Early phase dose-finding (EPDF) studies are critical for the development of new treatments, directly influencing whether compounds or interventions can be investigated in further trials to confirm their safety and efficacy. There exists guidance for clinical trial protocols and reporting of completed trials in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 and CONsolidated Standards Of Reporting Randomised Trials (CONSORT) 2010 statements. However, neither the original statements nor their extensions adequately cover the specific features of EPDF trials. The DEFINE (DosE-FIndiNg Extensions) study aims to enhance transparency, completeness, reproducibility and interpretation of EPDF trial protocols (SPIRIT-DEFINE) and their reports once completed (CONSORT-DEFINE), across all disease areas, building on the original SPIRIT 2013 and CONSORT 2010 statements.
A methodological review of published EPDF trials will be conducted to identify features and deficiencies in reporting and inform the initial generation of the candidate items. The early draft checklists will be enriched through a review of published and grey literature, real-world examples analysis, citation and reference searches and consultation with international experts, including regulators and journal editors. Development of CONSORT-DEFINE commenced in March 2021, followed by SPIRIT-DEFINE from January 2022. A modified Delphi process, involving worldwide, multidisciplinary and cross-sector key stakeholders, will be run to refine the checklists. An international consensus meeting in autumn 2022 will finalise the list of items to be included in both guidance extensions.
This project was approved by ICR\'s Committee for Clinical Research. The Health Research Authority confirmed Research Ethics Approval is not required. The dissemination strategy aims to maximise guideline awareness and uptake, including but not limited to dissemination in stakeholder meetings, conferences, peer-reviewed publications and on the EQUATOR Network and DEFINE study websites.
SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network.

In the past decade, the use of intraoperative neural monitoring (IONM) in thyroid and parathyroid surgery has been widely accepted by surgeons as a useful technology for improving laryngeal nerve identification and voice outcomes, facilitating neurophysiological research, educating and training surgeons, and reducing surgical complications and malpractice litigation. Informing patients about IONM is not only good practice and helpful in promoting the efficient use of IONM resources but is indispensable for effective shared decision making between the patient and surgeon. The International Neural Monitoring Study Group (INMSG) feels complete discussion of IONM in the preoperative planning and patient consent process is important in all patients undergoing thyroid and parathyroid surgery. The purpose of this publication is to evaluate the impact of IONM on the informed consent process before thyroid and parathyroid surgery and to review the current INMSG consensus on evidence-based consent. The objective of this consensus statement, which outlines general and specific considerations as well as recommended criteria for informed consent for the use of IONM, is to assist surgeons and patients in the processes of informed consent and shared decision making before thyroid and parathyroid surgery.

Chronic non-specific neck pain is highly prevalent, resulting in significant disability. Despite exercise being a mainstay treatment, guidance on optimal exercise and dosage variables is lacking. Combining submaximal effort deep cervical muscles exercise (motor control) and superficial cervical muscles exercise (segmental) reduces chronic non-specific neck pain, but evaluation of optimal exercise and dosage variables is prevented by clinical heterogeneity.
To gain consensus on important motor control and segmental exercise and dosage variables for chronic non-specific neck pain.
An international 3-round e-Delphi study, was conducted with experts in neck pain management (academic and clinical). In round 1, exercise and dosage variables were obtained from expert opinion and clinical trial data, then analysed thematically (two independent researchers) to develop themes and statements. In rounds 2 and 3, participants rated their agreement with statements (1-5 Likert scale). Statement consensus was evaluated using progressively increased a priori criteria using descriptive statistics.
Thirty-seven experts participated (10 countries). Twenty-nine responded to round 1 (79%), 26 round 2 (70%) and 24 round 3 (65%). Round 1 generated 79 statements outlining the interacting components of exercise prescription. Following rounds 2 and 3, consensus was achieved for 46 important components of exercise and dosage prescription across 5 themes (clinical reasoning, dosage variables, exercise variables, evaluation criteria and progression) and 2 subthemes (progression criteria and progression variables). Excellent agreement and qualitative data supports exercise prescription complexity and the need for individualised, acceptable, and feasible exercise. Only 37% of important exercise components were generated from clinical trial data. Agreement was highest (88%-96%) for 3 dosage variables: intensity of effort, frequency, and repetitions.
Multiple exercise and dosage variables are important, resulting in complex and individualised exercise prescription not found in clinical trials. Future research should use these important variables to prescribe an evidence-informed approach to exercise.

In this COVID-19 era, we need to rethink the criteria used to measure the results of person-centred care strategies.
To identify priorities, and criteria that health services can use to pursue actually the goal of achieving person-centred care.
Three-phase online qualitative study performed during May-July of 2020 using the Delphi technique.
An online platform was used for a consensus meeting of 114 participants, including health planning experts, health-care institution managers, clinicians and patients.
Criteria and indicators for the achievement of person-centred care.
The first round began with 125 proposals and 11 dimensions. After the second round, 28 ideas reached a high level of consensus among the participants. Ultimately, the workgroup agreed on 20 criteria for goals in the implementation of person-centred care during the COVID-19 era and 21 related indicators to measure goal achievement.
Nine dimensions and 28 priorities were identified. These priorities are also in accordance with the quadruple aim approach, which emphasizes the need for care for health-care professionals, without whom it is impossible to achieve a better quality of care.
Person-centred care continues to be a key objective. However, new metrics are needed to ensure its continued development during the restoration of public health services beyond the control of COVID-19.
Twelve professionals and patient representatives participated voluntarily in the construction of the baseline questionnaire and in the selection of the criteria and indicators using an online platform for consensus meetings.

Vasa previa is a condition where fetal blood vessels run unprotected in the membranes, outside the umbilical cord, and cross the internal opening of the cervix. During rupture of membranes, these vessels can rupture and put the baby at serious risk of severe blood loss and death. Numerous studies are being conducted to improve diagnostic modalities and establish clear management plans to improve pregnancy outcomes. However, the lack of a standardised set of outcomes for studies on vasa previa makes it difficult to compare study findings and draw meaningful conclusions. Through this project, we will be developing a core outcome set for studies on pregnant women with vasa previa (COVasP).
The development of COVasP will involve five steps. The first will be a systematic review, in which we will generate a long list of outcomes based on published studies in pregnancies complicated with vasa previa. The second will involve in-depth interviews with current and former patients, their family members and healthcare providers who care for these patients. This will be followed by a two-round Delphi survey, which will aim to narrow down the long list of outcomes into those considered important by four groups of \'stakeholders\': (1) patients, family members and patient advocates/representatives, (2) healthcare providers, (3) researchers, epidemiologists and methodologists and (4) other stakeholders directly or indirectly involved in the management of these pregnancies such as administrators, guideline developers and policymakers. The fourth step will involve a face-to-face consensus meeting using a nominal group approach to establish a finalised core outcome set. The final step will involve measuring and defining the identified outcomes using a combination of systematic reviews and Delphi surveys.
This study as well as consent forms for stakeholder participation have received approval from the Mount Sinai Hospital Research Ethics Board (REB number 18-0173-E) on 05 September 2018 and the Human Research Ethics Committee at The University of Technology Sydney, Australia on 30 July 2019 (UTS HREC reference number ETH19-3718). All progress will be documented on the international prospective register of systematic reviews and Core Outcome Measures in Effectiveness Trials databases. REGISTRATION DETAILS: http://www.comet-initiative.org/studies/details/1117.

Pregnancy and post partum are times of heightened risk for the development of venous thromboembolism (VTE), which in turn is one of the leading causes of maternal mortality and long-term morbidity. The current research aimed at improving health guidelines for women with pregnancy-associated VTE is limited by inconsistency in outcome reporting preventing comparison across studies, and lack of input from patients with respect to outcomes they propose are most important to measure. A suggested solution is the development of a core outcome set (COS) that defines the minimum criteria for outcome reporting in clinical trials and prospective studies. COSs function to facilitate data harmonisation and increase homogeneity in outcome reporting while incorporating the voice of women in this population in the planning of research to inform their ongoing care.
The development of a COS for studies on pregnancy-associated VTE will comprise five steps. First, a systematic review of the published literature will identify currently reported outcomes, their definitions and measurements if applicable. This will be followed by in-person interviews with patients, clinicians, researchers, hospital administrators and policy-makers to identify outcomes they consider important. Third, the long list of outcomes obtained from steps I and II will be condensed through online Delphi surveys involving an international group of relevant stakeholders including patients. This will be followed by a face-to-face consensus meeting with representatives of all stakeholder groups to arrive at a consensus on the final COS. Lastly, to determine how the identified core outcomes should be measured, another literature review and Delphi process will be carried out as necessary.
This study has been approved by the Mount Sinai Hospital Research Ethics Board (REB 18-0314-E). Study results will be published in open-access journals and presented at obstetrics, maternal-fetal medicine and haematology conferences. All progress will be documented on the international prospective register of systematic reviews (PROSPERO) and Core Outcome Measures in Effectiveness Trials databases.
CRD42019111479.

Non-alcoholic fatty liver disease (NAFLD) is a global public health concern. Its natural history, the development of non-alcoholic steatohepatitis (NASH) and fibrosis, is highly variable, prone to endogenous (e.g., genetics, microbiota) and exogenous (e.g., nutrition, alcohol, physical activity) disease modifiers, and can fluctuate over time. The complexity of its pathophysiology is reflected by the multitude of pharmacological targets in development. NASH clinical trials have provided valuable insight that is applicable to future trial design. Endpoints for NASH have evolved over the past decade and will continue to be refined. Currently accepted endpoints for conditional approval include resolution of NASH without worsening of fibrosis and/or improvement in fibrosis without worsening of NASH by standardized evaluation of paired liver histology. In pediatric NASH, practical obstacles, pubertal hormonal changes, and stringent safety requirements mandate adaptations in trial design. In adult patients with NASH-related cirrhosis, decrease in portal pressure as well as clinical events (e.g. decompensation, hepatocellular carcinoma, transplantation, death) are more prevalent and thereby are viable primary endpoints for clinical trials. Consideration of the natural fluctuation of disease, the clinical implication of the chosen primary endpoint, and factors that may affect placebo response will facilitate an accurate determination of efficacy of emerging therapeutics for NASH. Conclusion: The June 2018 American Association for the Study of Liver Diseases and European Association for the Study of the Liver joint workshop on NAFLD endpoints summarized important findings from ongoing and completed trials, defined the scientific evidence supporting distinct endpoints, and provided guidance for future trial design.

BACKGROUND: Health economists have shown a growing interest in deliberation and multi-criteria decision analysis (MCDA) as possible pathways to transparently integrate value judgments in cost-utility analyses. In line with these developments, this study piloted a consensus process to derive a German value set for the Short-Form Six-Dimension (SF-6D). In a conference setting, a group was tasked to deliberate on scores and weights for the SF-6D from the perspective of a self-determined and independent life.
METHODS: The one-day consensus conference was based on a deliberative process in combination with the MCDA method MACBETH (Measuring Attractiveness by a Categorical Based Evaluation Technique). According to MACBETH, participants were asked to qualitatively rate pairwise comparisons of SF-6D health states. The scoring within each dimension was conducted in parallel group sessions. Final agreement on the scores as well as weights for the SF-6D dimensions were derived in a subsequent plenary assembly. Results were analyzed using the software M-MACBETH and qualitative content analysis.
RESULTS: A total of 34 participants were recruited. While each of the 6 small groups presented a consented score, the plenary assembly reached consensus on all dimensions apart from pain. Concerning dimension weights, some participants favored prioritizing pain and mental health. Others disputed that trade-offs between dimensions and thus assigning weights were not acceptable in a context where this may involve withholding care from someone. As a consequence, no consensus on a value set was reached. Participants identified the group size of the plenary session and the applied weighting procedure as main obstacles to the process.
CONCLUSIONS: This pilot study presents a consensus-based approach for valuing health-related quality of life. However, further research is needed on deliberative processes that yield quantifiable results. Future conferences should explore smaller group sizes, longer durations of the deliberative process and alternatives to the additive value function applied in MACBETH.

The study design and protocol that underpin a randomised controlled trial (RCT) are critical for the ultimate success of the trial. Although RCTs are considered the gold standard for research, there are multiple threats to their validity such as participant recruitment and retention, identifying a meaningful change, and non-adherence to the protocol. For clinical RCTs, involving patients and clinicians in protocol design provides the opportunity to develop research protocols that are meaningful to their target audience and may help overcome some of the inherent threats in conducting RCTs. However, the majority of protocols do not describe the methodology underpinning their development, limiting the amount of learned experience shared between research groups.
With the purpose of reporting a collaborative approach towards developing a protocol, we present the findings from three sequential workshops that were conducted with the aim of developing a protocol to investigate the feasibility of adding a computerised test of attention, impulsivity and activity (QbTest) to medication management of children and young people with Attention deficit hyperactivity disorder (ADHD). Based on previous qualitative interviews with clinicians and families, each workshop prioritised topics for focused discussion. Information from the workshops was fed back to the participants for reflection in advance of the next workshop.
The workshops involved 21 multi-disciplinary ADHD experts, including clinicians, patient and public involvement (PPI) members, parents of young people with ADHD and researchers. The consensus workshops addressed key research issues such as: the most relevant outcome measures/ resource drivers; methods and time points for data collection; and the clinical protocol for utilising the QbTest, including when best to use this within the medication management process. The resulting protocol details a feasibility RCT design describing these factors.
Protocols which are co-developed may help overcome some of the risks associated with RCT completion (e.g. recruitment, retention, protocol adherence) and help prioritise outcomes of greater relevance to the populations under study. The methodology has potential value for researchers and organisations developing clinical guidelines, and offers insights into the valuable impact of PPI upon trial design.
Clinicaltrials.gov NCT03368573, 11th December 2017 (retrospectively registered).

Systematic reviews of high-quality randomised controlled trials are necessary to identify effective interventions to impact burn wound infection (BWI) outcomes. Evidence synthesis requires that BWI is reported in a consistent manner. Cochrane reviews investigating interventions for burns report that the indicators used to diagnose BWI are variable or not described, indicating a need to standardise reporting. BWI is complex and diagnosed by clinician judgement, informed by patient-reported symptoms, clinical signs, serum markers of inflammation and bacteria in the wound. Indicators for reporting BWI should be important for diagnosis, frequently observed in patients with BWI and assessed as part of routine healthcare. A minimum (core) set of indicators of BWI, reported consistently, will facilitate evidence synthesis and support clinical decision-making.
The Infection Consensus in Burns study aims to identify a core indicator set for reporting the diagnosis of BWI in research studies.
(1) Evidence review: a systematic review of indicators used in trials and observational studies reporting BWI outcomes to identify a long list of candidate indicators; (2) refinement of the long list into a smaller set of survey questions with an expert steering group; (3) a two-round Delphi survey with 100 multidisciplinary expert stakeholders, to achieve consensus on a short list of indicators; (4) a consensus meeting with expert stakeholders to agree on the BWI core indicator set.
Participants will be recruited through professional bodies, such that ethical approval from the National Health Service (NHS) Health Research Authority (HRA) is not needed. The core indicator set will be disseminated through peer-reviewed publication, co-production with journal editors, research funders and professional bodies, and presentation at national conferences.
CRD42018096647.