Protocol for a Feasibility study incorporating a Randomised Pilot Trial with an Embedded Process Evaluation and Feasibility Economic Analysis of ThinkCancer!: A primary care intervention to expedite cancer diagnosis in Wales
TL;DR: This study will allow us to test and further develop a novel evidenced-based complex intervention aimed at general practice teams to expedite the diagnosis of cancer in primary care and inform the future design of a full-scale definitive phase III trial.
Abstract: Background Relative to the rest of Europe, the UK has relatively poor cancer outcomes, with late diagnosis and a slow referral process being major contributors. General practitioners (GPs) are often faced with patients presenting with a multitude of non-specific symptoms that could be cancer. Safety netting can be used to manage diagnostic uncertainty by ensuring patients with vague symptoms are appropriately monitored, which is now even more crucial due to the ongoing Covid-19 pandemic and its major impact on cancer referrals. The ThinkCancer! Workshop is an educational behaviour change intervention aimed at the whole general practice team, designed to improve primary care approaches to ensure timely diagnosis of cancer. The workshop will consist of teaching and awareness sessions, the appointment of a Safety Netting Champion and the development of a bespoke Safety Netting Plan, and has been adapted so it can be delivered remotely. This study aims to assess the feasibility of the ThinkCancer! Intervention for a future definitive randomised controlled trial. Methods The ThinkCancer! study is a randomised, multisite feasibility trial, with an embedded process evaluation and feasibility economic analysis. Twenty-three to 30 general practices will be recruited across Wales, randomised in a ratio of 2:1 of intervention versus control who will follow usual care. The workshop will be delivered by a GP educator and will be adapted iteratively throughout the trial period. Baseline practice characteristics will be collected via questionnaire. We will also collect Primary Care Intervals (PCI), Two Week Wait (2WW) referral rates, conversion rates and detection rates at baseline and six months post-randomisation. Participant feedback, researcher reflections and economic costings will be collected following each workshop. A process evaluation will assess implementation using an adapted Normalisation Measure Development (NoMAD) questionnaire and qualitative interviews. An economic feasibility analysis will inform a future economic evaluation. Discussion This study will allow us to test and further develop a novel evidenced-based complex intervention aimed at general practice teams to expedite the diagnosis of cancer in primary care. The results from this study will inform the future design of a full-scale definitive phase III trial. Trial registratio intended registry: clinicaltrials.gov
Summary (8 min read)
- Cancer survival in the UK lags behind other western countries .
- Referral rates and adherence to guidelines are lower [2, 3], primary care providers (PCPs) are less likely to take action on potential cancer symptoms  and cancer tends to be diagnosed at a later stage, often only after patients have presented to acute or emergency secondary care services .
- Compared with the rest of Europe, the UK has relatively low 1-year survival, which could be due to later diagnosis .
- The timely diagnosis of cancer has become even more relevant as the authors enter a period in which primary care and cancer management have changed dramatically due to the ongoing COVID-19 pandemic [11–13].
- With an ever expanding role, PCPs are presented with a plethora of non-specific symptoms, of which only a small proportion are caused by cancer, and many overlap with other diseases .
Rationale and previous work
- This study comprises work package 4 of the Wales Interventions for Cancer Knowledge and Early Diagnosis programme.
- Work package 1 consisted of a review of reviews and a realist review, Work Package 2 comprised qualitative interviews with 20 GPs, four focus groups with primary care practice staff, and a combined quantitative survey and Discrete Choice Experiment (DCE), sent to GPs in Wales.
- Behaviour change at PCP level can be achieved through various mechanisms, including feedback, electronic prompts and training [22–24].
- This risk is especially high if the patient presents with vague symptoms .
- The workshop will be led by an educational facilitator who will guide the development of a bespoke safety netting plan for each practice.
1) To assess the feasibility of a future definitive RCT by monitoring recruitment and retention, outcome measure completion and reasons for decline.
- 2) To assess the acceptability, feasibility, and utility of the ThinkCancer!.
- Intervention as a whole and of each of its individual components, and refining the intervention as necessary.
- 3) To determine the most feasible and appropriate primary outcome measure for a definitive RCT and producing means and confidence intervals for calculating effect sizes for the design of a definitive trial.
- 4) To describe current contextual differences, and similarities, between general medical practices and their usual safety netting practices.
- This feasibility study incorporates a pragmatic, multisite, two-armed, superiority, pilot RCT.
- There is an embedded process evaluation and feasibility economic analysis.
- The unit of randomisation is the general medical practice, and the primary clinical outcome is collected at the practice level.
- The process evaluation, which will be based on a mixed-methods approach, will follow the MRC guidance for process evaluations of complex interventions .
- This study protocol was developed in line with the Standard Protocol Items: Recommendations for Interventional Trials guidelines ; the checklist and the schedule of procedures can be seen in Table 1.
- The setting for this study is primary care.
- The intervention will be delivered in-practice or online to individual general medical practices and incorporates a wholepractice approach.
- The trial will be conducted across Wales and practices will be recruited from all seven Welsh health boards.
- The proposed intervention, the ThinkCancer! workshop, has four chief components.
- The first are two educational sessions, one for all clinical staff (the ‘early diagnosis’ session) and one for non-clinical but patient-facing staff (the ‘cancer aware’ session).
- The third session (the ‘safety netting session’) involves the two final components of the intervention, the co-production of a bespoke Cancer Safety Netting Plan (CSNP) and appointment of a Cancer Safety Netting Champion (CSNC).
- Members of the research team will deliver the intervention; the GP Educator (AS) will oversee the workshop, supported by up to two researchers.
- The outcomes that will be reported in this feasibility study are as follows: Recruitment will be assessed quantitatively by capturing the numbers of practices ▪.
- The feasibility of using potential clinical primary outcomes, 2WW referral rate, PCI, conversion rates, and detection rates will be assessed quantitatively by determining: ▪ Ability to collect/capture data from the practices, based on completion rates of data collection forms ▪.
- The number of practices that actively nominate a safety netting champion ▪.
- For the health economics component, the authors will do the following: ▪ Determine the feasibility of collecting data relating to the costing of the intervention via costings forms ▪.
- Review relevant literature on the cost-effectiveness of online and mixed-methods Continuing Professional Development (CPD) programmes for health professionals in a community setting ▪ Consult the DIRUM database  to identify the most appropriate way of capturing the costs of the ThinkCancer!.
- The outcome measures relating to recruitment, retention and adherence/fidelity will be assessed using RAG criteria, as defined below: 1. Confirmation of adequate recruitment for a definitive trial at practice level.
- Confirmation of adequate retention for the definitive trial at practice level.
- At least 50% of the clinical staff should attend the workshops; b. Progression criteria relating to obtaining data regarding completion of outcome measures will be assessed using the following progression criteria: 1. Routine data.
- Go: data from 70% or more of individuals of each practice obtained; Review: data from < 70% of individuals from each practice obtained.
- The authors aim to recruit 23–30 general medical practices.
- The maximum that was considered possible to recruit is 30 practices.
- Practices will be randomised using a randomisation allocation ratio of 2:1 of intervention versus control.
- This is discussed further under statistical analyses.
- General practices will be identified through contact details publicly available via practice websites and through contact lists provided by the health boards across Wales.
- Practices will be invited to participate using a standardised invitation via email addressed to the practice manager, along with information about the study.
- They will also need to advise of their practice’s availability for potential workshop dates.
- Staff members involved in the design and implementation of a new cancer safety netting plan can consider using this as the basis of a quality improvement project for revalidation and appraisal purposes.
- The authors are aware that some challenges in the recruitment lay ahead, but they plan to work with the various research infrastructures in Wales to overcome this.
Eligibility to participate
- As feasibility is the main objective of this study, all types of general medical practice will be eligible for inclusion.
- This will aid intervention refinement and allow for a better understanding of what is feasible across a range of practices and also why some practices may not be able to take part.
- Any general practice in Wales is eligible for inclusion.
- The target audience for the intervention, based on a ‘whole team approach’, includes all practice staff members.
- These may include, for example, GPs, nurse practitioners, nurses, health care support workers , practice managers, administrators, receptionists or any other practice staff, clinical and non-clinical.
- Practices participating in other research are also eligible for inclusion; they will be asked to notify us of any cancer-related studies they may be participating in via the baseline questionnaire.
- Practice managers will be sent more detailed study information in the form of a ‘Research Information Sheet for Practices’ (RISP) and a link to an online baseline practice questionnaire after they have expressed an interest to take part in the study.
- Prior to the commencement of the ThinkCancer! workshop, Participant Information Sheets (PIS) will be provided by members of the research team and written consent will be obtained from all participating members of staff.
- Those who indicate that they would like to take part will be contacted at least 2 months after the intervention.
- And they will most likely be the person who completes the questionnaire, this task may be delegated to another member of the practice team with a particular interest in the study.the authors.
- Pilot workshop prior to full rollout of the feasibility study.
- The practice is an urban, large 12,000 patient training practice in a moderately deprived region of North East Wales.
- Data will not be collected or recorded for trial purposes and feedback from those participating will only be used to refine the intervention prior to its delivery across recruited practices.
Randomisation and blinding
- The general medical practice will be the unit of randomisation.
- Randomisation will be achieved online, through the remote randomisation centre at the North Wales Organisation for Randomisation Trials in Health at Bangor University.
- The randomisation system will use a dynamic adaptive allocation algorithm  to achieve randomisation, stratified for health board.
- ThinkCancer! is an open trial where blinding of participants, researchers and the statistician is not possible due to the nature of the intervention and 2:1 ratio for randomisation.
- Practices (and individuals within a practice) will be free to withdraw from the trial at any time, and their right to refuse participation will be respected throughout.
- The authors will seek to understand their reasons where possible.
- The feasibility study will be used to rehearse data collection approaches and assess their ease of use.
- All data collected in this study will be anonymised.
- Two-week wait referral data and PCI data will be collected directly from participating practices via Case Report Forms containing full instructions on how to extract the data from practice IT systems.
- The authors will work with the Practice Manager, CSNC or other delegated individuals to achieve this.
- The baseline and endline practice questionnaires will be available online to both intervention and control practices and are to be filled out by the practice manager or other designated person, ideally in collaboration with the practice team; SurveyMonkey™ will be the most likely platform.
- The baseline data may be used to inform some workshop planning—i.e. workshop content and delivery may be tailored to some extent to suit individual practice needs and circumstances.
- Baseline measures will include the following: ▪ Demographic information and practice characteristics (practice size, research-accredited status, number of clinical and non-clinical staff members, whether a teaching practice, etc.) ▪ Practice culture (e.g. team structure, diversity of team member roles, team decision-making processes) ▪.
- Practice knowledge with regard to safety netting and cancer awareness ▪.
- How widely they are used within the practice ○.
Feasibility and piloting data
- Recruitment, retention and questionnaire completion numbers will be recorded throughout the trial.
- Spreadsheet systems will be put in place to record practice responses and to track their progress in the trial (e.g. number of practices approached, whether they have responded to the initial invitation, whether they have agreed to be randomised, etc.).
- The same research team members will deliver the intervention in all practices; their observations will be collected and will inform any refinements of the intervention.
- Observations and reflections recorded by the research team may provide valuable data on the potential effects of contextual factors, site-by-site and componentby-component measures, and the appropriateness of individual questions included in the practice questionnaires.
- They will also describe the cancer safety netting plan proposed by the practice and whether the SSNAP tool is used.
- Health economics data collection sheets will be completed by the researchers following each workshop, and costings specific to the practice will be recorded.
- The authors will also use the feedback forms to determine staff roles within the practice for costing purposes.
- At least 2 months after the intervention, participants who consented to be contacted will be sent a link to complete an adapted Normalisation Measure Development instrument .
- This will assess the implementation of the cancer safety netting plan using Normalization Process Theory (NPT) principles, which may or may not include the SSNAP tool depending on uptake.
- Practice staff in both arms of the trial will be eligible to participate in the interviews as they will be invited to give feedback on all aspects of the trial process including the intervention where appropriate.
- The interviews will allow participants to explain how they were able to utilise aspects of the trial and how they worked in practice.
- Informed consent will be obtained and interviews recorded and transcribed verbatim.
- Topics may include acceptability, safety netting, data collection, uptake of the intervention and SSNAP tool and implications.
- These interviews will occur at least 2 months after the intervention has taken place; control practices will be invited two months postrandomisation.
- A risk assessment has found this trial to be low risk.
- Participating practices are encouraged to report any adverse events.
- The Chief Investigator (CI) will determine whether they are Adverse Events (AEs) or Serious Adverse Events (SAEs).
- They will be reported in line with current ICH-GCP Standard Operating Procedures .
- The authors do not expect any related SAEs for this study.
- A fully documented statistical analysis plan will be prepared by NWORTH, a registered clinical trials unit, and agreed by the co-investigators and approved by the trial governance structure, which will be known as the Trial Steering Committee (TSC).
- The statistical analysis plan will be approved prior to data collection being completed.
- Feasibility and process evaluation data such as practice recruitment rate, implementation and uptake of and adherence to the intervention, and follow-up rates will be summarised and presented as percentages.
- Exploratory analysis using ANCOVA for continuous outcomes and logistic regression for binary outcomes will consider adjustment for the stratification variables in assessment of the treatment effects.
- As this is a feasibility study, there will be no imputation of missing data over and above any scoring rules established for the outcomes.
- Alongside the statistical analysis plan, a Health Economics Analysis Plan (HEAP) will be produced setting out the objectives and methods for data collection and analysis of the health economics findings .
- The HEAP will be signed-off by the lead health economist and CI prior to any data being shared with the health economics researchers.
- In micro-costing, each component of resource use is estimated and then a unit cost is derived using 2019 national reference costs (in Great British Pounds Sterling) where available [51–53].
- In addition and separately, the costing of the development of the ThinkCancer!.
- Intervention will be determined based on the following: ▪ Online delivery format—live seminars/webinars, staff time and materials, exploration of whether health professional time should be collected in a full trial to reflect the co-production nature of CPD in own time or reflecting the opportunity cost of CPD in terms of time not spent on direct patient care activities.
- The transcribed telephone interviews, the free text responses from the feedback forms and the observational data, in text form, will be analysed for the process evaluation using Framework Analysis .
- Framework is a five-stage matrix-based system for analysing qualitative data which is highly appropriate for a feasibility study which is iterative in its development.
- Initially, all transcripts and textual data will be read thoroughly by the same researcher who conducted the interviews to achieve data familiarisation and immersion.
- An index of emergent themes will then be created and data coded according to the index.
- The completed charts will then be used for final stage which is in-depth interpretation .
- The study will be supported by the North Wales Organisation for Randomised Trials in Health , which is a fully registered Clinical Trials Unit.
- Therefore, the monitoring of data will have a more internal focus in the form of self-audits to ensure compliance with regulations.
- The operational working group will be responsible for the overall conduct, supervision and progress of the study.
- They consist of the immediate research team, supported by a wider group of experts.
Trial management group
- The trial management group (TMG) will meet once a month, consisting of the operational group and a wider team of experts, including a PPI member.
- The group will be responsible for the overall management of the trial and ensuring the study adheres to the protocol.
Trial governance structure
- A Trial Steering Committee (TSC) committee will provide independent oversight for the study, ensuring it is conducted according to the standards set out by the HRA Research Governance Framework .
- As the study includes an element of ongoing intervention refinement and is deemed low risk with very minimal likelihood of stopping early due to patient safety, a Data Monitoring and Ethics Committee (DMEC) will not be required .
- Meetings are expected to be biannual and the Sponsor and Funder will be updated following each meeting.
- The TSC will have an independent chairperson (Aneez Esmail) and at least three independent members including Patient and Public Involvement (PPI) representation, trial co-applicants, a statistician (Rhian Gabe), a health economist (Laura Ternent) and other independent members.
- A detailed data management plan will be written by NWORTH staff and approved as soon as possible following commencement of data collection, if not before.
- This plan will include the definition of the data quality checks that will be performed on the data throughout the life course of the trial.
- These will include source data validation, random data checks and timelines for data entry.
- Quality control will be maintained through adherence to the study protocol, Betsi Cadwaladr University Health Board/Bangor University Standard Operating Procedures (SOPs), principles of Good Clinical Practice, research governance and clinical trial regulations.
- All investigators, trial site and research staff will comply with the requirements and regulations of the EU General Data Protection Regulation 2018 (GDPR) regarding the collection, storage, processing and disclosure of personal information and will uphold the Regulation’s core principles.
- All research staff involved will have up to date GCP training.
- Research data will be retained as per the Sponsor’s research data management policy.
- As per the Sponsor’s research data management policy, research data and records will be archived along with the data management policy of the Sponsor.
- In line with legal requirements, trial documents will be archived centrally at a secure facility with appropriate environmental controls and adequate protection from fire, flood and unauthorized access.
- Archived material will be stored in tamper-proof archive boxes that are clearly labelled.
- Electronic archiving will be provided by the Sponsor for post-project deposit and retention of data.
- Destruction of essential documents will require authorisation from the Sponsor.
- On completion of the study a final report will be prepared for Cancer Research Wales.
- Findings will be disseminated through various media, including open-access peer-reviewed publications, national and international conferences, the programme web pages, social media, and through an end-ofprogramme symposium for key stakeholders.
- Findings will also be disseminated to participating practice teams via a newsletter.
- Publications arising directly from the WICKED programme and authorship on the final trial report will adhere to the BMJ guidelines on authorship and contribution, based on the International Committee of Medical Journal Editors Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals 2013 .
Patient and public involvement
- The study team recognises that the involvement of those with lived experiences will be vital in this research.
- Furthermore, a lay perspective is essential in the development and undertaking of research for the promotion of equality, diversity and transparency.
- Additionally, the trial PPI has been active in providing feedback on participantfacing documents.
- Two more PPI representatives have been recruited to the TSC through the North Wales Cancer Forum and have directly relevant experience.
- Their perspective as both a patient and a member of the public will inform the overall supervision of the trial.
- This study aims to test the feasibility of the ThinkCancer! intervention.
- The authors acknowledge that interventions aiming to increase cancer referrals bring with them a risk of over-diagnosis and overinvestigation of patients.
- Safety netting can minimise the risk of harm by ensuring referrals are appropriate [7, 29, 32].
- To their knowledge, there are no interventions targeting primary care with a focus on safety netting.
- The trial is currently open for recruitment.
- On sites that are not covered by the NHS Indemnity Scheme (e.g. GP surgeries in primary care), investigators/collaborators will need to ensure that their activity on the study is covered under their own professional indemnity.
- SD drafted the manuscript integrating comments from JR, AS, AH, NG, CW, RN, NW, RTE, BFA, RL, RJL and ACS.
- ZH was involved in the design of the study and contributed to the protocol via the statistical component and the outcome measures.
- RJL was involved in the intervention development and the previous work packages leading up to the ThinkCancer trial.
- Ethics approval and consent to participate 2North Wales Organisation for Randomised Trials in Health , Bangor University, The Normal Site, Holyhead Road, Gwynedd LL57 2PZ, UK.
- Round T. Primary care and cancer: facing the challenge of early diagnosis and survivorship.
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Q1. What are the contributions in "Protocol for a feasibility study incorporating a randomised pilot trial with an embedded process evaluation and feasibility economic analysis of thinkcancer!: a primary care intervention to expedite cancer diagnosis in wales" ?
The ThinkCancer ! workshop is an educational behaviour change intervention aimed at the whole general practice team, designed to improve primary care approaches to ensure timely diagnosis of cancer. This study aims to assess the feasibility of the ThinkCancer ! ( Continued on next page ) © The Author ( s ). This article is licensed under a Creative Commons Attribution 4. 0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author ( s ) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article 's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article 's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Org/licenses/by/4. 0/. The Creative Commons Public Domain Dedication waiver ( http: //creativecommons. org/publicdomain/zero/1. 0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ac. uk North Wales Centre for Primary Care Research ( NWCPCR ), Bangor University, Cambrian 2, Wrexham Technology Park, Wrexham LL13 7YP, UK Full list of author information is available at the end of the article Disbeschl et al.
Q2. What future works have the authors mentioned in the paper "Protocol for a feasibility study incorporating a randomised pilot trial with an embedded process evaluation and feasibility economic analysis of thinkcancer!: a primary care intervention to expedite cancer diagnosis in wales" ?
One of the key strengths of this intervention is that it can be iteratively developed throughout the study period, which will ensure the future definitive trial will adopt an optimal approach. In addition, involving the entire practice is a relatively novel approach, with great potential benefit.