Development of consensus-driven SPIRIT and CONSORT extensions for early phase dose-finding trials: the DEFINE study.

BACKGROUND: Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE). METHODS: The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants' feedback. RESULTS: The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar. CONCLUSIONS: By detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility. TRIAL REGISTRATION: SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network ( https://www.equator-network.org/ ).

Equality, diversity, and inclusion in oncology clinical trials: an audit of essential documents and data collection against INCLUDE under-served groups in a UK academic trial setting.

BACKGROUND: Clinical trials should be as inclusive as possible to facilitate equitable access to research and better reflect the population towards which any intervention is aimed. Informed by the UK's National Institute for Health and Care Research (NIHR) Innovations in Clinical Trial Design and Delivery for the Under-served (INCLUDE) guidance, we audited oncology trials conducted by the Clinical Trials and Statistics Unit at The Institute of Cancer Research, London (ICR-CTSU) to identify whether essential documents were overtly excluding any groups and whether sufficient data were collected to assess diversity of trial participants from groups suggested by INCLUDE as under-served by research in the UK. METHODS: Thirty cancer clinical trials managed by ICR-CTSU and approved between 2011-2021 were audited. The first ethics approved version of each trial's protocol, patient information sheet, and patient completed questionnaire, together with the first case report forms (CRFs) version were reviewed. A range of items aligned with the INCLUDE under-served groups were assessed, including age, sex and gender, socio-economic and health factors. The scope did not cover trial processes in participating hospitals. RESULTS: Data relating to participants' age, ethnic group and health status were well collected and no upper age limit was specified in any trials' eligibility criteria. 23/30 (77%) information sheets used at least one gendered term to address patients. Most CRFs did not specify whether they were collecting sex or gender and only included male or female categories. The median reading age for information sheets was 15-16 years (IQR: 14-15 - 16-17). Socio-economic factors were not routinely collected and not commonly mentioned in trial protocols. CONCLUSIONS: No systemic issues were identified in protocols which would explicitly prevent any under-served group from participating. Areas for improvement include reducing use of gendered words and improving readability of patient information. The challenge of fully assessing adequate inclusion of under-served populations remains, as socio-economic factors are not routinely collected because they fall beyond the data generally required for protocol-specified trial endpoint assessments. This audit has highlighted the need to agree and standardise demographic data collection to permit adequate monitoring of the under-served groups identified by the NIHR.

Perspectives on reproductive healthcare delivered through a basic package of health services in Afghanistan: a qualitative study.

BACKGROUND: Contracting-out non-state providers to deliver a minimum package of essential health services is an increasingly common health service delivery mechanism in conflict-affected settings, where government capacity and resources are particularly constrained. Afghanistan, the longest-running example of Basic Package of Health Services (BPHS) contracting in a conflict-affected setting, enables study of how implementation of a national intervention influences access to prioritised health services. This study explores stakeholder perspectives of sexual and reproductive health (SRH) services delivered through the BPHS in Afghanistan, using Bamyan Province as a case study. METHODS: Twenty-six in-depth interviews were conducted with health-system practitioners (e.g. policy/regulatory, middle management, frontline providers) and four focus groups with service-users. Inductive thematic coding used the WHO Health System Framework categories (i.e. service delivery, workforce, medicines, information, financing, stewardship), while allowing for emergent themes. RESULTS: Improvements were noted by respondents in all health-system components discussed, with significant improvements identified in service coverage and workforce, particularly improved gender balance, numbers, training, and standardisation. Despite improvements, remaining weaknesses included service access and usage - especially in remote areas, staff retention, workload, and community accountability. CONCLUSIONS: By including perspectives on SRH service provision and BPHS contracting across health-system components and levels, this study contributes to broader debates on the effects of contracting on perceptions and experiences among practitioners and service-users in conflict-affected countries.

Assessing the reporting quality of early phase dose-finding trial protocols: a methodological review.

Background: The paradigm of early phase dose-finding trials has evolved in recent years. Innovative dose-finding designs and protocols which combine phases I and II are becoming more popular in health research. However, the quality of these trial protocols is unknown due to a lack of specific reporting guidelines. Here, we evaluated the reporting quality of dose-finding trial protocols. Methods: We conducted a cross-sectional study of oncology and non-oncology early phase dose-finding trial protocols posted on ClinicalTrials.gov in 2017-2023. A checklist of items comprising: 1) the original 33-items from the SPIRIT 2013 Statement and 2) additional items unique to dose-finding trials were used to assess reporting quality. The primary endpoint was the overall proportion of adequately reported items. This study was registered with PROSPERO (no: CRD42022314572). Finding: A total of 106 trial protocols were included in the study with the rule-based 3 + 3 being the most used trial design (39.6%). Eleven model-based and model-assisted designs were identified in oncology trials only (11/58, 19.0%). The overall proportion of adequately reported items was 65.1% (95%CI: 63.9-66.3%). However, the reporting quality of each individual item varied substantially (range 9.4%-100%). Oncology study protocols showed lower reporting quality than non-oncology. In the multivariable analysis, trials with larger sample sizes and industry funding were associated with higher proportions of adequately reported items (all p-values <0.05). Interpretation: The overall reporting quality of early phase dose-finding trial protocols is suboptimal (65.1%). There is a need for improved completeness and transparency in early phase dose-finding trial protocols to facilitate rigorous trial conduct, reproducibility and external review. Funding: None.

Measuring urinary N-acetyl-S-(4-hydroxy-2-methyl-2-buten-1-yl)-L-cysteine (IPMA3) as a potential biomarker of isoprene exposure.

Isoprene, the 2-methyl analog of 1,3-butadiene, is identified as a possible human carcinogen by the International Agency for Research on Cancer (IARC). Isoprene is ubiquitous in the environment with numerous natural and anthropogenic sources. Tobacco smoke is the main exogenous source of isoprene exposure in indoor environments. Among smoke constituents, isoprene is thought to contribute significantly to cancer risk; however, no selective urinary biomarkers of isoprene exposure have been identified for humans. In this manuscript, we measured the minor isoprene metabolite IPMA1 (mixture of N-acetyl-S-(1-[hydroxymethyl]-2-methyl-2-propen-1-yl)-L-cysteine and N-acetyl-S-(2-hydroxy-3-methyl-3-buten-1-yl)-L-cysteine), and we identified IPMA3 (N-acetyl-S-(4-hydroxy-2-methyl-2-buten-1-yl)-L-cysteine) as a major isoprene metabolite and novel isoprene exposure biomarker for humans. Urinary isoprene metabolites were measured using ultra high performance liquid chromatography coupled with electrospray ionization triple quad tandem mass spectrometry (UPLC/ESI-MSMS). The detection rates of IPMA1 and IPMA3 are <20% and 82%, respectively. The selectivity and abundance of IPMA3 make it a useful urinary biomarker of isoprene exposure. The limit of detection of IPMA3 in urine was 0.5 ng mL-1. IPMA3 was stable under different storage temperatures and following ten freeze-thaw cycles. The average recovery of urine spiked with IPMA3 at three different levels was 99%. IPMA3 was measured in urine samples received from 75 anonymous subjects; the median (25th percentile, 75th percentile) IPMA3 level in smokers was 36.2 (18.2, 56.8) ng mL-1 and non-smokers 2.31 (2.31, 4.38) ng mL-1. Application of this method to large population studies will help to characterize isoprene exposure and assess potential health impact.

Simultaneous analysis of 28 urinary VOC metabolites using ultra high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC-ESI/MSMS).

Volatile organic compounds (VOCs) are ubiquitous in the environment, originating from many different natural and anthropogenic sources, including tobacco smoke. Long-term exposure to certain VOCs may increase the risk for cancer, birth defects, and neurocognitive impairment. Therefore, VOC exposure is an area of significant public health concern. Urinary VOC metabolites are useful biomarkers for assessing VOC exposure because of non-invasiveness of sampling and longer physiological half-lives of urinary metabolites compared with VOCs in blood and breath. We developed a method using reversed-phase ultra high performance liquid chromatography (UPLC) coupled with electrospray ionization tandem mass spectrometry (ESI/MSMS) to simultaneously quantify 28 urinary VOC metabolites as biomarkers of exposure. We describe a method that monitors metabolites of acrolein, acrylamide, acrylonitrile, benzene, 1-bromopropane, 1,3-butadiene, carbon-disulfide, crotonaldehyde, cyanide, N,N-dimethylformamide, ethylbenzene, ethylene oxide, propylene oxide, styrene, tetrachloroethylene, toluene, trichloroethylene, vinyl chloride and xylene. The method is accurate (mean accuracy for spiked matrix ranged from 84 to 104%), sensitive (limit of detection ranged from 0.5 to 20 ng mL(-1)) and precise (the relative standard deviations ranged from 2.5 to 11%). We applied this method to urine samples collected from 1203 non-smokers and 347 smokers and demonstrated that smokers have significantly elevated levels of tobacco-related biomarkers compared to non-smokers. We found significant (p<0.0001) correlations between serum cotinine and most of the tobacco-related biomarkers measured. These findings confirm that this method can effectively quantify urinary VOC metabolites in a population exposed to volatile organics.