Nicola Harman

The COMET Handbook: Version 1.0

The selection of appropriate outcomes is crucial when designing clinical trials in order to compare the effects of different interventions directly. For the findings to influence policy and practice, the outcomes need to be relevant and important to key stakeholders including patients and the public, health care professionals and others making decisions about health care. It is now widely acknowledged that insufficient attention has been paid to the choice of outcomes measured in clinical trials. Researchers are increasingly addressing this issue through the development and use of a core outcome set, an agreed standardised collection of outcomes which should be measured and reported, as a minimum, in all trials for a specific clinical area.Accumulating work in this area has identified the need for guidance on the development, implementation, evaluation and updating of core outcome sets. This Handbook, developed by the COMET Initiative, brings together current thinking and methodological research regarding those issues. We recommend a four-step process to develop a core outcome set. The aim is to update the contents of the Handbook as further research is identified.

MOMENT -- Management of Otitis Media with Effusion in Cleft Palate: protocol for a systematic review of the literature and identification of a core outcome set using a Delphi survey

BackgroundCleft palate (CP) has an incidence of approximately 1 in 700. Children with CP are also susceptible to otitis media with effusion (OME), with approximately 90% experiencing nontrivial OME. There are several approaches to the management of OME in children with CP. The Management of Otitis Media with Effusion in Children with Cleft Palate (MOMENT) study is a feasibility study that includes the development of a core outcome set for use in future trials of the management of OME in children with CP.Methods/DesignThe MOMENT study will include a systematic review of the literature to identify a list of outcomes that have previously been reported. This list of outcomes will be used in a Delphi study with cleft clinicians. The Delphi study is anticipated to include three rounds. The first round will ask clinicians to score the outcome list and to add any outcomes they think are relevant. The second round involves presentation of scores according to stakeholder group and the opportunity for participants to rescore outcomes. To ensure that the opinion of parents and children are sought, qualitative interviews will be completed with a purposive sample in parallel. In the final round of the Delphi process, participants will be shown the distribution of scores, for each outcome, for all stakeholder groups separately as well as a summary of the results concerning outcomes from the qualitative interviews with parents. A final consensus meeting will be held with all stakeholders, including parents and children, to review outcomes.DiscussionA core outcome set represents the minimum that should be measured in a clinical trial for a particular condition. The MOMENT study will aim to identify a core outcome set that can be used in future trials of the management of OME, improving the consistency of research in this clinical area.

The importance of integration of stakeholder views in core outcome set development : otitis media with effusion in children with cleft palate

Background Approximately 75% of children with cleft palate (CP) have Otitis Media with Effusion (OME) histories. Evidence for the effective management of OME in these children is lacking. The inconsistency in outcome measurement in previous studies has led to a call for the development of a Core Outcome Set (COS). Despite the increase in the number of published COS, involvement of patients in the COS development process, and methods to integrate the views of patients and health professionals, to date have been limited. Methods and Findings A list of outcomes measured in previous research was identified through reviewing the literature. Opinion on the importance of each of these outcomes was then sought from key stakeholders: Ear, Nose and Throat (ENT) surgeons, audiologists, cleft surgeons, speech and language therapists, specialist cleft nurses, psychologists, parents and children. The opinion of health professionals was sought in a three round Delphi survey where participants were asked to score each outcome using a bespoke online system. Parents and children were also asked to score outcomes in a survey and provided an in-depth insight into having OME through semi-structured interviews. The results of the Delphi survey, interviews and parent/patient survey were brought together in a final consensus meeting with representation from all stakeholders. A final set of eleven outcomes reached the definition of “consensus in” to form the recommended COS: hearing; chronic otitis media (COM); OME; receptive language skills; speech development; psycho social development; acute otitis media (AOM); cholesteatoma; side effects of treatment; listening skills; otalgia. Conclusions We have produced a recommendation about the outcomes that should be measured, as a minimum, in studies of the management of OME in children with CP. The development process included input from key stakeholders and used novel methodology to integrate the opinion of healthcare professionals, parents and children.

A patient and public involvement (PPI) toolkit for meaningful and flexible involvement in clinical trials - a work in progress.

Plain Language SummaryFunders of research are increasingly requiring researchers to involve patients and the public in their research. Patient and public involvement (PPI) in research can potentially help researchers make sure that the design of their research is relevant, that it is participant friendly and ethically sound. Using and sharing PPI resources can benefit those involved in undertaking PPI, but existing PPI resources are not used consistently and this can lead to duplication of effort. This paper describes how we are developing a toolkit to support clinical trials teams in a clinical trials unit. The toolkit will provide a key ‘off the shelf’ resource to support trial teams with limited resources, in undertaking PPI. Key activities in further developing and maintaining the toolkit are to:● listen to the views and experience of both research teams and patient and public contributors who use the tools;● modify the tools based on our experience of using them;● identify the need for future tools;● update the toolkit based on any newly identified resources that come to light;● raise awareness of the toolkit and● work in collaboration with others to either develop or test out PPI resources in order to reduce duplication of work in PPI.AbstractBackground Patient and public involvement (PPI) in research is increasingly a funder requirement due to the potential benefits in the design of relevant, participant friendly, ethically sound research. The use and sharing of resources can benefit PPI, but available resources are not consistently used leading to duplication of effort. This paper describes a developing toolkit to support clinical trials teams to undertake effective and meaningful PPI. Methods The first phase in developing the toolkit was to describe which PPI activities should be considered in the pathway of a clinical trial and at what stage these activities should take place. This pathway was informed through review of the type and timing of PPI activities within trials coordinated by the Clinical Trials Research Centre and previously described areas of potential PPI impact in trials.In the second phase, key websites around PPI and identification of resources opportunistically, e.g. in conversation with other trialists or social media, were used to identify resources. Tools were developed where gaps existed. Results A flowchart was developed describing PPI activities that should be considered in the clinical trial pathway and the point at which these activities should happen. Three toolkit domains were identified: planning PPI; supporting PPI; recording and evaluating PPI. Four main activities and corresponding tools were identified under the planning for PPI: developing a plan; identifying patient and public contributors; allocating appropriate costs; and managing expectations. In supporting PPI, tools were developed to review participant information sheets. These tools, which require a summary of potential trial participant characteristics and circumstances help to clarify requirements and expectations of PPI review. For recording and evaluating PPI, the planned PPI interventions should be monitored in terms of impact, and a tool to monitor public contributor experience is in development. Conclusions This toolkit provides a developing ‘off the shelf’ resource to support trial teams with limited resources in undertaking PPI. Key activities in further developing and maintaining the toolkit are to: listen to the views and experience of both research teams and public contributors using the tools, to identify the need for future tools, to modify tools based on experience of their use; to update the toolkit based on any newly identified resources that come to light; to raise awareness of the toolkit and to work in collaboration with others to both develop and test out PPI resources in order to reduce duplication of work in PPI.

Trial Steering Committees in randomised controlled trials: A survey of registered clinical trials units to establish current practice and experiences

Background: The Medical Research Council Guidelines for Good Clinical Practice outlines a three-committee trial oversight structure – the day-to-day Trial Management Group, the Data Monitoring Committee and the Trial Steering Committee. In this model, the Trial Steering Committee is the executive committee that oversees the trial and considers the recommendations from the Data Monitoring Committee. There is yet to be in-depth consideration establishing the Trial Steering Committee’s role and functionality. Methods: A survey to establish Trial Steering Committee’s current practices, role and the use and opinion on the Medical Research Council guidelines was undertaken within UK Clinical Research Collaborative registered Clinical Trials Units. Results: Completed surveys were obtained from 38 of 47 fully and partially registered Units. Individual items in the survey were analysed and reported spanning current Trial Steering Committee practices including its role, requirement and experience required for membership; methods to identify members; and meeting frequency. Terms (a document describing the committee’s remit, objectives and functionality) were obtained and analysed from 21 of 33 Units with documents in place at their Unit. A total of 20 responders suggested aspects of the current Medical Research Council Guidelines that need improvement. Conclusion: We present the first survey reporting on practices within UK Clinical Research Collaborative registered Clinical Trials Units on the experience and remits of Trial Steering Committees. We have identified a widespread adoption of Medical Research Council Guidelines for Trial Steering Committees in the United Kingdom, but limitations in this existing provision have been identified that need to be addressed.

The metabolic inter-relationships between changes in waist circumference, triglycerides, insulin sensitivity and small, dense low-density lipoprotein particles with acute weight loss in clinically obese children and adolescents

Small, dense LDL is highly atherogenic and the prevalence is higher in obesity. Weight loss lowers the prevalence of small, dense LDL.

The Predictive Ability of Triglycerides and Waist (Hypertriglyceridemic Waist) in Assessing Metabolic Triad Change in Obese Children and Adolescents

BACKGROUND The metabolic triad [fasting insulin, apolipoprotein B, and low-density lipoporotein (LDL) peak particle density] is characteristic of increased intra-abdominal adipose tissue and insulin resistance and can be predicted by the simple and adoptable screening tool, the hypertriglyceridemic waist. The associations between hypertriglyceridemic waist components [fasting triglycerides (TG) and waist circumference cut-points derived from a child-specific metabolic syndrome definition] with the metabolic triad were examined in obese youth before and after weight loss. METHODS A continuous metabolic triad score (MTS) was calculated as a cumulative and standardized residual score of fasting insulin, apolipoprotein B, and LDL peak particle density (z-scores of the metabolic triad variables regressed onto age and sex). The predictive ability of TG and waist in assessing metabolic triad change was undertaken in 75 clinically obese boys and girls, aged 8-18, body mass index (BMI) 34.2±6.4 kg/m(2) before and after weight loss. RESULTS Fasting TG concentrations (r(2)=0.216, P<0.0001) and waist circumference (r(2)=0.049, P=0.019) were both significant independent predictors of the cumulative MTS, together accounting for 26.5% of its total variance. All cardiometabolic risk factors [except a reduction in high-density lipoprotein cholesterol (HDL-C)] were favorably modified following weight loss. Fasting TG change was the only significant predictor of the MTS change (r(2)=0.177, P<0.0001). Waist circumference was not a significant predictor of MTS change. CONCLUSION The reduction in fasting TG concentration (but not waist circumference) was the only significant predictor of MTS change. Fasting TG may be the most important metabolic syndrome component to best characterize the metabolic heterogeneity in obese cohorts and the changes in metabolic risk in clinically obese youth.

Exploring the role and function of trial steering committees: results of an expert panel meeting

BackgroundThe independent oversight of clinical trials, which is recommended by the Medical Research Council (MRC) Guidelines for Good Clinical Practice, is typically provided by an independent advisory Data Monitoring Committee (DMC) and an independent executive committee, to whom the DMC makes recommendations. The detailed roles and function of this executive committee, known as the Trial Steering Committee (TSC), have not previously been studied or reviewed since those originally proposed by the MRC in 1998.MethodsAn expert panel (n = 7) was convened comprising statisticians, clinicians and trial methodologists with prior TSC experience. Twelve questions about the role and responsibilities of the TSC were discussed by the panel at two full-day meetings. Each meeting was transcribed in full and the discussions were summarised.ResultsThe expert panel reached agreement on the role of the TSC, to which it was accountable, the membership, the definition of independence, and the experience and training needed. The management of ethical issues, difficult/complex situations and issues the TSC should not ask the DMC to make recommendations on were more difficult to discuss without specific examples, but support existed for further work to help share issues and to provide appropriate training for TSC members. Additional topics discussed, which had not been identified by previous work relating to the DMCs but were pertinent to the role of the TSC, included the following: review of data sharing requests, indemnity, lifespan of the TSC, general TSC administration, and the roles of both the Funder and the Sponsor.ConclusionsThis paper presents recommendations that will contribute to the revision and update of the MRC TSC terms of reference. Uncertainty remains in some areas due to the absence of real-life examples; future guidance on these issues would benefit from a repository of case studies. Notably, the role of a patient and public involvement (PPI) contributor was not discussed, and further work is warranted to explore the role of a PPI contributor in independent trial oversight.

Trial steering committees for randomised controlled trials: updating and redeveloping guidance and terms of reference informed by current practice and experience

The DAMOCLES project established a Data Monitoring Committee Charter which has been widely used for randomised controlled trials since 2005. As established within DAMOCLES, the DMC is typical advisory, making recommendations to another executive body; considered the Trial Steering Committee. No evidence-based Charter exists for TSCs to establish their role and functionality in RCTs. The MRC Guidelines for Good Clinical Practice (1998) defines a three committee oversight structure: the day-to-day Trial Management Group, the DMC and the executive TSC. The document provides brief Terms of Reference for TSCs and represents the first attempt at guidance on TSC remit and structure. It is not known whether or how extensively this document has been used to inform TSC-like current roles and practice. There is acknowledged variation in practice in the UK and, moreover, internationally. The aim of this project was to re-visit the MRC Terms of Reference and provide dedicated guidance on TSC remit and structure by producing a comprehensive Terms of Reference and Charter that will promote a systematic and transparent approach to the oversight of RCTs. To inform this development, a survey to establish current practice and requirements within UK registered Clinical Trials Units has been undertaken. A cohort of published RCTs within medical journals and HTA monographs has been obtained to determine how TSC activities are currently reported and the literature reviewed to identify case studies of TSC activity in RCT conduct. Results of this work will be presented with how these findings impact development of more complete guidelines.

Design considerations in the development of a core outcome set

No gold standard method currently exists for the development of a core outcome set (COS) although key issues to consider have been identified [1]. Methodological decisions in the design of a project to develop a COS for otitis media with effusion (OME) in children with cleft palate (CP) will be explained.