The project has been split into four work packages (WPs) to represent the four objectives.
- A survey of relevant researchers about their experiences of using B-R methodologies within RCTs,
- A rapid literature review to assess any current recommendations for B-R methodologies,
- A two-day consensus workshop to gain agreement on the recommended design and methods that could be used in the NIHR/MRC setting,
- Create a guidance document to aid researchers on designing studies and potentially including B-R methodologies within NIHR/MRC grant applications.
WP1 - Survey
A web-based survey of current practice will be conducted using the Qualtrics (9) platform. The main objective of the survey is to elicit current use and initial opinions on the use of B-R methodologies in RCTs (industry or publicly funded). In addition, it will be used to identify any methodological updates currently in progress and understand the information required to be within the final guidance document.
The survey will be sent via email to a range of key stakeholders within clinical trials including: representatives of trial funding bodies, experts and researchers known to be working in the field to get a range of experiences.
Summary statistics will be completed on the results from the survey and presented as means and standard deviations or medians and inter-quartile ranges for continuous data and counts and percentages for categorical data. No formal statistical testing will take place on the survey data.
WP2 – Literature Search
A rapid methodological (10) review will be conducted of the published and unpublished guidance on B-R methodology using a pearl growing technique. Pearl growing is a method of iteratively developing search strategies based on the thesaurus and free-text terms associated with articles of known relevance (11). This will complement the review completed by the PROTECT group which focussed on B-R in drug development (12) by concentrating on B-R methodologies recommended for use in RCTs.
Eligible material will be published and unpublished guidance and methodological articles in English proposing B-R methodology between 1999 and 2019. This chosen time period was to ensure sufficient article identification without repetition and was supported by the timelines presented by Garrison (13). Formal search strategies will search MEDLINE and Web of Science starting with key terms and papers known to the research team to identify MeSH headings for the formal search strategy. Informal search strategies will focus on Google Scholar, grey literature, reference and citation tracking (14). The review will be registered on PROSPERO.
The review will link sources to broad methodological categories with other variables including context, rationale, procedures and author-identified methodological strengths and limitations. No formal, pre-specified assessment of methodological quality will take place with deductive reasoning - that bias could be a formal logical consequence of the proposed method – explicated in the narrative synthesis. We will apply the constant comparison method to extracted data (10). Narrative synthesis will involve one or more tables of B-R rationale and practices.
The results from the literature search will be coupled with the survey responses (WP1) to produce an overview of current possible methods of B-R, their potential uses in RCTs and any strengths and weaknesses found within the literature related to each one. These findings will then feed into the workshop to facilitate discussion about appropriate B-R methodologies.
WP3 – Workshop
To reach consensus on how to select a trial design and when to use B-R methodologies, a two-day expert consensus workshop will be completed which will include presentations, discussions and use the Nominal Group Technique (NGT) to reach consensus as appropriate (15). NGT is an interactive multi-stage approach which is designed to combine opinion into group consensus during a structured face-to-face meeting. This facilitates the generation of a wide range of ideas, encourages equal participation, helps to avoid conflict and the possibility of some viewpoints dominating, and crucially enables achievement of a credible solution within a short timeframe.
Elements of the workshop will be:
- A briefing document which summarised the findings of the survey and literature review (containing all B-R approaches identified) will be sent to workshop participants in advance;
- Presentations will used to set the scene of the workshop and give all the necessary background information to the topic. This will from different perspectives e.g. methodology and application so that all outlooks can be considered in the discussions.
- Brainstorming round/s – panel members will be asked to record their individual thoughts on elements of the guidance such as designing superiority/non-inferiority studies and using B-R methodologies. A ‘round robin’ sharing of ideas will then be completed to allow identification of all potential approaches, followed by a structured whole group discussion;
- A preliminary rating round will be completed to gain preferences on design and use of B-R methodologies, the results of which will be considered within a second structured group discussion;
- A second, final round of rating will be completed to elicit final preferences of approaches.
Participants of the workshop will be co-applicants of the project along with additional members identified from the responses to the survey. Participants will be invited to aim for input across industry, academia, funders and policy makers from within the UK and internationally if felt appropriate.
Key discussions from the workshop will be recorded, transcribed and analysed using thematic analysis (16) supported by the NVivo software. These results will be used to provide further detail to the preferences stated within the NGT.
WP4 – Guidance Document
Using the information gained in WP1-3 with a focus on results from the workshop, a guidance document will be written to incorporate the opinions and preferences of the expert group. The guidance will describe the methods for selecting a trial design, when it is appropriate to use B-R methods and how this relates to the different trial designs. Any key recommendations about particular methods will also be made as appropriate. Recommendations will be illustrated using RCT case studies.
There will be no limit to the number of participants approached for inclusion in the survey. It is anticipated there will be between 25-30 participants at the workshop which aims to achieve a diverse range of opinions whilst remaining appropriate for the proposed design (see for example Dimario et al (17)).
The guidance document produced from this project will be reported to the MRC and NIHR as well as other funding bodies and stakeholders. The guidance will be published in an appropriate peer reviewed journal and presented at relevant conferences.
The co-applicants of the study will make up an oversight committee which will provide strategic input to the focus, methodology and outputs of the project. These members have a wide range of experience of clinical trials within academia and the pharmaceutical industry to give a range of perspectives to direct the project. There will be two scheduled meetings with this group before the workshop to provide an update to applicants and get feedback as required.
A working group, consisting of SJ, JC, DH and NT, will manage the day-to-day running of the project with monthly meetings scheduled throughout the duration of the project to keep up to date with progress.