Identification of COS
We will include all the pediatric COS identified in our previous systematic review[4] and those subsequently included in the COMET database using the following inclusion criteria.
(1) The target population consists fully or partly of children (younger than 18 years). If the lower age limit is 16 years or above, we will check whether the COS primarily targets adults; if so, we will exclude it.
(2) The study type is COS for clinical trials.
(3) Children and/or their parents or other caregivers were involved in the development of the COS and their views were integrated to determine the importance of outcomes.
Identification of clinical trials
We will search Clinicaltrials.gov for trials on health conditions addressed by the included COS.
We will include trials that fulfill the following criteria: 1) the target population consists fully or partly of children (younger than 18 years); 2) the trial examines the effectiveness of an intervention compared with standard care or another comparator; and 3) time of trial commencement, defined as the date of trial registration, protocol publication, or start of participant recruitment whichever is the earliest, is later than the date the COS was published; and 4) randomized and non-randomized trials, and no restrictions on sample size, intervention type, or trial design.
We will exclude trials that 1) assessed the effectiveness of an intervention on comorbidities or complications of the health condition; 2) assessed the mechanisms or development of biomarkers for the effect of the intervention; 3) examined the pilot and feasibility studies; or 4) were secondary analyses of data from previously published clinical trials.
Assessing overlap in scope of topics between clinical trials and COS
We will use a previously developed framework[9] to assess the comparability of the scopes in each COS-trial pair (Table 1). Sixteen scenarios are possible, which can be further categorized into the following three main cases:
(1) The COS is very likely to be relevant if its scope is at least as broad as the outcome set of the trial (in terms of both the population and the intervention (scenarios ‘f’, ‘g’, ‘j’, and ‘k’).
(2) The COS may be relevant in scenarios in which the COS is narrower than the clinical trial in terms of the population, intervention or both (scenarios ‘a’, ‘b’, ‘c’, ‘e’, and ‘i’) or in which the clinical trial and COS target different subgroups of the population (scenarios ‘m’, ‘n’, and ‘o’). While all assessments of overlap in scope between a given clinical trial and a given COS should involve clinical expertise, this is particularly important in scenarios that involve different subgroups of the population (scenarios ‘m’, ‘n’, and ‘o’).
(3) The COS is unlikely to be relevant in scenarios in which the systematic review and the COS describe different (but related) interventions (scenarios ‘d’, ‘h’, ‘l’, and ‘p’).
Table 1. The framework for assessing overlap in scope between a COS and a clinical trial.
*Requires careful clinical consideration
#COS is unlikely to be relevant
Matching of COS and clinical trials
We will include COS-trial pairs that fulfill all of the following conditions:
(1) The pair is judged as either “very likely relevant”(white cells) and “may be relevant” (grey cells) as shown above;
(2) The number of relevant clinical trials on the topic is at least 40; and
(3) If two or more COS developed for same condition meet above two criteria, we will selected the COS according to the following criteria applied hierarchically: 1) both Delphi and consensus meeting were used in the consensus process; 2) higher ratio of children/parents to healthcare professionals in the consensus process; 3) children themselves (instead of their parents only) participated in the process, if applicable; and 4) children/parents from multiple regions were involved.
Matching of outcomes between the COS and clinical trial
In the comparison of the COS and the outcomes of the trial, three situations are possible[7,9]:
(1) Exact match: the outcomes match exactly including the use of the same or synonymous/equivalent terms (e.g., “overall survival” and “all-cause mortality”);
(2) General match: the outcomes match on a general level, including one outcome being part of another (e.g., “functioning” and “emotional functioning”; “disease activity” and “joint damage”) or outcomes being to large extent overlapping (e.g., “drug adherence” and “intake of any treatment”);
(3) Non-matches: for each pair of outcomes that is a general match, we will also assess which of the two outcomes, the core outcome or the trial outcome, is broader. When this cannot be determined, we will not make an assessment about the comparative breadth of the outcomes.
Data extraction
The following data will be extracted for each COS:
(1) Characteristics of the COS: first author, title, country(first author), category of the condition, name of the condition, date of publication, age range of target population, nature of intervention, list of core outcomes.
(2) Details of children/parents involvement: 1) countries/regions of patients involved in development, specific development process children/parents were involved in (forming the outcome list, rating the importance of outcomes); 2) methods of forming outcome list by involving the children/parents’ view (such as interview, focus group), types of patient representatives in forming list (such as children, parents, or both), number of children/ parents, age range of children (if applicable); 3) methods of rating the importance of outcomes by involving the patient's view (such as Delphi, consensus meeting), types of patient representatives in rating outcome importance, total number of participants, number of children/parents, age range of children, country/region of children/parents.
From clinical trials, the following data will be extracted:
(1) Basic information: first author, study title, link to the study protocol or trial registration;
(2) Characteristics of the trial: condition(s), type of intervention, age range of target population, time of trial commencement (date of trial registration, protocol publication, or start of participant recruitment whichever is the earliest), phase, study design, samples, type of funding, list of outcomes;
(3) Uptake of COS details: whether the outcomes of the COS were used (partially or completely); if used, list the primary and secondary outcomes separately.
Data analysis
Frequencies, percentages and medians with interquartile ranges (IQRs) will be used to describe the characteristics of the included clinical trials and COS. We will calculate the distribution of the 16 scenarios of overlap between COS and clinical trials as stated in Table 1; and for the outcomes in each clinical trial that are exact matches, general matches, and non-matches with outcomes in each relevant COS.
Survey and semi-structured interviews among COS developers and clinical trialists
Questionnaires with a mixture of multiple-choice and open-ended questions will be sent to pediatric COS developers and clinical trialists. We will first conduct an online survey, during which we ask the participants if they would be willing to be individually interviewed in person or online. For COS developers, we aim to examine their views on barriers and facilitators to improve the methodological quality of COS, and on actions to improve uptake of COS by clinical trialists. Among clinical trialist, we aim to examine their views on the knowledge, perceptions, and use of COS in relation to choosing outcomes; in addition, we also plan to explore the ideas about improving the methodological quality of COS among investigators who are familiar with COS.
Participants
Lead developers (first and corresponding authors) of the pediatric COS and lead authors of clinical trialists identified in this study will be invited to participate. If the lead developers or authors do not respond, other authors of the respective study will be approached.
Data collection
Potential participants will be contacted by email with an initial invitation that includes a detailed description of the purpose of this study. If no response is received, a reminder email will be sent 3 weeks later. In case of "out-of-office" responses, we will follow up with the potential participant on an individual basis. Before commencing the online survey, the participants will be required to confirm their consent by email.
Those who agree to participate in a semi-structured interview will be interviewed at a time that suits them. Each interview will last at least 30 minutes and will be audio-recorded so that any ambiguities can be clarified [10]. We will follow the “data saturation principle” and stop the interviews when there are no new ideas[11].
The survey questions and interview topic guide are informed by previous studies[6,8,12-14] and are presented in the Appendix.
Data analysis
Results from the survey of COS developers and trialists will be analyzed using descriptive methods. Answers to dichotomous questions will be presented as frequencies and percentages. Open-ended questions and the developers’ and clinical trialists’ views on the development and uptake of COS will be analyzed using a thematic analysis approach according to a framework consisting of the following steps[15]: 1) familiarizing ourselves with the data; 2) generating initial codes; 3) generating or developing draft themes; 4) reviewing the identified themes; and 5) defining and naming the themes.