassing approximately 2402 kidney transplant recipients at baseline but with considerable suspicion for overlap across publications. There were significant omissions of information across studies on patient selection for RAKT and/or analysis. Overall, the quality of studies was very low. Given suspicion of overlap across studies, it is difficult to determine how many RAKT recipients received living (LD) versus deceased donor (DD) organs, but a rough estimate suggests 89% received LD. While the current RAKT literature provides preliminary evidence on safety, there are significant omissions in reporting on patient selection for RAKT which limits interpretation of findings. Two recommendations: (1) international consensus is needed for reporting guidelines when publishing RAKT data and (2) larger controlled trials consistently reporting recipient characteristics are needed to clearly determine selection, safety, and outcomes across both LD and DD recipients.

Development and deployment of a histopathology-based deep learning algorithm for patient prescreening in a clinical trial.

Accurate identification of genetic alterations in tumors, such as Fibroblast Growth Factor Receptor, is crucial for treating with targeted therapies; however, molecular testing can delay patient care due to the time and tissue required. Successful development, validation, and deployment of an AI-based, biomarker-detection algorithm could reduce screening cost and accelerate patient recruitment. Here, we develop a deep-learning algorithm using >3000 H&E-stained whole slide images from patients with advanced urothelial cancers, optimized for high sensitivity to avoid ruling out trial-eligible patients. The algorithm is validated on a dataset of 350 patients, achieving an area under the curve of 0.75, specificity of 31.8% at 88.7% sensitivity, and projected 28.7% reduction in molecular testing. We successfully deploy the system in a non-interventional study comprising 89 global study clinical sites and demonstrate its potential to prioritize/deprioritize molecular testing resources and provide substantial cost savings in the drug development and clinical settings.

New horizons in liver transplantation for hepatocellular carcinoma.

Primary liver cancer was the third most common cause of death due to cancer worldwide in 2020. As the predominant type, hepatocellular carcinoma (HCC) represents the overwhelming majority of newly diagnosed primary liver tumours. Liver transplantation remains the treatment of choice for a cure in otherwise unresectable HCC. For nearly thirty years, the Milan and Barcelona Clinic Liver Cancer (BCLC) criteria have guided physicians' clinical decision-making for selection of liver transplant candidates in the treatment of HCC. More recently, studies have demonstrated survival benefit for patients transplanted beyond Milan criteria. This remains an area of active research and includes advancements in local-regional therapies and their role in downstaging tumours to within transplant criteria as a bridge to transplant. Other advancements on the horizon include the identification of tumour biomarkers that may lead to earlier diagnosis and more accurate prediction of prognosis and risk of recurrence, as well as new neoadjuvant therapies and post-transplant immunosuppression regimens that may allow for further expansion of transplant eligibility criteria. Additionally, several recent studies have investigated the potential survival benefit of combination therapy using local-regional intervention with systemic immunotherapy to downstage otherwise unresectable disease that is beyond Milan criteria. Liver transplantation will continue to play an important role in the treatment of HCC for the foreseeable future and based on currently available evidence, both local-regional therapies and immunomodulation in combination are poised to change the landscape of liver transplantation for HCC as we currently know it.

Trial Participation in Neurodegenerative Diseases: Barriers and Facilitators: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Clinical trials in neurodegenerative diseases often encounter selective enrollment and under-representation of certain patient populations. This delays drug development and substantially limits the generalizability of clinical trial results. To inform recruitment and retention strategies, and to better understand the generalizability of clinical trial populations, we investigated which factors drive participation. METHODS: We reviewed the literature systematically to identify barriers to and facilitators of trial participation in 4 major neurodegenerative disease areas: Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease. Inclusion criteria included original research articles published in a peer-reviewed journal and evaluating barriers to and/or facilitators of participation in a clinical trial with a drug therapy (either symptomatic or disease-modifying). The Critical Appraisal Skills Program checklist for qualitative studies was used to assess and ensure the quality of the studies. Qualitative thematic analyses were employed to identify key enablers of trial participation. Subsequently, we pooled quantitative data of each enabler using meta-analytical models. RESULTS: Overall, we identified 36 studies, enrolling a cumulative sample size of 5,269 patients, caregivers, and health care professionals. In total, the thematic analysis resulted in 31 unique enablers of trial participation; the key factors were patient-related (own health benefit and altruism), study-related (treatment and study burden), and health care professional-related (information availability and patient-physician relationship). When meta-analyzed across studies, responders reported that the reason to participate was mainly driven by (1) the relationship with clinical staff (70% of the respondents; 95% CI 53%-83%), (2) the availability of study information (67%, 95% CI 38%-87%), and (3) the use or absence of a placebo or sham-control arm (53% 95% CI 32%-72%). There was, however, significant heterogeneity between studies (all p < 0.001). DISCUSSION: We have provided a comprehensive list of reasons why patients participate in clinical trials for neurodegenerative diseases. These results may help to increase participation rates, better inform patients, and facilitate patient-centric approaches, thereby potentially reducing selection mechanisms and improving generalizability of trial results.

Multi-arm multi-stage (MAMS) randomised selection designs: impact of treatment selection rules on the operating characteristics.

BACKGROUND: Multi-arm multi-stage (MAMS) randomised trial designs have been proposed to evaluate multiple research questions in the confirmatory setting. In designs with several interventions, such as the 8-arm 3-stage ROSSINI-2 trial for preventing surgical wound infection, there are likely to be strict limits on the number of individuals that can be recruited or the funds available to support the protocol. These limitations may mean that not all research treatments can continue to accrue the required sample size for the definitive analysis of the primary outcome measure at the final stage. In these cases, an additional treatment selection rule can be applied at the early stages of the trial to restrict the maximum number of research arms that can progress to the subsequent stage(s). This article provides guidelines on how to implement treatment selection within the MAMS framework. It explores the impact of treatment selection rules, interim lack-of-benefit stopping boundaries and the timing of treatment selection on the operating characteristics of the MAMS selection design. METHODS: We outline the steps to design a MAMS selection trial. Extensive simulation studies are used to explore the maximum/expected sample sizes, familywise type I error rate (FWER), and overall power of the design under both binding and non-binding interim stopping boundaries for lack-of-benefit. RESULTS: Pre-specification of a treatment selection rule reduces the maximum sample size by approximately 25% in our simulations. The familywise type I error rate of a MAMS selection design is smaller than that of the standard MAMS design with similar design specifications without the additional treatment selection rule. In designs with strict selection rules - for example, when only one research arm is selected from 7 arms - the final stage significance levels can be relaxed for the primary analyses to ensure that the overall type I error for the trial is not underspent. When conducting treatment selection from several treatment arms, it is important to select a large enough subset of research arms (that is, more than one research arm) at early stages to maintain the overall power at the pre-specified level. CONCLUSIONS: Multi-arm multi-stage selection designs gain efficiency over the standard MAMS design by reducing the overall sample size. Diligent pre-specification of the treatment selection rule, final stage significance level and interim stopping boundaries for lack-of-benefit are key to controlling the operating characteristics of a MAMS selection design. We provide guidance on these design features to ensure control of the operating characteristics.

Mapping Strategies for Reaching Socioeconomically Disadvantaged Populations in Clinical Trials.

Importance: Socioeconomically disadvantaged patients, such as persons with low income and those with low educational attainment, are less likely to participate in clinical trials than those with higher earnings and higher educational attainment, despite the former being more likely to have chronic medical conditions. Ways to improve the representation of socioeconomically disadvantaged patients in clinical trials deserve attention. Objective: To examine whether current recruitment and enrollment strategies used by US clinical research sites appropriately include patients from socioeconomically disadvantaged backgrounds. Design, Setting, and Participants: This survey study was conducted between April and July 2023. An online survey was distributed among US clinical research sites to explore their use of these strategies and the types of patient sociodemographic and socioeconomic data they collect. The survey was distributed by 13 pharmaceutical companies and 1 clinical research organization. Eight targeted strategies known to increase the recruitment and retention of socioeconomically disadvantaged participants as well as 6 general strategies to recruit and retain clinical trial participants were identified. Data analysis was performed between August and September 2023. Main Outcomes and Measures: Proportions of for-profit vs nonprofit or governmental sites that use recruitment and retention strategies, proportions that have partnerships with community organizations that target socioeconomically disadvantaged groups, and the distribution of sociodemographic and socioeconomic data collected by sites about their patients. A χ2 test of independence was performed to assess the association between research site ownership type and levels of adoption of strategies. Results: A total of 492 responses were collected from 381 clinical research sites in the US (219 for-profit sites [57.5%] and 162 nonprofit or governmental sites [42.5%]). Overall, compared with nonprofit or governmental sites, for-profit sites reported higher use of strategies shown to increase the recruitment and retention of socioeconomically disadvantaged populations, including always or often providing after-hours visits (84 of 173 for-profit sites [48.6%]; 22 of 123 nonprofit or governmental sites [17.9%]) and offering financial compensation (135 of 162 for-profit sites [83.3%]; 60 of 123 nonprofit or governmental sites [48.8%]). Additionally, there was an association between research site ownership type and levels of adoption of these strategies; for example, for-profit sites were more likely to provide after-hours visits (χ2 = 30.33; P < .001) and offer financial compensation (χ2 = 49.35; P < .001). Only 7.2% of for-profit sites (12 of 167) and 13.0% of nonprofit or governmental sites (16 of 123) collected information on the patient's annual income. Conclusions and Relevance: In this survey study, we found an association between a clinical research site's ownership type (for-profit vs nonprofit or governmental) and how often it used strategies to engage socioeconomically diverse populations in clinical research. Regardless of ownership type, most clinical research sites did not collect socioeconomic information from patients. Adoption of strategies to engage socioeconomically diverse populations, particularly by nonprofit or governmental sites, may help minimize barriers to participation for socioeconomically disadvantaged patients.

PCI vs. CABG in left main with multi-vessel coronary artery disease and diabetes: Case report.

This case challenges the conventional preference for coronary artery bypass grafting (CABG) over percutaneous coronary intervention (PCI) in patients with diabetes, left main coronary artery disease (LMCAD) and multivessel disease. Current guidelines generally recommend CABG, especially in the context of LMCAD. However, our case involves a male patient with diabetes with LMCAD and extensive multivessel disease who was successfully treated with PCI, demonstrating a favorable outcome. Despite the high-risk profile, including a SYNTAX score of 28, the PCI approach was selected. This decision was supported by evidence suggesting comparable outcomes between PCI and CABG in similar patients. Our case highlights the potential of PCI as not just a viable, but potentially superior alternative in specific high-risk patients with diabetes, contrary to the prevailing belief in favor of CABG for all patients with left main involvement.

Recruitment and retention of adolescents for an ecological momentary assessment measurement burst mental health study: The MHIM engagement strategy.

INTRODUCTION: Recruitment and long-term retention of adolescent participants in longitudinal research are challenging and may be especially so in studies involving remote measurement and biosampling components. The ability to effectively recruit and retain participants can be supported by the use of specific evidence-based engagement strategies that are built in from the earliest stages. METHODS: Informed by a review of the evidence on effective engagement strategies and consultations with adolescents (via two Young Person Advisory Groups [YPAGs]; ages 11-13 and 14-17), the current protocol describes the planned participant engagement strategy for the Mental Health in the Moment Study: a multimodal measurement burst study of adolescent mental health across ages 11-19. RESULTS: The protocol incorporates engagement strategies in four key domains: consultations/co-design with the target population, incentives, relationship-building and burden/barrier reduction. In addition to describing general engagement strategies in longitudinal studies, we also discuss specific concerns regarding engagement in data collection methods such as biosampling and ecological momentary assessment where a paucity of evidence exists. CONCLUSION: Engagement strategies for adolescent mental health studies should be based on existing evidence and consultations with adolescents. We present our approach in developing the planned engagement strategies and also discuss limitations and future directions in engaging adolescents in longitudinal research. PATIENT OR PUBLIC CONTRIBUTION: The study design for this project places a strong emphasis on the active engagement of adolescents throughout its development. Specifically, the feedback and suggestions provided by the YPAGs have been instrumental in refining our strategies for maximising the recruitment and retention of participants.

Determining capacity of people with dementia to take part in research: an electronic survey study of researcher confidence, competence and training needs.

BACKGROUND: Researchers are required to determine whether a person has capacity to consent to a research study before they are able to participate. The Mental Capacity Act and accompanying Code of Practice for England and Wales provide some guidance on this process, but researchers have identified that it can be difficult to determine capacity to consent when a person has complex cognitive or communication needs. This study aimed to understand the experiences and opinions of researchers who recruit people with dementia to research projects, to inform the future development of training resources. METHODS: A mixed method, cross-sectional, electronic survey was circulated via social media and research networks in England and Wales. The survey remained open for ten weeks and included open and closed questions exploring respondents' confidence in determining capacity in the context of recruiting people with dementia to consent, their views on training and support they have experienced and their suggestions for future training and support needs. RESULTS: 60 respondents completed the survey from across England and Wales. Although 75% of respondents had experience of determining capacity to consent with people with dementia to research, only 13% rated themselves as feeling 'very confident' in this. Qualitative content analysis of open responses led to the generation of six themes, explaining researchers' confidence, competence and future training needs in this area: (1) Researcher uncertainties, (2) Lack of time, (3) Balancing information complexity with accessibility, (4) Gatekeepers, (5) Existing enablers and (6) Envisioning future training. CONCLUSIONS: Researchers would benefit from specific training in undertaking conversations around consent with people with dementia. People with dementia may have fluctuating capacity, and despite support from caregivers, researchers have little practical guidance on methods of determining a person's ability to understand or appreciate the information they have provided during the consent process. Given the development of large complex trials within dementia research, there is an urgency to develop specific and practical guidance and training for researchers working with people with dementia and their families.

Increasing inclusion and equity for Black women in breast cancer clinical trials.

Black women diagnosed with breast cancer experience a disproportionately high mortality rate. The disparity in outcomes between Black and White women is multifactorial, with a large portion attributed to lower participation of minorities in clinical trials. The lack of diversity in clinical trials continues to both reflect and contribute to health care inequities, limiting the generalizability of research findings. In addition, women who do not enroll in clinical trials miss out on the standard-of-care or often better patient care provided in these trials. Barriers to enrolling diverse populations encompass system-, provider-, and patient-level barriers. Identifying these barriers and providing actionable solutions are key to bolstering enrollment in clinical trials and ultimately eliminating cancer disparities. This review elucidates the barriers to clinical trial participation in Black women diagnosed with breast cancer and discusses ways to overcome these challenges.

Reasons for unsuccessful recruitment of children with atopic dermatitis in primary care in the Netherlands to a cohort study with an embedded pragmatic, randomised controlled open-label trial: a survey.

BACKGROUND: The Rotterdam Eczema Study was an observational cohort study with an embedded pragmatic randomised controlled open-label trial. It was conducted in children with atopic dermatitis (AD) in the Dutch primary care system. The objective of the trial was to determine whether a potent topical corticosteroid (TCS) is more effective than a low-potency TCS. OBJECTIVE: We are aiming to communicate transparently about the poor recruitment for the trial part and to explore the reasons why recruitment was weak. DESIGN: We used a survey to find out what patients in the cohort did when they experienced a flare-up. METHODS: Descriptive statistics were used to present the baseline characteristics of participants in the trial and the results of the survey. RESULTS: In total, 367 patients were included in the cohort. Of these, 32 were randomly assigned to a trial treatment; they had a median age of 4.0 years (IQR 2.0-9.8). A total of 69 of the 86 children (80.2%) who could participate in the survey responded. 39 (56.5%) suffered a flare-up during the follow-up (making them potentially eligible for inclusion in the trial). 26 out of 39 (66.7%) increased their use of an emollient and/or TCS themselves. Only 12 of the 39 (30.7%) contacted their general practitioner (GP) as instructed in the study protocol, but 8 out of these 12 did not meet the inclusion criteria for the trial. CONCLUSION: The main reason why cohort participants did not take part in the trial was that they did not contact their GPs when they experienced an AD flare-up. Furthermore, the majority of patients who contacted their GPs did not match the inclusion criteria of the trial. We expect that the lessons learnt from this study will be useful when developing future studies of children with AD in primary care.

Value of Real-World Evidence for Treatment Selection: A Case Study in Colon Cancer.

PURPOSE: Real-world evidence (RWE)-derived from analysis of real-world data (RWD)-has the potential to guide personalized treatment decisions. However, because of potential confounding, generating valid RWE is challenging. This study demonstrates how to responsibly generate RWE for treatment decisions. We validate our approach by demonstrating that we can uncover an existing adjuvant chemotherapy (ACT) guideline for stage II and III colon cancer (CC)-which came about using both data from randomized controlled trials and expert consensus-solely using RWD. METHODS: Data from the population-based Netherlands Cancer Registry from a total of 27,056 patients with stage II and III CC who underwent curative surgery were analyzed to estimate the overall survival (OS) benefit of ACT. Focusing on 5-year OS, the benefit of ACT was estimated for each patient using G-computation methods by adjusting for patient and tumor characteristics and estimated propensity score. Subsequently, on the basis of these estimates, an ACT decision tree was constructed. RESULTS: The constructed decision tree corresponds to the current Dutch guideline: patients with stage III or stage II with T stage 4 should receive surgery and ACT, whereas patients with stage II with T stage 3 should only receive surgery. Interestingly, we do not find sufficient RWE to conclude against ACT for stage II with T stage 4 and microsatellite instability-high (MSI-H), a recent addition to the current guideline. CONCLUSION: RWE, if used carefully, can provide a valuable addition to our construction of evidence on clinical decision making and therefore ultimately affect treatment guidelines. Next to validating the ACT decisions advised in the current Dutch guideline, this paper suggests additional attention should be paid to MSI-H in future iterations of the guideline.

Brief Educational Workshops in Secondary Schools Trial (BESST trial), a school-based cluster randomised controlled trial of the DISCOVER workshop for 16-18-year-olds: recruitment and baseline characteristics.

BACKGROUND: The Brief Educational Workshops in Secondary Schools Trial (BESST) is an England-wide school-based cluster randomised controlled trial assessing the clinical and cost-effectiveness of an open-access psychological workshop programme (DISCOVER) for 16-18-year-olds. This baseline paper describes the self-referral and other recruitment processes used in this study and the baseline characteristics of the enrolled schools and participants. METHOD: We enrolled 900 participants from 57 Secondary schools across England from 4th October 2021 to 10th November 2022. Schools were randomised to receive either the DISCOVER day-long Stress workshop or treatment as usual which included signposting information. Participants will be followed up for 6 months with outcome data collection at baseline, 3-month, and 6-month post randomisation. RESULTS: Schools were recruited from a geographically and ethnically diverse sample across England. To reduce stigma, students were invited to self-refer into the study if they wanted help for stress. Their mean age was 17.2 (SD = 0.6), 641 (71%) were female and 411 (45.6%) were from ethnic minority groups. The general wellbeing of our sample measured using the Mood and Feelings Questionnaire (MFQ) found 314 (35%) of students exhibited symptoms of depression at baseline. Eighty percent of students reported low wellbeing on the Warwick Edinburgh Mental Wellbeing Scale (WEMWBS) suggesting that although the overall sample mean is below the cut-off for depression, the self-referral approach used in this study supports distressed students in coming forward. CONCLUSION: The BESST study will continue to follow up participants to collect outcome data and results will be analysed once all the data have been collected. TRIAL REGISTRATION: ISRCTN registry ISRCTN90912799. Registered on 28 May 2020.

Association between hospital ownership and patient selection, management, and outcomes after carotid endarterectomy or carotid artery stenting : - Secondary data analysis of the Bavarian statutory quality assurance database.

BACKGROUND: This study analyses the association between hospital ownership and patient selection, treatment, and outcome of carotid endarterectomy (CEA) or carotid artery stenting (CAS). METHODS: The analysis is based on the Bavarian subset of the nationwide German statutory quality assurance database. All patients receiving CEA or CAS for carotid artery stenosis between 2014 and 2018 were included. Hospitals were subdivided into four groups: university hospitals, public hospitals, hospitals owned by charitable organizations, and private hospitals. The primary outcome was any stroke or death until discharge from hospital. Research was funded by Germany's Federal Joint Committee Innovation Fund (01VSF19016 ISAR-IQ). RESULTS: In total, 22,446 patients were included. The majority of patients were treated in public hospitals (62%), followed by private hospitals (17%), university hospitals (16%), and hospitals under charitable ownership (6%). Two thirds of patients were male (68%), and the median age was 72 years. CAS was most often applied in university hospitals (25%) and most rarely used in private hospitals (9%). Compared to university hospitals, patients in private hospitals were more likely asymptomatic (65% vs. 49%). In asymptomatic patients, the risk of stroke or death was 1.3% in university hospitals, 1.5% in public hospitals, 1.0% in hospitals of charitable owners, and 1.2% in private hospitals. In symptomatic patients, these figures were 3.0%, 2.5%, 3.4%, and 1.2% respectively. Univariate analysis revealed no statistically significant differences between hospital groups. In the multivariable analysis, compared to university hospitals, the odds ratio of stroke or death in asymptomatic patients treated by CEA was significantly lower in charitable hospitals (OR 0.19 [95%-CI 0.07-0.56, p = 0.002]) and private hospitals (OR 0.47 [95%-CI 0.23-0.98, p = 0.043]). In symptomatic patients (elective treatment, CEA), patients treated in private or public hospitals showed a significantly lower odds ratio compared to university hospitals (0.36 [95%-CI 0.17-0.72, p = 0.004] and 0.65 [95%-CI 0.42-1.00, p = 0.048], respectively). CONCLUSIONS: Hospital ownership was related to patient selection and treatment, but not generally to outcomes. The lower risk of stroke or death in the subgroup of electively treated patients in private hospitals might be due to the right timing, the choice of treatment modality or actually to better structural and process quality.