Operational complexities in international clinical trials: a systematic review of challenges and proposed solutions.

OBJECTIVE: International trials can be challenging to operationalise due to incompatibilities between country-specific policies and infrastructures. The aim of this systematic review was to identify the operational complexities of conducting international trials and identify potential solutions for overcoming them. DESIGN: Systematic review. DATA SOURCES: Medline, Embase and Health Management Information Consortium were searched from 2006 to 30 January 2023. ELIGIBILITY CRITERIA: All studies reporting operational challenges (eg, site selection, trial management, intervention management, data management) of conducting international trials were included. DATA EXTRACTION AND SYNTHESIS: Search results were independently screened by at least two reviewers and data were extracted into a proforma. RESULTS: 38 studies (35 RCTs, 2 reports and 1 qualitative study) fulfilled the inclusion criteria. The median sample size was 1202 (IQR 332-4056) and median number of sites was 40 (IQR 13-78). 88.6% of studies had an academic sponsor and 80% were funded through government sources. Operational complexities were particularly reported during trial set-up due to lack of harmonisation in regulatory approvals and in relation to sponsorship structure, with associated budgetary impacts. Additional challenges included site selection, staff training, lengthy contract negotiations, site monitoring, communication, trial oversight, recruitment, data management, drug procurement and distribution, pharmacy involvement and biospecimen processing and transport. CONCLUSIONS: International collaborative trials are valuable in cases where recruitment may be difficult, diversifying participation and applicability. However, multiple operational and regulatory challenges are encountered when implementing a trial in multiple countries. Careful planning and communication between trials units and investigators, with an emphasis on establishing adequately resourced cross-border sponsorship structures and regulatory approvals, may help to overcome these barriers and realise the benefits of the approach. OPEN SCIENCE FRAMEWORK REGISTRATION NUMBER: osf-registrations-yvtjb-v1.

Ethnic minority representation in UK COVID-19 trials: systematic review and meta-analysis.

BACKGROUND: The COVID-19 pandemic has highlighted health disparities affecting ethnic minority communities. There is growing concern about the lack of diversity in clinical trials. This study aimed to assess the representation of ethnic groups in UK-based COVID-19 randomised controlled trials (RCTs). METHODS: A systematic review and meta-analysis were undertaken. A search strategy was developed for MEDLINE (Ovid) and Google Scholar (1st January 2020-4th May 2022). Prospective COVID-19 RCTs for vaccines or therapeutics that reported UK data separately with a minimum of 50 participants were eligible. Search results were independently screened, and data extracted into proforma. Percentage of ethnic groups at all trial stages was mapped against Office of National Statistics (ONS) statistics. Post hoc DerSimonian-Laird random-effects meta-analysis of percentages and a meta-regression assessing recruitment over time were conducted. Due to the nature of the review question, risk of bias was not assessed. Data analysis was conducted in Stata v17.0. A protocol was registered (PROSPERO CRD42021244185). RESULTS: In total, 5319 articles were identified; 30 studies were included, with 118,912 participants. Enrolment to trials was the only stage consistently reported (17 trials). Meta-analysis showed significant heterogeneity across studies, in relation to census-expected proportions at study enrolment. All ethnic groups, apart from Other (1.7% [95% CI 1.1-2.8%] vs ONS 1%) were represented to a lesser extent than ONS statistics, most marked in Black (1% [0.6-1.5%] vs 3.3%) and Asian (5.8% [4.4-7.6%] vs 7.5%) groups, but also apparent in White (84.8% [81.6-87.5%] vs 86%) and Mixed 1.6% [1.2-2.1%] vs 2.2%) groups. Meta-regression showed recruitment of Black participants increased over time (p = 0.009). CONCLUSIONS: Asian, Black and Mixed ethnic groups are under-represented or incorrectly classified in UK COVID-19 RCTs. Reporting by ethnicity lacks consistency and transparency. Under-representation in clinical trials occurs at multiple levels and requires complex solutions, which should be considered throughout trial conduct. These findings may not apply outside of the UK setting.

Humoral and cellular immunity in patients with rare autoimmune rheumatic diseases following SARS-CoV-2 vaccination.

OBJECTIVES: Coronavirus 2019 vaccine responses in rare autoimmune rheumatic diseases (RAIRDs) remain poorly understood; in particular there is little known about whether people develop effective T cell responses. We conducted an observational study to evaluate the short-term humoral and cell-mediated T cell response after the second severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in RAIRD patients compared with healthy controls (HCs). METHODS: Blood samples were collected after the second dose and anti-spike, anti-nucleocapsid antibody levels and SARS-CoV-2-specific T cell responses were measured and compared with those of HCs. Activation-induced marker and deep phenotyping assays were used to identify differences in T cells between high and no/low antibody groups, followed by multidimensional clustering. RESULTS: A total of 50 patients with RAIRDs were included (31 with AAV, 4 with other systemic vasculitis, 9 with SLE and 6 with myositis). The median anti-spike levels were significantly lower in RAIRD patients compared with HCs (P < 0.0001). Fifteen (33%) patients had undetectable levels and 26 (57%) had levels lower than the lowest HC. Rituximab in the last 12 months (P = 0.003) was associated with reduced immunogenicity compared with a longer pre-vaccination period. There was a significant difference in B cell percentages (P = 0.03) and spike-specific CD4+ T cells (P = 0.02) between no/low antibody vs high antibody groups. Patients in the no/low antibody group had a higher percentage of terminally differentiated (exhausted) T cells. CONCLUSIONS: Following two doses, most RAIRD patients have lower antibody levels than the lowest HC and lower anti-spike T cells. RAIRD patients with no/low antibodies have diminished numbers and poor quality of memory T cells that lack proliferative and functional capacities.

Antibody response to four doses of SARS-CoV-2 vaccine in rare autoimmune rheumatic diseases: an observational study.

Objective: Antibody responses to coronavirus disease 2019 (COVID-19) vaccines are reduced among immunocompromised patients but are not well quantified among people with rare disease. We conducted an observational study to evaluate the antibody responses to the booster SARS-CoV-2 vaccine in people with rare autoimmune rheumatic diseases (RAIRD). Methods: Blood samples were collected after second, before third, after third and after fourth vaccine doses. Anti-spike and anti-nucleocapsid antibody levels were measured using an in-house ELISA. Logistic regression models were built to determine the predictors for non-response. Results were compared with age- and sex-matched healthy controls. Results: Forty-three people with RAIRD were included, with a median age of 56 years. Anti-spike seropositivity increased from 42.9% after second dose to 51.2% after third dose and 65.6% after fourth dose. Median anti-spike antibody levels increased from 33.6 (interquartile range 7.8-724.5) binding antibody units after second dose to 239.4 (interquartile range 35.8-1051.1) binding antibody units after the booster dose (third dose, or fourth dose if eligible). Of the participants who had sufficient antibody levels post-second dose, 22.2% had insufficient levels after the booster, and 34.9% of participants had lower antibodies after the booster than the lowest healthy control had after the second dose. Rituximab in the 6 months prior to booster (P = 0.02) and non-White ethnicity (P = 0.04) were associated with non-response. There was a dose-response relationship between the timing of rituximab and generation of sufficient antibodies (P = 0.03). Conclusion: Although the booster dose increased anti-spike IgG and seropositivity rates, some people with RAIRD, particularly those on rituximab, had insufficient antibody levels despite three or four doses.

Parathyroid carcinoma presenting with ventricular bigeminy in pregnancy.

Parathyroid carcinoma is very rare in pregnancy. Clinical features are similar to primary hyperparathyroidism. A 38-year-old pregnant woman had repeated hospital admissions for palpitations, headaches, dizziness and polydipsia. Blood investigations showed severe hypercalcaemia with raised parathyroid hormone and 24-hour ECG showed ventricular bigeminy and premature ventricular contractions. Neck ultrasound showed a lesion in the right thyroid lobe. Consequently, she underwent an en bloc resection of the right parathyroid and thyroid lobe at 23 weeks gestation. Histology results confirmed parathyroid cancer. This case highlights the complexities of identifying hypercalcaemia in pregnancy due to the overlapping features with common disorders of pregnancy. Early recognition and timely surgical management can prevent maternal and fetal complications. Also, the case demonstrates the value of interprofessional collaboration between different specialities in providing quality care and improving outcomes. An abridged version of this case was presented at European Congress of Endocrinology 2021.

'It is designed for everybody to find their own level and to improve themselves'; views of older people and instructors of the Falls Management Exercise (FaME) programme.

BACKGROUND: Older adults are at increased risk of falls due to ageing, decreased muscle strength and impaired balance. Clinical trials have demonstrated the efficacy and effectiveness of the Falls Management Exercise (FaME) programme in improving functioning and preventing falls. However, programme completion is often low, impacting the potential benefits of FaME. OBJECTIVE: To explore the barriers and facilitators for participation and completion of the FaME programme from an instructor and participant perspective. METHODS: Semi-structured interviews were conducted with 20 FaME users and seven Postural Stability Instructors from the East Midlands region of England, UK. Interviews were conducted using a topic guide and explored their views of the programme, intended benefits, reasons for participating, instructor's approach and venue facilities. Data were transcribed verbatim and analysed using thematic analysis. Written informed consent was obtained from all participants and instructors. RESULTS: Common themes identified by participants and instructors for adherence related to perceived health benefits, psychological well-being, intervention characteristics, cost, instructors' qualities, opportunity to socialise, venue accessibility and facilities. Further factors such as maintaining independence, discipline, relationship with peers and caring responsibilities influenced participants' engagement with the programme. Instructor factors such as progression were also reported as important predictors. CONCLUSIONS: Instructor and participant factors influence uptake, attendance and adherence of FaME. The findings from this study can inform the development and improvement of additional falls-prevention programmes. It can also guide marketing strategies to promote uptake of exercise-based falls-prevention programmes among older adults.

Improving prevention, monitoring and management of diabetes among ethnic minorities: contextualizing the six G's approach.

OBJECTIVE: People from Black, Asian and Minority Ethnic (BAME) groups are known to have an increased risk of developing diabetes and face greater barriers to accessing healthcare resources compared to their 'white British' counterparts. The extent of these barriers varies by demographics and different socioeconomic circumstances that people find themselves in. The purpose of this paper is to present and discuss a new framework to understand, disentangle and tackle these barriers so that improvements in the effectiveness of diabetes interventions for BAME communities can be achieved. RESULTS: The main mediators of lifestyle behavioural change are gender, generation, geography, genes, God/religion, and gaps in knowledge and economic resources. Dietary and cultural practices of these individuals significantly vary according to gender, generation, geographical origin and religion. Recognition of these factors is essential in increasing knowledge of healthy eating, engagement in physical activity and utilisation of healthcare services. Use of the six G's framework alongside a community centred approach is crucial in developing and implementing culturally sensitive interventions for diabetes prevention and management in BAME communities. This could improve their health outcomes and overall wellbeing.