Abstract
Background
Selecting appropriate outcomes is crucial for enhancing the comparability and relevance of clinical trials, yet uptake of core outcome sets (COS) remains low. This study aims to develop a framework to improve the quality and value of choosing outcomes in cardiovascular disease research (FAVOUR), so that the uptake of COS may be improved.
Methods
The mixed-methods will be used to develop a framework: (1) a systematic review will be conducted to identify current rationales, values and preferences of different stakeholders of outcome selection in clinical trials; (2) semi-structured interviews with patients and healthcare professionals will be used to identify the evidence, values and preferences of different stakeholders in outcome selection and measurement; (3) two rounds of Delphi survey will be conducted to prioritise items for the framework; and (4) a consensus meeting will be carried out to finalise the framework.
Ethics and dissemination
This study has been approved by the ethics committee of Dongzhimen Hospital, Beijing University of Chinese Medicine (Approval No.: 2025DZMEC-148-02). The results will be disseminated through peer-reviewed journals and conference presentations.
Trial registration number
This research has been registered in the Core Outcome Measures in Effectiveness Trial database (https://www.comet-initiative.org/Studies/Details/3723).
Keywords: Cardiovascular Disease, Patients, Patient Reported Outcome Measures
STRENGTHS AND LIMITATIONS OF THIS STUDY.
The study will use mixed-methods design.
Multiple stakeholders across different areas will be invited to participate.
Qualitative research methods, such as interviews, can help obtain a deeper understanding of patients’ values and preferences.
Patient participation will be involved in refining the topic guide.
The systematic review will be focused on specific dates and journals, which has certain limitations.
Introduction
Selecting outcomes is important in clinical trials and systematic reviews. The Consolidated Standards of Reporting Trials (CONSORT)-Outcomes 2022 Extension recommended 17 outcome-specific reporting items in any clinical trial that includes any population.1 Researchers are required to provide a rationale for the selection of the outcome domain for the primary outcome and whether it originates from a core outcome set (COS).
A COS is an agreed and standardised minimum set of outcomes that should be measured and reported in all clinical trials in specific areas of health or healthcare (https://www.cometinitiative.org/). A COS can improve the consistency of outcome reporting in clinical trials, allowing results to be merged for evidence. By the end of 2024, there were more than 600 completed COS.2 A high-quality COS should involve different stakeholders, including patients with the condition or their representatives, healthcare professionals with experience caring for patients with the condition and COS users (eg, clinical trialists or industry).3 The involvement of patients and the public in a COS is important because a COS developed collaboratively with patients improves the relevance and comparability of clinical trials.4
Researchers have explored the uptake of COS in different types of research. The use of COS is low in clinical trials and systematic reviews,5 6 and it varies across different conditions.7 Although the use of COS has improved in Cochrane systematic reviews, the uptake remains low.8 In addition, some core outcomes are never reported in clinical trials.9 When studies do not report a COS, information is wasted if a relevant COS is available.
Researchers have also identified barriers and facilitators to the use of COS by different stakeholders.8 In-depth qualitative interviews have identified barriers and facilitators that influence the use of COS by principal investigators in randomised controlled trials (RCTs).10 Strategies to increase the uptake of COS in trials have been recommended on the basis of behavioural science, including activities, documents and videos/videographics relevant to prompting trialists to reflect on various aspects, such as their knowledge about COS, the choice of outcomes and measurement issues.11 However, studies have reported that the following COS factors are barriers: poor quality; broad or narrow scope; lack of appropriate measurement instruments; increased patient and research burden when measuring additional outcomes; or expensive measurements.5 8 11–14
To consider the preferences and values of different stakeholders, the importance of outcomes identified through systematic reviews and patient interviews is rated by various stakeholders during the development of a COS. However, the rationale for selecting specific outcomes often lacks evidence, which may lead to the inclusion of outcomes that demonstrate efficacy in animal studies but fail to show effectiveness or cannot be applied in clinical trials.15
Most perspectives provided by researchers in high-income countries. According to previous interviews, trialists from China do not use relevant COS because they believe that core outcomes can not reflect study objectives or that it is impossible to observe significant endpoint outcomes (eg, mortality) with small sample sizes or short-term follow-up.16
The purpose of this study is to identify the rationale and values of core outcome selection in cardiovascular disease, which will improve selecting outcomes in clinical trials (ie, the rationale or the values and preferences of trialists and patients in the selection of outcomes) and COS development, as well as help COS users to assess the quality of COS.
Methods and analysis
This study will use mixed-methods to develop an evidence and value framework (shown in figure 1). The study findings will be reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA), guidelines and Standards for Reporting Qualitative Research (SRQR).17 The detailed COS-STAndardised Protocol (COS-STAP) items are provided in online supplemental file 1.
Figure 1. The process for developing the FAVOUR. CBM, Chinese Biomedical Literature Database; CNKI, China National Knowledge Infrastructure; COS, core outcome sets; FAVOUR, framework to improve the quality and value of choosing outcomes in cardiovascular disease research; RCT, randomised controlled trials.
Phase 1: systematic review
Rationale of outcome selection in clinical trials
A comprehensive search of RCTs published between 1 November 2024 and 1 April 2025 will be conducted in the following five major medical journals: New England Journal of Medicine (NEJM), The Lancet, Journal of the American Medical Association (JAMA), British Medical Journal (BMJ) and Annals of Internal Medicine. Online supplemental file 2 provides the search strategy. Studies will be included if they are phase III or IV RCTs, and studies will be excluded if they are non-interventional clinical trials.
After duplication, two reviewers (SW and SL) will screen titles and abstracts independently, and they will read the full text to determine the final eligible trials. Two researchers (HC and SC) will independently extract and cross-verify the data. Discrepancies will be resolved through discussion or consultation with a third reviewer (SW). The following data will be extracted: first author’s name and country, number of study centres, study population, sample size, disease areas, interventions, type of study, trial phase and fundings. The rationale of outcome selection in clinical trials will also be extracted, including whether the trials searched for an existing COS before initiation or whether a COS was used. The rationales applied in outcome selection will also be explored to elucidate the importance of the outcome domain to the individuals involved in the trial, the expected effect of the intervention on the outcome domain and the ability to assess the effect accurately, safely and feasibly during the trial.1 18 If the rationale of outcome selection in clinical trials can not be extracted, we will contact the first author or the corresponding author to get more information. To assess the quality of outcome reporting, all included studies will be assessed using the CONSORT 2022–outcome extension.1
In addition, we will search publications and guidelines from regulatory authorities (such as the Food and Drug Administration (FDA) of the USA, the European Medicines Agency (EMA) and National Medical Products Administration of China, etc) to identify the guidance of outcome choosing. Only published in Chinese or English language will be included.
Values and preferences of trialists and patients in the selection of core outcomes
To identify studies relevant to the uptake of COS, PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang Data and Chinese Biomedical Literature Database (CBM) will be searched from database inception to 1 January 2026. Online supplemental file 3 provides the full search strategy. The Sample, Phenomenon of Interest, Design, Evaluation Content, model, Research Type (SPIDER) framework will be used to develop the inclusion criteria:
S (Sample): studies focusing on the application of COS;
PI (Phenomenon of Interest): studies that describe issues in the uptake of COS, researcher values, researcher preferences, researcher experiences, and identified facilitators or barriers for using COS;
D (Design): qualitative research such as interviews and consensus meetings;
E (Evaluation): research involving values and preferences of trialists and patients relevant to outcome selection and measure;
R (Research type): qualitative studies.
The following studies will be excluded: (1) non-peer-reviewed or duplicate publications; (2) articles not written in Chinese or English; and (3) studies with incomplete or inaccessible data.
Two researchers (SW and SC) will independently screen and extract data using a back-to-back approach, with cross-checking for consistency. Disagreements will be resolved through discussion with a third reviewer (RQ). After automatic de-duplication using NoteExpress 4.1.0, titles and abstracts will be screened to exclude irrelevant studies, followed by full-text review to confirm final inclusion. The following data will be extracted using Excel 2021: (1) general study information, including title, first author’s name, publication year, type of disease and methods; and (2) general COS characteristics, including study type, intervention, quantity of COS included, number of outcomes and statements regarding the values and preferences of trialists and patients. The methodological quality of included studies will be assessed using the Critical Appraisal Skills Programme (CASP) checklist.19 20
Descriptive analysis will be performed for the general study characteristics. The rationale for outcome selection will be analysed using thematic analysis.21 This process will include the following three steps: line-by-line coding of the extracted data; categorization of ‘free code’ into descriptive themes; and development of analytical themes.21 One reviewer (SW) will independently code the results of all included studies, and the other reviewer (SL) will independently code the results of 20% of the articles selected at random. The independent coding will be cross-checked to ensure the comprehensiveness of the codes being assigned. The codes will then be grouped into descriptive themes, followed by the creation of analytical themes by the reviewer (SW), which will be reviewed and discussed with the reviewer (SL) until a consensus is reached on the final analytical themes. Any disagreements will be resolved through discussion with a third reviewer (RQ). All extracted data will be compiled into NVivo 15.0 qualitative data analysis software, with source citations and frequency counts for relevant items.
Phase 2: semi-structured interview
Topic guide
The results of the systematic reviews will be used to generate the preliminary list of topic guides. All authors will discuss and revise the interview guide, and three experts will then be invited to have face-to-face conversations to further refine the guide (online supplemental file 4). A new question will be introduced only when the participants have fully expressed their thoughts on the previous topic discussed.
Pilot interview
The pilot interview will be performed before the formal interviews to revise the topic guide and ensure its clarity and understandability. Two to three patients and five healthcare professionals will be recruited for the pilot interview, and they will be screened using the same inclusion and exclusion criteria applied to participants in the formal interviews.
The number of participants was determined on the basis of thematic saturation. All data generated from the pilot interviews will be included in the final data analysis.
Patient involvement and participation
Patients will be recruited from three affiliated hospitals of Beijing University of Chinese Medicine. Recruitment will be conducted through posters and online advertisements. Before the interviews, the research team will screen potential participants to ensure that they meet the eligibility criteria. The eligibility criteria are as follows: aged between 18 and 90 years; patients are able to communicate with others; and diagnosis of one or more conditions, including angina pectoris, myocardial infarction, acute heart failure, hypertension or atrial fibrillation.
The exclusion criteria are as follows: individuals with severe illnesses (such as shock) that make them unsuitable for study participation; those with severe psychological or mental illnesses that impede normal communication; and those who refuse to participate.
Interviews with healthcare professionals
Healthcare professionals will be recruited from regulatory agencies (the National Medical Products Administration, the National Administration of Traditional Chinese Medicine, the US Food and Drug Administration and European Medicines Agency), the Core Outcome Measures in Effectiveness Trials (COMET) initiative, three affiliated hospitals of Beijing University of Chinese Medicine, the Clinical Research Branch of the Chinese Association of Chinese Medicine and the Cardiovascular Disease Branch of the Chinese Association of Integrative Medicine. Recruitment will be conducted via email and WeChat invitations. Prior to formal interviews, the research team will review each potential participant’s background to confirm eligibility. Eligibility requires a minimum of 3 years of working experience and a doctoral degree or a senior professional title. The additional requirements for different stakeholders are as follows:
Clinicians should work in a Grade 3A hospital and have clinical experience of cardiovascular disease;
Clinical trialists should have the experience in the design or implementation of at least one clinical trial on cardiovascular disease;
Methodologists, systematic reviewers and guideline developers should have experience in the design or implementation of clinical trials/clinical practice/systematic review/clinical guidelines on cardiovascular disease and at least two publications in core journals in China or Science Citation Index journals in the fields of evidence-based medicine or cardiovascular disease as first author or corresponding author;
The members of regulatory agencies and the Ethics Committee should have more than 2 years of professional experience.
Sample size
To ensure representation across stakeholder groups, purposive sampling will be used to recruit a panel of patients and healthcare professionals, with a minimum of two participants per stakeholder and a total sample size of at least 10 experts and 10 patients.22 A snowball effect strategy will be adopted for patients and healthcare professionals to increase the sample size.23 On the basis of previous research experience, the recruitment of healthcare professionals and patients will continue until data saturation is achieved. If new themes or perspectives emerge during the final interviews, an additional two or three participants will be interviewed until no further new insights are identified.
Data management and analysis
Semi-structured interviews will be conducted by trained and qualified interviewers who will first explain the objectives of the study to participants. Before the interview, participants will be given a study information sheet, and informed consent will be obtained. Once consent is granted, individual interviews will be conducted. Socioeconomic and demographic data of all participants will also be gathered. During the interviews, healthcare professionals will be asked about their rationale, preferences and values in the selection of outcomes, whereas patients will be asked about their preferences and values in the measurement of outcomes. If participants struggle with responses, interviewers will provide a checklist from the systematic review as guidance to facilitate understanding and discussion.
The interviews will be recorded, and the names of participants and any other personal information will be replaced with codes or numbers in the collected data. This anonymised data will be stored separately from any original personal information, ensuring that only authorised researchers can access it. During the analysis and reporting phases, only de-identified data will be used to ensure that reports or published content do not contain any personal identifiable information. After transcribing each recording into text, the transcriptions will be imported into the NVivo 15.0 software. Two researchers (SW and SL) will independently perform preliminary coding and thematic summarisation of the evidence and value identified in the interviews. A thematic analysis approach will be employed to construct a framework of evidence and values relevant to outcome selection, focusing on themes emerging from healthcare professionals and patients.21
Phase 3: two-round Delphi survey
The objective of the Delphi survey is to explore the importance of different items among different stakeholders. On the basis of the systematic review and interviews, a Delphi survey questionnaire will be developed to evaluate the importance of each item in the evidence and value framework for selecting outcomes in cardiovascular disease clinical trials.
Various stakeholder groups, including clinicians, clinical trialists, methodologists, systematic reviewers and guideline developers, will participate in two rounds of the Delphi survey. The inclusion and exclusion criteria for the Delphi participants are the same as those outlined for selecting healthcare professionals in Section 2.2. A snowball sample size will be used.23 Participants will be asked to recommend any eligible colleagues who may be interested in the research.23
The Delphi survey will be conducted via an online survey platform (WenJuanXing) and distributed via WeChat and/or email. The invitation will include an explanation of the study rationale and a link to the Delphi survey. Each Delphi survey round will be open for 2 weeks. If no response is received within the first week, a reminder will be sent via email or text message. In round 1 of the Delphi survey, participants will be presented with the rationale behind the survey and will be asked to score the importance of the items on a 9-point Likert scale. The 9-point Likert scale is often divided into three categories for COS projects as follows: limited importance (scores 1–3); important but not critical (scores 4–6); and critical importance(scores 7–9).24 At the end of the survey, participants will be asked to provide any new items they considered are important but not listed on the round 1 of the Delphi survey. Any new items suggested by participants during round 1 will be reviewed by the study group for suitability and novelty for inclusion in round 2.
At the end of round 1 of Delphi survey, items will be categorised as ‘consensus in,’ ‘consensus out’ or ‘no consensus’ according to the scores and predetermined consensus thresholds (table 1).25 Items categorised as ‘consensus in’ will be included in round 2 of the Delphi survey, and the participants will be asked to rank the importance of items using a 9-point Likert scale. Participants who complete round 1 of the survey will be invited to participate in round 2, in which they will rate the importance of items and any new items suggested in round 1 using the same 1–9 Likert scale. At the end of round 2, items will be categorised as ‘consensus in,’ ‘consensus out’ or ‘no consensus’ according to their scores and consensus thresholds. ‘Consensus in’ and ‘no consensus’ items will be taken forward to the consensus meeting, whereas ‘consensus out’ items will be excluded.
Table 1. Consensus definition.
| Consensus classification | Definition |
|---|---|
| Consensus in | ≥70% of participants rate the item as 7–9, and <15% rate it as 1–3; the item will be included. |
| Consensus out | ≤50% of participants rate the item as 7–9; the item will be excluded. |
| No consensus | All other scenarios do not meet the above two criteria. |
Phase 4: consensus meeting
To finalise the evidence and value framework, a consensus meeting will be conducted online. Healthcare professionals who complete both rounds of the Delphi survey will be randomly selected to participate in the meeting, with a total sample size ranging from 10 to 15 individuals.
With the assistance of a moderator, the results of the Delphi survey will be presented in the meeting, including items that did not achieve consensus. The ‘consensus in’ items will be voted for inclusion during the meeting, and these items will be discussed and ranked from most to least important. The average ranking of importance will be presented to all participants, who will then discuss the items. After discussion, participants will vote on whether each outcome should be included or excluded. A vote of at least 70% in favour of inclusion will be included in the final framework.
Discussion
In this research, we will use cardiovascular disease as an example to develop a framework to help researchers (including clinical trialists and COS developers) improve the quality and value of outcomes in research. Clinical trialists may select outcomes from a COS or other outcomes of choice. However, some outcomes that lack high-quality evidence related to disease progression or prognosis or outcomes that are not important to specific populations or interventions were considered in clinical trials (eg, many outcomes were reported only once in clinical trials of specific disease area).26–31
Therefore, it is important to ensure the COS is evidence based, validated and acceptable.12 Previous research showed that measuring some outcomes may increase the burden on patients or researchers, so that the COS may not be used in clinical trials, a value and preference framework may help COS developers and participants consider those factors when determining outcome importance.5 12 13 32–36
The COMET Initiative has established a series of methodological standards, including the Core Outcome Set-Standards for Development (COS-STAD),3 and the Core Outcome Set–Standards for Reporting (COS-STAR),37 which collectively promote the standardisation of COS development and reporting. In particular, the COS-STAD defines the minimum standards for COS development through 11 core recommendations addressing key methodological domains, including the definition of scope, stakeholder involvement and consensus processes.3 In COS-STAD, the preferences and values are reflected by the involvement of different stakeholders, the importance of outcomes was determined on the basis of their own experience. Unlike existing COS methodological guidance, this study will focus on developing a framework including evidence of outcome selection and the preferences and values of different stakeholders when determining the importance of outcomes. It will help participants consider various domains about outcomes and recommend significant outcomes that will be used by all clinical trialists.
In addition, global regulatory agencies such as FDA and EMA provide recommendations on outcome selection.38–41 However, perspectives of regulatory have not been systematically incorporated into many COS development processes. A cross-sectional comparison of published COS with outcomes recommended by FDA and EMA regulatory guidance found that although some outcomes overlap, important discrepancies remained between COS and regulatory guidance, suggesting that COS may not always capture outcomes prioritised for regulatory evaluation.42 Furthermore, Aiyegbusi et al highlighted that regulatory guidance should be considered as an important external evidence source during COS development, particularly in areas where treatment approval relies on well-defined clinical endpoints.43 Therefore, integrating regulatory recommendations is important for COS developers and clinical trialists to choose important outcomes.
For COS developers, the involvement of patients and the public is important to determine which outcomes are important to patients. However, even though outcomes are important, there are many reasons for trialists not to select outcomes. Collaboration among different stakeholders is important to improve the uptake of COS, and COS developers should consider this situation during the research process. When developing a list of outcomes, it is important for COS developers to assess the quality of outcomes and their relevance to the scope of COS to avoid consensus outcomes that will not be used by trialists. Participants score the importance of outcomes on the basis of their experience, and they may not be familiar with all outcomes. Although developing a domain set is the first stage of COS development, it is important for COS developers to consider the types of outcome measurement instruments and the potential burden to patients and researchers. If COS developers recommend a COS that is too expensive to measeure or one that uses measurement instruments which will reduce patient adherence, the COS may not be used12 34 36. When the framework is completed, we will use it to assess the importance of outcomes in COS and compare the results to the perspectives of trialists. We hope this framework also will provide information to COS developers to help them develop or update COS that can reduce burden to patients and researchers in the future.
In addition, this study has some strengths, such as various data sources (including published clinical trials, and publications and guidelines from regulatory authorities), as well as using mixed-methods design to incorporate the perspectives of multiple stakeholders, including patients, clinicians and researchers, through semi-structured interviews, Delphi surveys and consensus meetings to identify their preferences and values regarding outcome selection and reporting. Qualitative methods such as interviews can help to obtain a deeper understanding of patients’ values and preferences.44 45
This study also has certain limitations. Only high-quality RCTs published between November 2024 and April 2025 will be analysed, because we would like to examine adherence to the CONSORT-Outcomes 2022 guideline two years after it was pulished.1 Our selection of publication timepoints and journals adequately satisfies the objectives of this exploratory analysis. Furthermore, the sampled journals serve as suitable benchmarks for evaluating researcher adherence to the CONSORT-Outcomes 2022 standard: these widely respected general medical journals are well-known for enforcing rigorous reporting standards for clinical trials.5 46
Supplementary material
Acknowledgements
We are grateful to Professor Paula Williamson from the COMET Initiative for her comments on an earlier version of the manuscript.
Footnotes
Funding: This work was supported by funds from the National Natural Science Foundation of China (Grant No. 82274354).
Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2026-119104).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Consent obtained directly from patient(s).
Patient and public involvement: Two to three patients will be invited to participate in the pilot interview and contribute to the revision of the topic guide. Patients will be invited to participate in the interview to understand their preferences and values of outcome measurement in clinical trials.
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