Trial Forge Guidance 5: ethical considerations in randomised Studies Within A Trial (SWATs)

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To improve trial processes, trialists can do Studies Within A Trial (SWATs) that compare trial process alternatives. Although SWATs are recognized by funders, there are differences in how they are implemented, such as different consent requirements in the UK and Ireland. This complicates SWAT conduct, raises ethical considerations, and highlights the need for standardised, ethical approaches to SWATs. The purpose of the current study was to devise guidance to address this. Methods We used existing systematic reviews, searched PubMed and the SWAT register, and contacted SWAT teams known to the authors to identify relevant randomised SWATs. We extracted information on any challenges in the SWAT approval process, as well as challenges implementing the SWAT. We held three consensus building forums, all including representatives from nine key stakeholder groups representing a broad range of roles in trials. We presented participants with two SWATs to start conversation on perceived ethical issues. Consensus building forums were recorded, transcribed, and analysed using NVivo, focusing on ethical principles, challenges, and solutions. Results We developed guidance on ethical considerations applicable to randomised SWATs. The guidelines cover all stages of a SWAT, from development and SWAT team selection to communication of results. Conclusions Studies Within a Trial are generally perceived to be low risk and low burden to participants. However, there are still variation in ethical standards applied to these studies by researchers, sponsors and ethics committees. In addition, SWATs are uniquely distinct from trials, presenting specific for their ethical conduct. These guidelines will be helpful to anyone planning or reviewing SWATs in understanding these differences and their ethical implications and provide a practical guide for the ethical conduct of SWATs. Trial methodology SWAT Study Within a Trial methodology guidance research ethics Trial Forge Figures Figure 1 Background It is well known that randomised controlled trials are often inefficient in terms of recruiting to target and on time, as well as in retaining participants until the end of the trial( 1 – 8 ). A consequence of this is that it inevitably leads to delays, which have both a financial and human impact( 9 ). When trial findings are delayed, knowledge about potentially lifesaving treatments are delayed too. Trialists are very aware of these inefficiencies and employ a number of strategies to improve them, particularly for recruitment and retention, but a lack of evaluation means that it is generally difficult to determine the impact of these steps( 4 , 5 , 10 ). Studies Within A Trial (SWATs) are a robust, cost-effective method of conducting primary methodological research in trials to provide evidence on how to improve trial processes, both through randomised and non-randomised evaluations( 11 ). A SWAT is a self-contained research study that is embedded within a host trial with the aim of evaluating or exploring alternative ways of delivering or organising a particular trial process( 12 , 13 ). For the remainder of this manuscript, we will consider randomised SWATs only. SWATs are often constrained by the host trial in which they are embedded, which restricts the number of potential participants. Consequently, power calculations are not always done for SWATs( 12 ). The usefulness of findings of SWATs to future trials is only fully realised through replication (across clinical areas, participant groups, countries etc.) and inclusion in meta-analyses( 14 ). Despite SWAT-like trial methodology work from as far back as 1986( 4 ), progress has been slow. Nearly forty years later, there is still limited high certainty evidence to support trial process decisions, even for recruitment and retention, which has been the focus of most randomised SWAT activity ( 4 , 5 ). The value of SWATs is recognised by funding bodies in Ireland ( www.hrb.ie ) and the UK through the provision of dedicated SWAT funding (e.g., see https://www.nihr.ac.uk/documents/methodological-sub-studies-studies-within-a-trial-or-project-swat-and-studies-within-a-review-swar/21512 ). Canada also recently started to provide SWAT funding through their Accelerating Clinical Trials (ACT) consortium which is funded by the Canadian Institutes for Health Research (CIHR) ( https://act-aec.ca/funded-projects/ ). Despite this, there are some systematic differences in how SWATs can be done within and across different jurisdictions. For example, in the UK, separate participant consent to take part in the SWAT is not usual, because doing so is often considered likely to undermine the evaluation. In Ireland, it depends on the ethics committee, with separate consent likely to be required. For example, SWAT 107( 15 ) implemented at the pre-screening phase, and SWAT 141( 16 ), both set in Irish-led host trials, required separate SWAT consent in addition to host trial consent. In comparison, a SWAT by Kho et al 2020( 17 ) conducted in the UK did not need to collect consent for a SWAT that evaluated a similar intervention. From a research perspective, this can make conducting SWATs harder and potentially introduces differences into SWAT conduct, making their usefulness for meta-analyses more uncertain. The challenge facing ethics committees and trialists is how best to conduct a SWAT that is ethical, provides robust evidence on trial methodology, and does not impact the host trial, or the trial participants, negatively. The purpose of the current study was to devise guidance documentation, Trial Forge Guidance 5 (TFG5) for ethics committees, trialists, methodologists, funders, approvals agencies and others, to enable more harmonisation of SWAT conduct across borders, disciplines and ethics committees. This guidance will support the ethically appropriate design, approval and conduct of SWATs to address key inefficiencies in trial processes. This work is part of a series of guidance on SWATs and how to improve clinical trials more generally, initiated by Trial Forge ( https://www.trialforge.org/ ). Methods Data search and extraction To identify SWATs, we used the Cochrane systematic reviews for strategies to improve recruitment and retention in randomised trials( 4 , 5 ) and searched the literature via PubMed, the F1000 SWAT Collection and SWAT register (the Northern Ireland SWAT Repository) (searches were conducted in August 2022).We contacted known SWAT teams with collections of SWATs (e.g., PROMETHEUS team in York, UK) to identify unpublished SWATs. Our eligibility criteria were: ( 1 ) the SWAT intervention was randomised; ( 2 ) the SWAT involved a real host trial (i.e. the host trial was not a mock/pretend trial); ( 3 ) if published, the SWAT was published in or later than 2010. If there was more than one record for a SWAT, the most recent was included. We developed a data extraction form, piloted it on three SWATs by duplicate extraction (HB and FS), and decided on data categories as presented in Table 1 . Authors of included SWATs were not contacted for further information. Full data extraction was performed in duplicate by two reviewers (HB and GSH). Table 1 Data categories Data categories Explanation SWAT identifiers · first author last name · year of publication · citation SWAT descriptives · type of randomised SWAT · SWAT registration details · number of host trials · host trial registration(s) · SWAT country · SWAT sponsor · SWAT population age · SWAT population sex or gender · SWAT population ethnicity · SWAT population main health condition · number randomised in SWAT · description of the SWAT intervention · SWAT primary outcome Outcomes of interest · Patient and Public Involvement in SWAT development · If SWAT needed ethical approval · ethical approval text (if yes) · the justification for not needing ethical approval (if no) · whether SWAT participants or their legal guardians consented to participate · whether others consented to participate (e.g. health care staff) · description of the consent process and what participants consented to · if consent was not collected the justification for this · SWAT documentation for participants (e.g. participant information sheet, consent form) · who recruited and how were participants introduced and recruited to the SWAT · any steps taken in recruitment of vulnerable participants (e.g. any additional protections invoked, who consents on their behalf) · description of the SWAT randomisation · any statement regarding risk to participants · any description of confidentiality risks and steps taken to protect confidentiality · any description of ethical considerations or challenges · whether any ethical challenges were highlighted by the ethics committee and if there were a description of them · any challenges put forward by any other committee/review body other than the ethics committee and what it was · whether results of the SWAT were shared with participants (relevant to participant facing SWATs only) · any data sharing statement or text about the availability of the SWAT data SWAT using factorial design · yes or no because this design can cause SWATs to be excluded from meta-analyses due to possible contamination between interventions Consensus building forums Sixty invitation emails were sent directly to potential participants. Potential participants were identified by the project team and the opportunity to take part was advertised at the International Clinical Trials Methodology Conference 2022 and on social media, as well as with an established patient and public involvement (PPI) group in Ireland. We held three consensus building forums, all including representatives from nine relevant parties representing a broad range of roles in trials: sponsor representatives, clinical site members, other site members who approve study access, funders, PPI partners, research ethics committee members, trialists and methodologists, ethicists and trial managers. The purpose was to elicit their views on process, challenges and ethical issues when conducting SWATs. We focused our attention on issues that are specific to SWATs and/or are treated differently in the SWAT literature compared to standard practice in research. Attendees were sent a preparation pack one week before the consensus building forum. It contained educational materials to help attendees understand what a SWAT is and what an ethics review entails. We also provided a short description of two randomised SWATs, SWAT 13( 18 ) and SWAT 24( 19 ), from the Northern Ireland SWAT repository, which we selected to use as a starting point to evoke discussion amongst the forum attendees. All these materials are provided in Supplementary File 1. Each meeting started with a recorded presentation by bioethicist and co-author, CW, which introduced ethical principles that guide the design and conduct of trials: respect for persons, justice, beneficence and respect for communities( 20 ). In addition, the video highlighted how these principles are applied to SWATs. These four ethical principles are internationally accepted and encompass the World Medical Association Declaration of Helsinki principles( 21 ). Ethical issues in SWATs, starting with the case studies were explored in an open discussion where participants also suggested solutions without prompting. Data analysis SWAT data extraction Descriptive statistics (frequencies) were used for quantitative data. Analysis was carried out using IBM SPSS Statistics, version 29.0.1.0 (171). Qualitative data extracted from the SWATs were content analysed using descriptive codes. Findings are presented as a narrative summary. Consensus building forums were audio recorded and transcribed verbatim. Written comments made by attendees during the forums were also saved and included in the analysis. All transcripts and written comments were analysed using NVivo (version 12; QSR International) for data management. Consensus building forums were content-analysed using a directed approach( 22 ), by initially identifying the relevant ethical principle(s) (deductive coding) and then further sub-categorised using descriptive labels for both challenges and suggested solutions (inductive coding). Results Eighty-nine sources of randomised SWATs were eligible for inclusion. We use the term ‘sources of SWATs’ because one publication may report multiple SWATs and not all included SWATs have been published. Of 182 registrations on the Northern Ireland SWAT repository, 140 were randomised SWATs (others were not randomised and some registrations were blank (repository accessed August 2022)). None were found to contain ethical information relevant to this study, so this SWAT source was excluded (Figure 1). Figure 1: PRISMA flow diagram One hundred and three SWATs from sources other than the Northern Ireland SWAT repository were included and Table 2 presents their characteristics, categorised by the stage of the SWAT in relation to ethical review. Fifty percent (n = 52) of SWATs had registration details. The host trials spanned a wide range of medical conditions and health areas. For example, of the 103 SWATs, the single most frequent condition was cancer (n=12, 12%), followed by mental health (n = 9) and smoking (n = 5). Of the SWATs that were successfully embedded and evaluated (n = 92) the number of trial participants randomised to the SWATs ranged from 14 to 20,759. Table 2: List of SWATs included according to stage of ethical review SWAT Details Where we looked for SWATs Number (n = 103) (%) Planned SWATs but not submitted for ethics review The Northern Ireland SWAT Repository a ; Protocol published in a journal 7(7) Abandoned before being submitted for ethics review PROMETHEUS; Authors’ knowledge 1(1) Reviewed and approved and SWAT goes ahead Cochrane recruitment review; Cochrane retention review; F1000 SWAT collection b ; PubMed search 90(87) Reviewed but not progressed due to feedback from ethics committee. Trial team judged the feedback made the SWAT unfeasible. PROMETHEUS (pump prime funding for SWATs in the UK); Author’s knowledge 3 (3) SWATs that were abandoned or partially abandoned (e.g. a clinical site did not give approval) despite the SWAT being ethically approved NI SWAT Repository; PROMETHEUS; F1000 SWAT collection; PubMed search; Cochrane recruitment review; Cochrane retention review; Authors’ knowledge 2(2) a https://www.qub.ac.uk/sites/TheNorthernIrelandNetworkforTrialsMethodologyResearch/SWATSWARInformation/Repositories/SWATStore/ b https://f1000research.com/collections/swat Thirty-nine people expressed an interest in attending the consensus building forum and 32 attended. Table 3 describes the number of stakeholder types attending the meetings. Although many had several roles, Table 3 shows the role for which they were invited to the consensus building forum. Table 3: The number of stakeholder types that attended all three consensus building forums and the countries where stakeholders were based. Stakeholder Type N Country (n) Sponsor representatives e.g., University sponsor representative, NHS sponsor representative 4 Ireland (1) UK (3) Other site members who approve study access e.g., NHS R&D, clinical site approvals 0 N/A Clinical site members e.g., CRF/CRC Ireland, NIHR CRN UK 1 Ireland (1) Funders e.g., Government funding bodies, charities, industry 6 Ireland (5) UK (1) PPI partners/organisations to approach to invite PPI partners e.g., Experienced PPI partners, trial participants, research ethics committee lay members 7 Ireland (3) UK (4) Research ethics committee members e.g., NHS REC members, University research ethics committee members 1 UK (1) Trialists/methodologists 6 Canada (1) Switzerland (1) UK (4) Ethicists 2 Germany (1) UK (1) Trial managers/Clinical research associates 5 UK (5) Total 32 The guidance: Trial Forge Guidance 5 Our full guidance document, Trial Forge Guidance 5, is presented in Supplementary File 2. Here we present the ethical considerations derived from the data extraction as well as the consensus building forums. We also provide suggested solutions to the concerns raised. In addition, the guidance includes text providing background information on SWATs, which is intended to educate the reader about the purpose of SWATs, how they can be used to inform design choices in the host trial, and how SWATs are different from other types of studies (supplementary file 2). This text was written by the authors based on consensus building forum attendees request for education of ethics committees about SWATs. Table 4: Ethical Issues in SWATs and actions to address them (Excerpt from Trial Forge Guidance Five, Supplementary File 2) SWAT phase SWAT stage Ethical considerations Consider these actions and solutions Design/planning/ Protocol development SWAT team members 1. Is there resource waste due to developing interventions for groups who will not benefit? 2. Is there resource waste as the intervention isn’t appropriate e.g., causes unintended harm/upset or isn’t accessible to all? 3. Is the integrity of the host trial protected? 4. Does the SWAT intervention meet Equality, Diversity and Inclusivity criteria? 5. Is the research team diverse?* Involve PPI partners in SWAT design as early as possible. Getting PPI partners’ views on the SWAT intervention early will help ensure it is acceptable to SWAT participants. It will also reassure ethics committees that people with lived experience have been involved in the development of the SWAT. Earlier studies have linked factorial designs to potential research waste(5). If a factorial design is proposed, ask if it is the correct choice for a SWAT. Is it likely to be excluded from future reviews due to potential intervention interactions and therefore represent research waste?* Consider whether the SWAT intervention choice may disproportionately undermine the autonomy of one or more groups within the host trial by limiting their ability to take part in the SWAT more than others. Design 6. Should participants be provided with a choice about whether to receive the SWAT intervention? Are checks of acceptability of the SWAT intervention with potential participants needed? Do participants need a choice regarding whether they receive the SWAT intervention or not? PPI can help to answer this question Are potential participants likely to meet/know each other and discuss the SWAT intervention? What might happen if they find out they are treated differently (e.g. one receives a monetary incentive and the other does not). Consider whether the intervention is appropriate for the population.* Protocol Registration 7. Can you help other SWAT teams identify a Research Ethics Committee (REC) with experience in this type of SWAT? Is the REC that provided the approval for the SWAT listed in the SWAT protocol on the SWAT Repository Store? Although not all SWATs on the SWAT Repository Store will have gone through the approval process it should be added as an update when appropriate. All SWAT websites (e.g., PROMETHEUS, Implement SWATs, Trial Forge) should provide a list of ethics committees that are familiar with SWATs* Ethics submission 8. Is the Research Ethics Committee (REC) you plan to submit to familiar with SWATs? If possible, choose a REC that is familiar with SWATs. If the REC is familiar with SWATs you may not need to provide much background information about SWATs in your submission. If the REC is not familiar with SWATs, we suggest including general SWAT information text, including the purpose of SWATs, the potential benefit of SWATs (including to the host trial), the principle that SWATs should never affect the implementation of the host trial. This text is provided in TFG5.* Recruitment Informed consent 9. Is it ethical to randomise trial participants to a SWAT without informing them? 9. Will informing participants about the SWAT risk influencing the findings? For REC: Reassure the REC that the SWAT intervention poses a minimal risk to participants and might even be done without ethical approval (e.g. newsletters might already be sent from the trial office to participants) and why this would be a proportionate approach. Reassure the ethics committee that the secure data collection and storage arrangements in keeping with data protection regulations will be followed. Explain to the REC that knowledge of the SWAT is likely to change actions in relation to the target behaviour and therefore any results may not be reliable. For participants (only relevant if SWAT participants also are participants in the host trial): Include a generic description of SWATs in the host trial participant information leaflet. Ensure to include that a low-risk SWAT might be conducted and while they can’t be fully informed about their participation, they will receive the results (if they wish to). Consider giving participants the possibility of opting out of taking part in SWATs and instructions on how they do this?* Data collection 10. Are the SWAT findings generalizable to the wider population? Who is included in the SWAT? In order to establish generalisability of any intervention we need to know who was included in the study. Collect and report appropriate information to describe the SWAT participants in terms of equity, diversity, inclusion (EDI) characteristics, e.g. age, sex, gender, race, ethnicity and ancestry, socioeconomic status and location of the trial, and trial and SWAT coordination sites. This will also allow later sub-group analyses to be done. Be prepared to share SWAT data to enable sub-group analyses e.g. using any of the EDI characteristics listed above. Analysis Progress review 11. To protect the host trial, should a progress review of the SWAT be conducted? The team should consult a statistician to decide prospectively on the need for a review point for the SWAT. This might be to decide whether one or other trial process being investigated by the SWAT is more promising. This is especially true if the SWAT is being done to actively inform a trial process decision within the host trial, not just for future trials.* End of SWAT/host trial/Dissemination 12. Is the SWAT Intervention fair to all, including those not in the intervention group? If the SWAT intervention is associated with any benefit for participants, this benefit should also be made available for those not randomised to the intervention, once the SWAT is complete. A benefit could be a financial incentive or a newsletter. 13. Debriefing – trial participants should be told about the SWAT when complete. If your participants are 'blinded' to their participation in a SWAT they should be fully informed at the end of the SWAT or host trial, whichever is appropriate for your SWAT. A description of the SWAT as well as the results of the SWAT, if participants want to receive it, should be sent to them. This can be included when participants are sent the results of the host trial. In the UK the Health Research Authority (HRA) recommends sending trial results to trial participants: https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/research-transparency/informing-participants/communicating-study-findings-participants-guidance/* *Issues and solutions added by the study authors on reflection after the consensus building forums. All other issues and solutions were suggested by participants in the consensus-building forum. Discussion of the guidance There are four ethical principles that govern trials: respect for persons, beneficence, justice, and respect for communities. The ethical principle of respect for persons requires researchers to obtain the informed consent of prospective research participants (unless conditions for a waiver of consent applies) and to preserve the confidentiality of private information. The ethical principle of beneficence means that researchers must maximize the benefits of research participation while minimizing risks. The ethical principle of justice obliges researchers to select research participants fairly and to ensure they have reasonable access to any beneficial treatment identified. Finally, the ethical principle of respect for communities calls on researchers to respect communal values, protect and empower social institutions, and, where applicable, abide by the decisions of the legitimate communal authority. Our consensus building forum participants were given a presentation on these principles to provide a framework for our discussion on the ethical issues in SWATs. We present our discussion using the same framework, divided into the five key parts of the trial presented in Table 4: design/planning/ protocol development, recruitment, data collection, analysis, and dissemination. Design/planning/protocol development (including Ethical considerations 1-8) The ethical principle of beneficence emerged in what is a fundamental issue prevalent in SWATs – the absence of equipoise. Since there is no recognised process to identify when equipoise is or is not present, SWAT teams face challenges in selecting interventions for testing, potentially leading to the adoption of interventions that may not be optimal for the participant population of the host trial. The authors and consensus building forum participants concluded that the interventions selected for testing may not always be the most suitable (Ethical consideration 1): “ So trying to determine equipoise I think is really difficult [..]. You might want to for example, look at the process of what ’ s the best way to see people for visits in a clinical trial, and you might do for example, face to face visits versus telephone visits. But by doing that you then don ’ t offer the other things, that maybe lots of patients prefer video consultations and they don ’ t like either face to face visits or telephone. But because there ’ s a real lack of data to guide selection of interventions, I think that ’ s one of the big challenges, one of the big ethical dilemmas of SWATs how to overcome that problem is challenging (…)” (Participant 14; trialist/methodologist, meeting 2). Also, regarding ethical consideration 1, and the principle of respect for communities, there was also a consideration of PPI partners being helpful in preventing resource waste and ensuring that the SWAT will provide a benefit to society: “ I suppose the other one is the perceived balance of... kind of the opportunity cost of the finance and thinking about Charles’ [CW, Bioethicist on project team] ’ principle of respect for communities, which communities are we thinking about and who, or what, activities don ’ t get this money if it ’ s invested in trying to persuade a few more people to return a questionnaire.” (Participant 4, ethicist, meeting 1) Ethical consideration 2 addressed concerns around causing unintended harm/upset by the proposed intervention: “.. I wonder if sometimes assumptions might be made about harm where actually we don ’ t have evidence of harm and some of these could be sort of reframed as research questions. Like if you’ve got this intervention and some people might not be able to use it or access it, maybe that’s part of your SWAT actually is understanding that as opposed to assuming that they can ’ t and not running the SWAT. (Participant 7, sponsor representative, meeting 1). Although the primary aim of Research Ethics Committees (RECs) is to safeguard research participants against undue risks and burdens, there is a tendency to err on the side of caution when there is a lack of evidence regarding potential risk or burden associated with an intervention. This cautious approach can sometimes lead to a loss of perspective on the appropriate level of concern. Recognizing this issue, the authors sought to emphasize the importance of proportionality in the guidance materials. This was supported during the consensus-building meeting. “Also the idea of proportionality that underpins all of this doesn’t it, so is it a proportionate approach to require ethical approval, is it proportionate to require individual consent to take part in the SWAT as well as the study, and how you might justify whether your approach is proportionate or not, and that’s the role often of perhaps qualitative research to explore whether a SWAT is feasible and also whether the approach you’re proposing is proportionate or not, and also the role of a public involvement contribution in that.” (Participant 9, trialist/methodologist, meeting 2). The safeguarding of the host trial(s) was discussed extensively, and several ethical considerations were raised, governed by the principle of beneficence. This was discussed in relation to the case study involving monetary incentives. It was noted that what researchers perceive as an incentive might not necessarily be perceived as such by SWAT participants. This mismatch in perception could lead to unintended consequences for the host trial, for example, a lower return rate for questionnaires: “(…) but the bit that strikes me most about this is that there is an assumption that this is an incentive [£5 voucher], and that... I’d be curious to know if there’s ways in which you can measure whether this is a disincentive. (Participant 10, patient and public involvement partner, meeting 1) Another aspect concerning the protection of host trial(s) highlighted how the SWAT intervention could intersect with ongoing societal issues, such as the general cost-of-living. This context may render certain incentives, like monetary rewards, more appealing to specific participant demographics rather than being universally attractive, potentially leading to biased questionnaire responses: “Then, my final thought is really that particularly in the current economic climate if you were rewarding people who returned their questionnaire with a voucher, would you be skewing the data in the sense that some people might... much more incentivised to do that who really, really... that £5 would make a big difference to them than other people?”. (Participant 8, PPI partner, meeting 1) “I was just going to say from a practical experience of delivering SWATs when we talk to our participants, my work is done with the elderly and I think we do we have to be really mindful about this being coercive because I know with this group of people they’ll often ring up and they’ll say they want to withdraw from a study, but they’ll do it in such a nice way, they’ll say, “If it’s not too much trouble dear, I’d really like to... if I could come out”, and it would be so easy to coerce them and say, “Well actually...” and cajole them into it, and obviously we don’t. But I think just have to be mindful that some people are really very vulnerable, and I have seen some letters on this nudge theory, or whatever else you want to call it, where it has been pretty heavy handed and I wasn’t really happy about that." ( Participant 6, Trialist/Methodologist, meeting 2) The SWAT literature provides current evidence on practice, which was considered relevant to future SWAT design. For example, 31 of the 92 SWATs we identified that had been conducted (and data collection completed) did not report the sex or gender of participants. Among those remaining, either sex or gender was reported, but never both, and none acknowledged non-binary genders or intersex individuals. Only one SWAT reported sex, transgender status, and 'other'. Thirty of the 92 SWATs that had been conducted did not report participants' age. Only 19 provided information on ethnicity or race. This makes it hard to know who the SWAT intervention is designed and relevant for. In relation to ethical consideration 2 (the intervention isn’t appropriate), among the 103 included SWATs, eight (8%) reported various ethical considerations or challenges that affected the SWAT, unrelated to any review committee's challenges. These included concerns about data confidentiality, ensuring equal access to information, maintaining participant confidentiality, protecting staff when handling monetary incentives, fairness regarding monetary incentives, and providing justification for not collecting consent for the SWAT when participants have already consented to the mode of contact as part of the host trial consent process. Pertaining to risks, one SWAT acknowledged the potential for harm to participants, specifically regarding feeling pressured to participate in the recruitment intervention group, although this wasn't quantified. The remaining SWATs did not address any risks associated with participating, except for the seven described as low-risk and not requiring ethical approval. Regarding participant confidentiality, three SWATs reported measures taken to safeguard it: reminder telephone calls avoiding voicemail, ensuring anonymity by sending vouchers via email instead of post, and discussing confidentiality during initial contact in a SWAT involving community health advisor volunteers. In summary, in terms of the guidance, the solution offered at the consensus building forums was to include public and patient partners in the SWAT team to help identify and avoid these issues. Of 103 included SWATs, just 17 (17%) reported PPI involvement. Ethical considerations 7 and 8 focused on RECs experience of SWATs. Five (6%) SWATs encountered challenges raised by the REC during review—two were conducted and three were abandoned post-ethics. One of these, SWAT 141, focused on pre-host trial screening to assess whether patients' guided self-reflection on their illness could enhance recruitment. The committee requested detailed information in the intervention arm participant information leaflet (PIL), including specifics about required involvement (time, location, travel), and asked for control arm participants to receive a PIL and provide written informed consent for completing an anonymous questionnaire. Another, SWAT 107, also focused on pre-host trial screening recruitment, testing an animation on general clinical trial information and key concepts. The committee requested additional information for the protocol and a PIL for SWAT participants, along with informed consent for intervention arm participants. There was some confusion in the REC response due to the lack of distinction between SWAT and host trial recruitment. In another conducted SWAT, where the intervention was a theoretically informed newsletter, the team was asked to send the newsletter to the control group as well, affecting the timing for outcome measurement. The last two SWATs were replications of SWAT 24. While one aimed to replicate SWAT 24 (a factorial design) within a single host trial, changes requested by the ethics committee, labelling the intervention email and letter as coercive, led the trial team to consider it no longer worth testing (personal communication). RECRUITMENT (including ethical principle 9) Respect for persons emerged in our consensus building forum and was debated at length, primarily when discussing informed consent. The ethical principle requires the informed consent of prospective research participants, unless conditions for a waiver of consent apply. However, requiring informed consent can cause problems for many, if not most, SWATs. SWATs are typically about trial processes that will happen in one form or another regardless of the SWAT, are low risk, and knowledge of participation in a SWAT might influence how participants interact with it, undermining the evaluation. SWAT investigators typically request that host trial participants are not consulted or informed about the SWAT. Our consensus building forum participants had differing views on this. In one of the forums there was a desire to give SWAT participants a choice, not about whether to participate in the SWAT, but about whether to accept or refuse an intervention. Of course, this is likely to result in the intervention changing, which is problematic from a SWAT design and implementation perspective. This discussion originated around the use of monetary incentives (shopping vouchers) to enhance retention: “ Offering payment doesn't mandate that people accept it. (…). Again, it’s very paternalistic.” (Participant 10, PPI partner, meeting 2, chat). “… making you feel respected, trusted... and not (e.g.) taken for a cheapskate or someone who would only be motivated by money, and not inclined to do something that is socially valuable unless there was money involved." (Participant 4, Ethicist, meeting 1, chat)”. The discussion highlighted that not all incentives will be perceived in the same way by everyone. One forum participant suggested that offering a choice either in whether to receive the incentive, or the type of incentive, would give SWAT participants some autonomy of their participation: “(…)is there any way that people could have a choice over what gift voucher they receive or what... if we ’ re calling it an incentive (inaudible) it might not be, whatever incentive they receive, I ’ m thinking that if it was a large trial, you might also get the additional information about which is the best way of... you know, what type of voucher or what type of financial reward, or if it may not even be financial, it might be something completely different, is most likely to result in people... I don ’ t know, completing the questionnaires.” (Participant 8, PPI Partner, meeting 1) Three solutions emerged from the consensus building forums, two by the forum participants and one by the authors. Firstly, it was suggested to include a blanket consent at the time of host trial consent, i.e. a general description of SWATs and that when taking part in the host trial, participants might also take part in a SWAT: “ I just think there ’ s the risk of making research so laborious that this kind of work doesn’t get done [..]In the States they did update the common rule in 2018 exactly because RECs were totally overwhelmed… with all these kind of research requests and they introduced the concept of broad consent. [..] But I think it ’ s important that people are aware, that they ’ re informed you know, it might not be an individual consent, I ’ m thinking of one trial in particular, but there was a notification given to patients and they were all told that their particular facility may or may not be randomised to an intervention and the IRB ’ s [Institutional Review Board which is a research ethics committee in the US]) approved that. Individual consent wasn’t obtained but… there was notifications provided to everybody about a pragmatic cluster randomised trial.” (Participant 4, Funder, meeting 2). The second suggestion was to fully debrief SWAT participants about the purpose of the SWAT and what was involved when the SWAT is completed: “ (…) it ’ s no different, really, to a blinded clinical trial where you might tell people what arm they ’ re on at the end and which IMP [investigational medical product] they received. I suppose in that sense it is justifiable ethical, as long as you’re transparent at the end of the study. ” (Participant 6, Sponsor Representative, meeting 3). The authors added to this the best time to inform participants of the SWAT findings would be together with information about the host trial results, as it is current best practice to do so(23, 24). Additionally, the authors suggested having public and patient partners on the SWAT team as an essential part of working towards a solution to the concerns raised, to ensure SWAT participants’ right to autonomy is respected. The SWAT literature provides an overview of current practice. Out of the 90 SWATs that reported needing ethical approval, the majority (50; 56%) did not seek explicit consent from participants. Twelve (13%) reported seeking consent from SWAT participants or legal guardians, 16 (18%) described consent to be given indirectly (e.g. the SWAT was described in the host trial PIL; SWAT participants consented to receive SMS text messages in the host trial which were part of the SWAT intervention; return of a questionnaire was taken to indicate consent), two (2%) included consent for both SWAT arms after ethical review (SWAT 107 and 141), and the remaining 12 (13%) did not report whether consent was collected or not from participants or legal guardians. Two (2%) SWATs reported obtaining consent from doctors and volunteer community health advisors in addition to patient consent. One SWAT described collecting consent indirectly as the intervention involved use of text messages and participants consented to be contacted this way for the host trial. It was unclear if this SWAT had ethics committee approval or not. In the 50 SWATs that did not seek consent, 27 provided a justification for not doing so, nine had the need for consent waived by the research ethics committee, six SWATs were described as low risk, three declared they were not withholding information, in seven SWATs participants were not aware of taking part in a SWAT, and in two SWATs the host trial consent was described to encompass the SWAT. Additionally, one SWAT was described as low risk but also described collecting consent indirectly. SWATs without consent were observed across many countries. In summary, practices vary, but our consensus building forum participants were open to host trial consent without the need for separate SWAT consent from participants, with the caveat that they are informed at some point that their data has been included in a SWAT. DATA COLLECTION (including ethical consideration 10) In terms of the principle of justice there was a discussion around whether SWAT interventions target the parts of the host trial population that it needs to target: “ (…)... so you ’ re deliberately trying to incentivise people who are not responding to the survey, (…) , maybe there are certain groups who the financial incentive doesn’t have a big impact for, so this question of looking at who ’ s responding, I think it’s particularly important, because (…) those principles that get reviewed at the ethics committees, justice is maybe one of the ones that doesn’t get as much attention as the consent or the risks and benefits, [..].” (Participant 2,Trialist/Methodologist, meeting 1) Additionally, the overall issue of the inclusivity and appropriateness of SWATs for the population being investigated emerged. Issues can involve e.g., whether all participants have a mobile phone (or a particular brand of mobile phone) or whether the theory underlying the SWAT intervention is generalisable to all or only some of the population: “ (…) whether there are, then, any implications or concerns about fairness, equality of respect, which I would also include as justice, by the way. I wouldn’t just see justice as a purely distributive matter. I think we should be attending to more relational understandings of justice as well – are people treated as equals, are people related to as equals. You know, it ’ s unlikely that there ’ s a huge problem here, but if the behavioural theory that has informed the thing had been developed. In one very narrow population, then there might be concerns.” (Participant 4, Ethicist, meeting 1) The authors have tackled this issue in the guidance document for SWATs, recognizing that the generalisability of evidence relies on the representativeness of the sample of participants involved. ANALYSIS (including ethical consideration 11) Protection of the host trial was discussed extensively with many issues arising for the design stage. However, protection of the host trial also emerged at the analysis stage. In terms of justice, it was highlighted that in other countries subgroup analysis is becoming a requirement: “ In Canada there is now increasing requirement to include Sex and Gender-Based Analyses (SGBA+). I wonder how often studies look at sub-analyses?” ( Participant 2, Trialist/Methodologist, meeting 1, chat) . However, due to the generally restricted sample size in SWATs, any subgroup analysis will probably have to be done at the pooling stage. In Trial Forge Guidance 4 the authors suggest SWAT teams make their data available for subgroup analysis and to describe who took part in the SWAT(25). END OF SWAT/HOST TRIAL/DISSEMINATION (including ethical principles 12 and 13). The principle of justice prevails here. Justice requires that when the trial is complete research participants have reasonable access to any beneficial treatment identified. In SWATs it may appear convenient to overlook the principle of justice when participants are unaware of their involvement. However, such behaviour is neither ethical nor in line with best practice. During consensus building forums there was a proposal to treat SWAT participants similarly to those in host trials where participants are provided access to the intervention treatment. In SWATs this intervention could be a monetary incentive, supplementary information through a newsletter, or something entirely different. Only seven (7%) of the SWATs we identified reported to have (n=4) or plan (n=3) to inform SWAT participants of the SWAT results. The authors included this point as a final step in the process of a SWAT/host trial and dissemination . “ (…), much like giving patients with placebo/standard of care, the opportunity/access to intervention treatment that is done in many drug treatment trials.” (Participant 14, Trialist/Methodologist, meeting 2, chat) There was a general call to educate RECs and other review bodies about SWATs in the consensus building forums and to help other SWAT teams by letting them know which RECs have experience of a specific SWAT protocol to achieve consistency in the review process. As educating RECs and other review committees about SWAT is not quickly achievable, we have developed this general information about SWATs as part of this guidance. SWAT teams can then submit this text at the time of review (see TFG5 guidance). Participants in the consensus building forums also suggested updating the SWAT registry entry to show which RECs had approved SWAT evaluations. “ I know the REC that had reviewed the SWAT initially had a bit of pushback and it was then that we had to go back and say, “ Well, this has been approved before.” That was a point that I ’ d scribbled down at the start, you know, if the SWAT repository or whatever… it would always be quite good to know what ethics committees had actually reviewed what SWATs. I think if I was putting an application in now for a SWAT, I ’ d want to reference that because that ’ s happened, I ’ d want to say, “ This has actually been approved by X, Y, Z.” If I see that sometimes in a REC, I ’ m like, “ Well, okay, that ’ s how many people have thought that this was all right previously. ” (Participant 2, TM, meeting 3). In relation to respect for communities the suggested solution was also to include PPI partners on the SWAT team for the REC to be confident that someone similar to SWAT participants has been consulted about all aspects of the SWAT and the intervention. Strengths and limitations This guidance has been developed for randomised SWATs as these constitute the majority of SWATs (NI SWAT Repository). While this does not mean the guidance is not relevant to SWATs using other designs, it will likely exclude ethical challenges specific to these designs. Consensus building forum participants were based exclusively in the global north, in addition, the majority were based in either Ireland or the UK. However, this also reflects the literature where all 103 SWATs included were conducted in the global north and most in either Ireland or the UK. Hence, this reflects a limitation of the area of research rather than a study-specific limitation per se. Conclusion Although SWATs are generally low risk and low burden to participants this does not mean ethical standards for research do not apply. While similar in many ways to other research studies, SWATs have important differences that have implications for their ethical conduct. We anticipate this guidance will not only guide all relevant parties in the ethical conduct of SWATs but also provide education about SWATs, their purpose, limitations, and the need for these studies in making clinical trials more efficient, particularly making replication of SWATs possible so the evidence for target interventions can increase. Abbreviations REC Research Ethics Committee SWAT Study Within A Trial PIL Participant Information Leaflet PPI Patient and Public Involvement UK United Kingdom HRA Health Research Authority (United Kingdom) Declarations Ethics approval and consent to participate Ethical approval was given by the Clinical Research Ethics Committee of the Cork Teaching Hospitals, Ireland (ECM 4 (m) 20/09/2022). Verbal consent was collected from all attendees at the start of each consensus building forum. Consent for publication All authors agree to the publication of this paper. Availability of data and materials All materials are available in supplementary files in this paper. The transcripts of the consensus building forums generated and analysed during the current study is not publicly available due it containing information that could compromise participant consent (but are available from the corresponding author on reasonable request). Competing interests CW receives consulting income from Cardialen and Eli Lilly & Company. ST is an Editor-in-Chief of Trials. MB is a Senior Editor with Trials and received unrestricted grants from Moderna unrelated to this work. The other authors declare that they have no competing interests. Funding Funding for this work was received from the Health Research Board - Trials Methodology Research Network (HRB-TMRN) under the working group award scheme (HRB-TMRN 2021-1). Authors' contributions FS, RC, MC and ST conceived the idea for the project. HB, FS, RC, MC, EM, MB, AP, KG, CW, HG, PH and ST contributed to the initial design and development of the project. HB, FS and ST drafted the manuscript and guidance document, and this was revised with input from all authors. All authors have read and approved the final manuscript and guidance document. Acknowledgements We would like to thank our contributors in the consensus building forums who gave their time to enable this work. Special thanks are due to Dr Darren Dahly who contributed to the initial stages of the project. Authors' information (optional) References Desai M. Recruitment and retention of participants in clinical studies: Critical issues and challenges. Perspect Clin Res. 2020;11(2):51. Shiely F, Murphy D, Millar SR. Clinical research nurse predictions of trial failure, recruitment and retention: a case for their early inclusion in trial design. Trials. 2023;24(1):458. Brøgger-Mikkelsen M, Ali Z, Zibert JR, Andersen AD, Thomsen SF. Online patient recruitment in clinical trials: systematic review and meta-analysis. J Med Internet Res. 2020;22(11):e22179. Treweek S, Pitkethly M, Cook J, Fraser C, Mitchell E, Sullivan F et al. Strategies to improve recruitment to randomised trials. Cochrane database Syst reviews. 2018(2). Gillies K, Kearney A, Keenan C, Treweek S, Hudson J, Brueton VC et al. Strategies to improve retention in randomised trials. Cochrane Database Syst Reviews. 2021(3). 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How much is the lack of retention evidence costing trial teams in Ireland and the UK? Trials. 2022;23(1):1–13. Clark L, Arundel C, Coleman E, Doherty L, Parker A, Hewitt C, et al. The PROMoting the USE of SWATs (PROMETHEUS) programme: Lessons learnt and future developments for SWATs. Res Methods Med Health Sci. 2022;3(4):100–6. Treweek S, Bevan S, Bower P, Campbell M, Christie J, Clarke M, et al. Trial forge guidance 1: what is a study within a trial (SWAT)? Trials. 2018;19(1):139. Treweek S, Bevan S, Bower P, Briel M, Campbell M, Christie J, et al. Trial Forge Guidance 2: how to decide if a further Study Within A Trial (SWAT) is needed. Trials. 2020;21(1):1–9. Arundel CE, Clark L, Coleman E, Doherty L, Parker A, Torgerson DJ. Challenges and solutions to the implementation of studies within a trial: The experiences of the PROMETHEUS programme. Res Methods Med Health Sci. 2023;4(1):16–23. Shiely F. 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Qual Health Res. 2005;15(9):1277–88. Bruhn H, Campbell M, Entwistle V, Humphreys R, Jayacodi S, Knapp P, et al. What, how, when and who of trial results summaries for trial participants: stakeholder-informed guidance from the RECAP project. BMJ open. 2022;12(3):e057019. Authority HR. Publication and dissemination of research findings 2023 [ https://www.hra.nhs.uk/planning-and-improving-research/best-practice/publication-and-dissemination-research-findings/ Arundel CE, Clark LK, Parker A, Beard D, Coleman E, Cooper C, et al. Trial Forge Guidance 4: a guideline for reporting the results of randomised Studies Within A Trial (SWATs). Trials. 2024;25(1):183. 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11:51:37","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":187108,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary2TFG5v111.09.2024.docx","url":"https://assets-eu.researchsquare.com/files/rs-5073175/v1/d0f5d5256dbb3176bdeefd31.docx"}],"financialInterests":"","formattedTitle":"Trial Forge Guidance 5: ethical considerations in randomised Studies Within A Trial (SWATs)","fulltext":[{"header":"Background","content":"\u003cp\u003eIt is well known that randomised controlled trials are often inefficient in terms of recruiting to target and on time, as well as in retaining participants until the end of the trial(\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). A consequence of this is that it inevitably leads to delays, which have both a financial and human impact(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). When trial findings are delayed, knowledge about potentially lifesaving treatments are delayed too. Trialists are very aware of these inefficiencies and employ a number of strategies to improve them, particularly for recruitment and retention, but a lack of evaluation means that it is generally difficult to determine the impact of these steps(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eStudies Within A Trial (SWATs) are a robust, cost-effective method of conducting primary methodological research in trials to provide evidence on how to improve trial processes, both through randomised and non-randomised evaluations(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). A SWAT is a self-contained research study that is embedded within a host trial with the aim of evaluating or exploring alternative ways of delivering or organising a particular trial process(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). For the remainder of this manuscript, we will consider randomised SWATs only. SWATs are often constrained by the host trial in which they are embedded, which restricts the number of potential participants. Consequently, power calculations are not always done for SWATs(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The usefulness of findings of SWATs to future trials is only fully realised through replication (across clinical areas, participant groups, countries etc.) and inclusion in meta-analyses(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Despite SWAT-like trial methodology work from as far back as 1986(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), progress has been slow. Nearly forty years later, there is still limited high certainty evidence to support trial process decisions, even for recruitment and retention, which has been the focus of most randomised SWAT activity (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe value of SWATs is recognised by funding bodies in Ireland (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.hrb.ie\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.hrb.ie\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and the UK through the provision of dedicated SWAT funding (e.g., see \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.nihr.ac.uk/documents/methodological-sub-studies-studies-within-a-trial-or-project-swat-and-studies-within-a-review-swar/21512\u003c/span\u003e\u003cspan address=\"https://www.nihr.ac.uk/documents/methodological-sub-studies-studies-within-a-trial-or-project-swat-and-studies-within-a-review-swar/21512\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Canada also recently started to provide SWAT funding through their Accelerating Clinical Trials (ACT) consortium which is funded by the Canadian Institutes for Health Research (CIHR) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://act-aec.ca/funded-projects/\u003c/span\u003e\u003cspan address=\"https://act-aec.ca/funded-projects/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Despite this, there are some systematic differences in how SWATs can be done within and across different jurisdictions. For example, in the UK, separate participant consent to take part in the SWAT is not usual, because doing so is often considered likely to undermine the evaluation. In Ireland, it depends on the ethics committee, with separate consent likely to be required. For example, SWAT 107(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) implemented at the pre-screening phase, and SWAT 141(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), both set in Irish-led host trials, required separate SWAT consent in addition to host trial consent. In comparison, a SWAT by Kho et al 2020(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) conducted in the UK did not need to collect consent for a SWAT that evaluated a similar intervention. From a research perspective, this can make conducting SWATs harder and potentially introduces differences into SWAT conduct, making their usefulness for meta-analyses more uncertain. The challenge facing ethics committees and trialists is how best to conduct a SWAT that is ethical, provides robust evidence on trial methodology, and does not impact the host trial, or the trial participants, negatively.\u003c/p\u003e \u003cp\u003eThe purpose of the current study was to devise guidance documentation, Trial Forge Guidance 5 (TFG5) for ethics committees, trialists, methodologists, funders, approvals agencies and others, to enable more harmonisation of SWAT conduct across borders, disciplines and ethics committees. This guidance will support the ethically appropriate design, approval and conduct of SWATs to address key inefficiencies in trial processes.\u003c/p\u003e \u003cp\u003eThis work is part of a series of guidance on SWATs and how to improve clinical trials more generally, initiated by Trial Forge (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.trialforge.org/\u003c/span\u003e\u003cspan address=\"https://www.trialforge.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData search and extraction\u003c/h2\u003e \u003cp\u003eTo identify SWATs, we used the Cochrane systematic reviews for strategies to improve recruitment and retention in randomised trials(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) and searched the literature via PubMed, the F1000 SWAT Collection and SWAT register (the Northern Ireland SWAT Repository) (searches were conducted in August 2022).We contacted known SWAT teams with collections of SWATs (e.g., PROMETHEUS team in York, UK) to identify unpublished SWATs. Our eligibility criteria were: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) the SWAT intervention was randomised; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) the SWAT involved a real host trial (i.e. the host trial was not a mock/pretend trial); (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) if published, the SWAT was published in or later than 2010. If there was more than one record for a SWAT, the most recent was included.\u003c/p\u003e \u003cp\u003eWe developed a data extraction form, piloted it on three SWATs by duplicate extraction (HB and FS), and decided on data categories as presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Authors of included SWATs were not contacted for further information. Full data extraction was performed in duplicate by two reviewers (HB and GSH).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eData categories\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eData categories\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExplanation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSWAT identifiers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026middot; first author last name\u003c/p\u003e \u003cp\u003e\u0026middot; year of publication\u003c/p\u003e \u003cp\u003e\u0026middot; citation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSWAT descriptives\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026middot; type of randomised SWAT\u003c/p\u003e \u003cp\u003e\u0026middot; SWAT registration details\u003c/p\u003e \u003cp\u003e\u0026middot; number of host trials\u003c/p\u003e \u003cp\u003e\u0026middot; host trial registration(s)\u003c/p\u003e \u003cp\u003e\u0026middot; SWAT country\u003c/p\u003e \u003cp\u003e\u0026middot; SWAT sponsor\u003c/p\u003e \u003cp\u003e\u0026middot; SWAT population age\u003c/p\u003e \u003cp\u003e\u0026middot; SWAT population sex or gender\u003c/p\u003e \u003cp\u003e\u0026middot; SWAT population ethnicity\u003c/p\u003e \u003cp\u003e\u0026middot; SWAT population main health condition\u003c/p\u003e \u003cp\u003e\u0026middot; number randomised in SWAT\u003c/p\u003e \u003cp\u003e\u0026middot; description of the SWAT intervention\u003c/p\u003e \u003cp\u003e\u0026middot; SWAT primary outcome\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcomes of interest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026middot; Patient and Public Involvement in SWAT development\u003c/p\u003e \u003cp\u003e\u0026middot; If SWAT needed ethical approval\u003c/p\u003e \u003cp\u003e\u0026middot; ethical approval text (if yes)\u003c/p\u003e \u003cp\u003e\u0026middot; the justification for not needing ethical approval (if no)\u003c/p\u003e \u003cp\u003e\u0026middot; whether SWAT participants or their legal guardians consented to participate\u003c/p\u003e \u003cp\u003e\u0026middot; whether others consented to participate (e.g. health care staff)\u003c/p\u003e \u003cp\u003e\u0026middot; description of the consent process and what participants consented to\u003c/p\u003e \u003cp\u003e\u0026middot; if consent was not collected the justification for this\u003c/p\u003e \u003cp\u003e\u0026middot; SWAT documentation for participants (e.g. participant information sheet, consent form)\u003c/p\u003e \u003cp\u003e\u0026middot; who recruited and how were participants introduced and recruited to the SWAT\u003c/p\u003e \u003cp\u003e\u0026middot; any steps taken in recruitment of vulnerable participants (e.g. any additional protections invoked, who consents on their behalf)\u003c/p\u003e \u003cp\u003e\u0026middot; description of the SWAT randomisation\u003c/p\u003e \u003cp\u003e\u0026middot; any statement regarding risk to participants\u003c/p\u003e \u003cp\u003e\u0026middot; any description of confidentiality risks and steps taken to protect confidentiality\u003c/p\u003e \u003cp\u003e\u0026middot; any description of ethical considerations or challenges\u003c/p\u003e \u003cp\u003e\u0026middot; whether any ethical challenges were highlighted by the ethics committee and if there were a description of them\u003c/p\u003e \u003cp\u003e\u0026middot; any challenges put forward by any other committee/review body other than the ethics committee and what it was\u003c/p\u003e \u003cp\u003e\u0026middot; whether results of the SWAT were shared with participants (relevant to participant facing SWATs only)\u003c/p\u003e \u003cp\u003e\u0026middot; any data sharing statement or text about the availability of the SWAT data\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSWAT using factorial design\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026middot; yes or no because this design can cause SWATs to be excluded from meta-analyses due to possible contamination between interventions\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eConsensus building forums\u003c/h2\u003e \u003cp\u003eSixty invitation emails were sent directly to potential participants. Potential participants were identified by the project team and the opportunity to take part was advertised at the International Clinical Trials Methodology Conference 2022 and on social media, as well as with an established patient and public involvement (PPI) group in Ireland. We held three consensus building forums, all including representatives from nine relevant parties representing a broad range of roles in trials: sponsor representatives, clinical site members, other site members who approve study access, funders, PPI partners, research ethics committee members, trialists and methodologists, ethicists and trial managers. The purpose was to elicit their views on process, challenges and ethical issues when conducting SWATs. We focused our attention on issues that are specific to SWATs and/or are treated differently in the SWAT literature compared to standard practice in research.\u003c/p\u003e \u003cp\u003eAttendees were sent a preparation pack one week before the consensus building forum. It contained educational materials to help attendees understand what a SWAT is and what an ethics review entails. We also provided a short description of two randomised SWATs, SWAT 13(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) and SWAT 24(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), from the Northern Ireland SWAT repository, which we selected to use as a starting point to evoke discussion amongst the forum attendees. All these materials are provided in Supplementary File 1. Each meeting started with a recorded presentation by bioethicist and co-author, CW, which introduced ethical principles that guide the design and conduct of trials: respect for persons, justice, beneficence and respect for communities(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). In addition, the video highlighted how these principles are applied to SWATs. These four ethical principles are internationally accepted and encompass the World Medical Association Declaration of Helsinki principles(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Ethical issues in SWATs, starting with the case studies were explored in an open discussion where participants also suggested solutions without prompting.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eSWAT data extraction\u003c/h2\u003e \u003cp\u003eDescriptive statistics (frequencies) were used for quantitative data. Analysis was carried out using IBM SPSS Statistics, version 29.0.1.0 (171). Qualitative data extracted from the SWATs were content analysed using descriptive codes. Findings are presented as a narrative summary.\u003c/p\u003e \u003cp\u003eConsensus building forums were audio recorded and transcribed verbatim. Written comments made by attendees during the forums were also saved and included in the analysis. All transcripts and written comments were analysed using NVivo (version 12; QSR International) for data management. Consensus building forums were content-analysed using a directed approach(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), by initially identifying the relevant ethical principle(s) (deductive coding) and then further sub-categorised using descriptive labels for both challenges and suggested solutions (inductive coding).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eEighty-nine sources of randomised SWATs were eligible for inclusion. \u0026nbsp;We use the term \u0026lsquo;sources of SWATs\u0026rsquo; because one publication may report multiple SWATs and not all included SWATs have been published. Of 182 registrations on the Northern Ireland SWAT repository, 140 were randomised SWATs (others were not randomised and some registrations were blank (repository accessed August 2022)). None were found to contain ethical information relevant to this study, so this SWAT source was excluded (Figure 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1: PRISMA flow diagram\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOne hundred and three SWATs from sources other than the Northern Ireland SWAT repository were included and Table 2 presents their characteristics, categorised by the stage of the SWAT in relation to ethical review. Fifty percent (n = 52) of SWATs had registration details. The host trials spanned a wide range of medical conditions and health areas. For example, of the 103 SWATs, the single most frequent condition was cancer (n=12, 12%), followed by mental health (n = 9) and smoking (n = 5). Of the SWATs that were successfully embedded and evaluated (n = 92) the number of trial participants randomised to the SWATs ranged from 14 to 20,759.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: List of SWATs included according to stage of ethical review\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"570\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSWAT Details\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWhere we looked for SWATs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber (n = 103) (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003ePlanned SWATs but not submitted for ethics review\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eThe Northern Ireland SWAT Repository\u003csup\u003ea\u003c/sup\u003e; Protocol published in a journal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003e7(7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003eAbandoned before being submitted for ethics review\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003ePROMETHEUS; Authors\u0026rsquo; knowledge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003e1(1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003eReviewed and approved and SWAT goes ahead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eCochrane recruitment review; Cochrane retention review; F1000 SWAT collection\u003csup\u003eb\u003c/sup\u003e; PubMed search\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003e90(87)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003eReviewed but not progressed due to feedback from ethics committee. Trial team judged the feedback made the SWAT unfeasible.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003ePROMETHEUS (pump prime funding for SWATs in the UK); Author\u0026rsquo;s knowledge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003e3 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 232px;\"\u003e\n \u003cp\u003eSWATs that were abandoned or partially abandoned (e.g. a clinical site did not give approval) despite the SWAT being ethically approved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003eNI SWAT Repository; PROMETHEUS; F1000 SWAT collection; PubMed search; Cochrane recruitment review; Cochrane retention review; Authors\u0026rsquo; knowledge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 169px;\"\u003e\n \u003cp\u003e2(2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003ehttps://www.qub.ac.uk/sites/TheNorthernIrelandNetworkforTrialsMethodologyResearch/SWATSWARInformation/Repositories/SWATStore/\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003ehttps://f1000research.com/collections/swat\u003c/p\u003e\n\u003cp\u003eThirty-nine people expressed an interest in attending the consensus building forum and 32 attended. Table 3 describes the number of stakeholder types attending the meetings. \u0026nbsp;Although many had several roles, Table 3 shows the role for which they were invited to the consensus building forum.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: \u0026nbsp; The number of stakeholder types that attended all three consensus building forums and the countries where stakeholders were based.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"652\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 510px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStakeholder Type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCountry (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 510px;\"\u003e\n \u003cp\u003eSponsor representatives\u003c/p\u003e\n \u003cp\u003ee.g., University sponsor representative, NHS sponsor representative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003eIreland (1)\u003c/p\u003e\n \u003cp\u003eUK (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 510px;\"\u003e\n \u003cp\u003eOther site members who approve study access\u003c/p\u003e\n \u003cp\u003ee.g., NHS R\u0026amp;D, clinical site approvals\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 510px;\"\u003e\n \u003cp\u003eClinical site members\u003c/p\u003e\n \u003cp\u003ee.g., CRF/CRC Ireland, NIHR CRN UK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003eIreland (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 510px;\"\u003e\n \u003cp\u003eFunders\u003c/p\u003e\n \u003cp\u003ee.g., Government funding bodies, charities, industry\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003eIreland (5)\u003c/p\u003e\n \u003cp\u003eUK (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 510px;\"\u003e\n \u003cp\u003ePPI partners/organisations to approach to invite PPI partners\u003c/p\u003e\n \u003cp\u003ee.g., Experienced PPI partners, trial participants, research ethics committee lay members\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003eIreland (3)\u003c/p\u003e\n \u003cp\u003eUK (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 510px;\"\u003e\n \u003cp\u003eResearch ethics committee members\u003c/p\u003e\n \u003cp\u003ee.g., NHS REC members, University research ethics committee members\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003eUK (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 510px;\"\u003e\n \u003cp\u003eTrialists/methodologists\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003eCanada (1)\u003c/p\u003e\n \u003cp\u003eSwitzerland (1)\u003c/p\u003e\n \u003cp\u003eUK (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 510px;\"\u003e\n \u003cp\u003eEthicists\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003eGermany (1)\u003c/p\u003e\n \u003cp\u003eUK (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 510px;\"\u003e\n \u003cp\u003eTrial managers/Clinical research associates\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003eUK (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 510px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eThe guidance: Trial Forge Guidance 5\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur full guidance document, Trial Forge Guidance 5, is presented in Supplementary File 2. Here we present the ethical considerations derived from the data extraction as well as the consensus building forums. We also provide suggested solutions to the concerns raised. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn addition, the guidance includes text providing background information on SWATs, which is intended to educate the reader about the purpose of SWATs, how they can be used to inform design choices in the host trial, and how SWATs are different from other types of studies (supplementary file 2). \u0026nbsp;This text was written by the authors based on consensus building forum attendees request for education of ethics committees about SWATs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4:\u0026nbsp;\u003c/strong\u003eEthical Issues in SWATs and actions to address them (Excerpt from Trial Forge Guidance Five, Supplementary File 2)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"926\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSWAT phase\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSWAT stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEthical considerations\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 558px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eConsider these actions and solutions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDesign/planning/ Protocol development\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003eSWAT team members\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e1. Is there resource waste due to developing interventions for groups who will not benefit?\u003c/p\u003e\n \u003cp\u003e2. Is there resource waste as the intervention isn\u0026rsquo;t appropriate e.g., causes unintended harm/upset or isn\u0026rsquo;t accessible to all?\u003c/p\u003e\n \u003cp\u003e3. Is the integrity of the host trial protected?\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4. Does the SWAT intervention meet Equality, Diversity and Inclusivity criteria?\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5. Is the research team diverse?*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 558px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eInvolve PPI partners in SWAT design as early as possible. Getting PPI partners\u0026rsquo; views on the SWAT intervention early will help ensure it is acceptable to SWAT participants. It will also reassure ethics committees that people with lived experience have been involved in the development of the SWAT. \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eEarlier studies have linked factorial designs to potential research waste(5). If a factorial design is proposed, ask if it is the correct choice for a SWAT. \u0026nbsp; \u0026nbsp; Is it likely to be excluded from future reviews due to potential intervention interactions and therefore represent research waste?*\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eConsider whether the SWAT intervention choice may disproportionately undermine the autonomy of one or more groups within the host trial by limiting their ability to take part in the SWAT more than others. \u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003eDesign\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e6. Should participants be provided with a choice about whether to receive the SWAT intervention?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 558px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eAre checks of acceptability of the SWAT intervention with potential participants needed? Do participants need a choice regarding whether they receive the SWAT intervention or not? PPI can help to answer this question\u003c/li\u003e\n \u003cli\u003eAre potential participants likely to meet/know each other and discuss the SWAT intervention? What might happen if they find out they are treated differently (e.g. one receives a monetary incentive and the other does not). Consider whether the intervention is appropriate for the population.*\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003eProtocol Registration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e7. Can you help other SWAT teams identify a Research Ethics Committee (REC) with experience in this type of SWAT?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 558px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eIs the REC that provided the approval for the SWAT listed in the SWAT protocol on the SWAT Repository Store? \u0026nbsp;Although not all SWATs on the SWAT Repository Store will have gone through the approval process it should be added as an update when appropriate. \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAll SWAT websites (e.g., PROMETHEUS, Implement SWATs, Trial Forge) should provide a list of ethics committees that are familiar with SWATs*\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003eEthics submission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e8. Is the Research Ethics Committee (REC) you plan to submit to familiar with SWATs?\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 558px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eIf possible, choose a REC that is familiar with SWATs. If the REC is familiar with SWATs you may not need to provide much background information about SWATs in your submission.\u003c/li\u003e\n \u003cli\u003eIf the REC is not familiar with SWATs, we suggest including general SWAT information text, including the purpose of SWATs, the potential benefit of SWATs (including to the host trial), the principle that SWATs should never affect the implementation of the host trial. This text is provided in TFG5.*\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecruitment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003eInformed consent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e9. Is it ethical to randomise trial participants to a SWAT without informing them? \u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9.\u0026nbsp;Will informing participants about the SWAT risk influencing the findings?\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 558px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFor REC:\u003c/strong\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eReassure the REC that the SWAT intervention poses a minimal risk to participants and might even be done without ethical approval (e.g. newsletters might already be sent from the trial office to participants) and why this would be a proportionate approach. Reassure the ethics committee that the secure data collection and storage arrangements in keeping with data protection regulations will be followed.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eExplain to the REC that knowledge of the SWAT is likely to change actions in relation to the target behaviour and therefore any results may not be reliable.\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFor participants (only relevant if SWAT participants also are participants in the host trial):\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cul\u003e\n \u003cli\u003eInclude a generic description of SWATs in the host trial participant information leaflet. Ensure to include that a low-risk SWAT might be conducted and while they can\u0026rsquo;t be fully informed about their participation, they will receive the results (if they wish to). \u0026nbsp;\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eConsider giving participants the possibility of opting out of taking part in SWATs and instructions on how they do this?*\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e10. Are the SWAT findings generalizable to the wider population?\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 558px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eWho is included in the SWAT? In order to establish generalisability of any intervention we need to know who was included in the study. Collect and report appropriate information to describe the SWAT participants in terms of equity, diversity, inclusion (EDI) characteristics, e.g. age, sex, gender, race, ethnicity and ancestry, socioeconomic status and location of the trial, and trial and SWAT coordination sites. This will also allow later sub-group analyses to be done. \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eBe prepared to share SWAT data to enable sub-group analyses e.g. using any of the EDI characteristics listed above.\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnalysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003eProgress review\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e11. To protect the host trial, should a progress review of the SWAT be conducted?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 558px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eThe team should consult a statistician to decide prospectively on the need for a review point for the SWAT. This might be to decide whether one or other trial process being investigated by the SWAT is more promising. This is especially true if the SWAT is being done to actively inform a trial process decision within the host trial, not just for future trials.*\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEnd of SWAT/host trial/Dissemination\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e12. Is the SWAT Intervention fair to all, including those not in the intervention group?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 558px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eIf the SWAT intervention is associated with any benefit for participants, this benefit should also be made available for those not randomised to the intervention, once the SWAT is complete. A benefit could be a financial incentive or a newsletter.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e13. Debriefing \u0026ndash; trial participants should be told about the SWAT when complete.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 558px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eIf your participants are \u0026apos;blinded\u0026apos; to their participation in a SWAT they should be fully informed at the end of the SWAT or host trial, whichever is appropriate for your SWAT. A description of the SWAT as well as the results of the SWAT, if participants want to receive it, should be sent to them. This can be included when participants are sent the results of the host trial.\u003c/li\u003e\n \u003cli\u003eIn the UK the Health Research Authority (HRA) recommends sending trial results to trial participants: https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/research-transparency/informing-participants/communicating-study-findings-participants-guidance/*\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003e*Issues and solutions added by the study authors on reflection after the consensus building forums. All other issues and solutions were suggested by participants in the consensus-building forum.\u0026nbsp;\u003c/em\u003e\u003c/p\u003e"},{"header":"Discussion of the guidance ","content":"\u003cp\u003eThere are four ethical principles that govern trials: respect for persons, beneficence, justice, and respect for communities. The ethical principle of respect for persons requires researchers to obtain the informed consent of prospective research participants (unless conditions for a waiver of consent applies) and to preserve the confidentiality of private information. The ethical principle of beneficence means that researchers must maximize the benefits of research participation while minimizing risks. The ethical principle of justice obliges researchers to select research participants fairly and to ensure they have reasonable access to any beneficial treatment identified. Finally, the ethical principle of respect for communities calls on researchers to respect communal values, protect and empower social institutions, and, where applicable, abide by the decisions of the legitimate communal authority.\u003c/p\u003e\n\u003cp\u003eOur consensus building forum participants were given a presentation on these principles to provide a framework for our discussion on the ethical issues in SWATs. We present our discussion using the same framework, divided into the five key parts of the trial presented in Table 4: design/planning/ protocol development, recruitment, data collection, analysis, and dissemination.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDesign/planning/protocol development (including Ethical considerations 1-8)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ethical principle of beneficence emerged in what is a fundamental issue prevalent in SWATs \u0026ndash; the absence of equipoise. Since there is no recognised process to identify when equipoise is or is not present, SWAT teams face challenges in selecting interventions for testing, potentially leading to the adoption of interventions that may not be optimal for the participant population of the host trial. The authors and consensus building forum participants concluded that the interventions selected for testing may not always be the most suitable (Ethical consideration 1):\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026ldquo;\u003cem\u003eSo trying to determine equipoise I think is really difficult [..]. You might want to for example, look at the process of what\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003es the best way to see people for visits in a clinical trial, and you might do for example, face to face visits versus telephone visits. But by doing that you then don\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003et offer the other things, that maybe lots of patients prefer video consultations and they don\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003et like either face to face visits or telephone. But because there\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003es a real lack of data to guide selection of interventions, I think that\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003es one of the big challenges, one of the big ethical dilemmas of SWATs how to overcome that problem is challenging (\u0026hellip;)\u0026rdquo;\u0026nbsp;\u003c/em\u003e(Participant 14; trialist/methodologist, meeting 2).\u003c/p\u003e\n\u003cp\u003eAlso, regarding ethical consideration 1, and the principle of respect for communities, there was also a consideration of PPI partners being helpful in preventing resource waste and ensuring that the SWAT will provide a benefit to society:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026ldquo;\u003cem\u003eI suppose the other one is the perceived balance of... kind of the opportunity cost of the finance and thinking about Charles\u0026rsquo; [CW, Bioethicist on project team]\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003eprinciple of respect for communities, which communities are we thinking about and who, or what, activities don\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003et get this money if it\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003es invested in trying to persuade a few more people to return a questionnaire.\u0026rdquo;\u0026nbsp;\u003c/em\u003e(Participant 4, ethicist, meeting 1)\u003c/p\u003e\n\u003cp\u003eEthical consideration 2 addressed concerns around causing unintended harm/upset by the proposed intervention:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026ldquo;..\u003cem\u003e\u0026nbsp;I wonder if sometimes assumptions might be made about harm where actually we don\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003et have evidence of harm and some of these could be sort of reframed as research questions. Like if you\u0026rsquo;ve got this intervention and some people might not be able to use it or access it, maybe that\u0026rsquo;s part of your SWAT actually is understanding that as opposed to assuming that they can\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003et and not running the SWAT.\u0026nbsp;\u003c/em\u003e(Participant 7, sponsor representative, meeting 1).\u003cem\u003e\u0026nbsp;\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAlthough the primary aim of Research Ethics Committees (RECs) is to safeguard research participants against undue risks and burdens, there is a tendency to err on the side of caution when there is a lack of evidence regarding potential risk or burden associated with an intervention. This cautious approach can sometimes lead to a loss of perspective on the appropriate level of concern. Recognizing this issue, the authors sought to emphasize the importance of proportionality in the guidance materials. This was supported during the consensus-building meeting.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cem\u003e\u0026ldquo;Also the idea of proportionality that underpins all of this doesn\u0026rsquo;t it, so is it a proportionate approach to require ethical approval, is it proportionate to require individual consent to take part in the SWAT as well as the study, and how you might justify whether your approach is proportionate or not, and that\u0026rsquo;s the role often of perhaps qualitative research to explore whether a SWAT is feasible and also whether the approach you\u0026rsquo;re proposing is proportionate or not, and also the role of a public involvement contribution in that.\u0026rdquo;\u0026nbsp;\u003c/em\u003e(Participant 9, trialist/methodologist, meeting 2).\u003c/p\u003e\n\u003cp\u003eThe safeguarding of the host trial(s) was discussed extensively, and several ethical considerations were raised, governed by the principle of beneficence. This was discussed in relation to the case study involving monetary incentives. It was noted that what researchers perceive as an incentive might not necessarily be perceived as such by SWAT participants. This mismatch in perception could lead to unintended consequences for the host trial, for example, a lower return rate for questionnaires:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cem\u003e\u0026ldquo;(\u0026hellip;) but the bit that strikes me most about this is that there is an assumption that this is an incentive [\u0026pound;5 voucher], and that... I\u0026rsquo;d be curious to know if there\u0026rsquo;s ways in which you can measure whether this is a disincentive.\u0026nbsp;\u003c/em\u003e(Participant 10, patient and public involvement partner, meeting 1)\u003c/p\u003e\n\u003cp\u003eAnother aspect concerning the protection of host trial(s) highlighted how the SWAT intervention could intersect with ongoing societal issues, such as the general cost-of-living. This context may render certain incentives, like monetary rewards, more appealing to specific participant demographics rather than being universally attractive, potentially leading to biased questionnaire responses:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026ldquo;Then, my final thought is really that particularly in the current economic climate if you were rewarding people who returned their questionnaire with a voucher, would you be skewing the data in the sense that some people might... much more incentivised to do that who really, really... that \u0026pound;5 would make a big difference to them than other people?\u0026rdquo;.\u0026nbsp;\u003c/em\u003e(Participant 8, PPI partner, meeting 1)\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cem\u003e\u0026ldquo;I was just going to say from a practical experience of delivering SWATs when we talk to our participants, my work is done with the elderly and I think we do we have to be really mindful about this being coercive because I know with this group of people they\u0026rsquo;ll often ring up and they\u0026rsquo;ll say they want to withdraw from a study, but they\u0026rsquo;ll do it in such a nice way, they\u0026rsquo;ll say, \u0026ldquo;If it\u0026rsquo;s not too much trouble dear, I\u0026rsquo;d really like to... if I could come out\u0026rdquo;, and it would be so easy to coerce them and say, \u0026ldquo;Well actually...\u0026rdquo; and cajole them into it, and obviously we don\u0026rsquo;t. \u0026nbsp;But I think just have to be mindful that some people are really very vulnerable, and I have seen some letters on this nudge theory, or whatever else you want to call it, where it has been pretty heavy handed and I wasn\u0026rsquo;t really happy about that.\u0026quot; (\u003c/em\u003eParticipant 6, Trialist/Methodologist, meeting 2)\u003c/p\u003e\n\u003cp\u003eThe SWAT literature provides current evidence on practice, which was considered relevant to future SWAT design. For example, 31 of the 92 SWATs we identified that had been conducted (and data collection completed) did not report the sex or gender of participants. Among those remaining, either sex or gender was reported, but never both, and none acknowledged non-binary genders or intersex individuals. Only one SWAT reported sex, transgender status, and \u0026apos;other\u0026apos;. Thirty of the 92 SWATs that had been conducted did not report participants\u0026apos; age. Only 19 provided information on ethnicity or race. This makes it hard to know who the SWAT intervention is designed and relevant for.\u003c/p\u003e\n\u003cp\u003eIn relation to ethical consideration 2 (the intervention isn\u0026rsquo;t appropriate), among the 103 included SWATs, eight (8%) reported various ethical considerations or challenges that affected the SWAT, unrelated to any review committee\u0026apos;s challenges. These included concerns about data confidentiality, ensuring equal access to information, maintaining participant confidentiality, protecting staff when handling monetary incentives, fairness regarding monetary incentives, and providing justification for not collecting consent for the SWAT when participants have already consented to the mode of contact as part of the host trial consent process. Pertaining to risks, one SWAT acknowledged the potential for harm to participants, specifically regarding feeling pressured to participate in the recruitment intervention group, although this wasn\u0026apos;t quantified. The remaining SWATs did not address any risks associated with participating, except for the seven described as low-risk and not requiring ethical approval. Regarding participant confidentiality, three SWATs reported measures taken to safeguard it: reminder telephone calls avoiding voicemail, ensuring anonymity by sending vouchers via email instead of post, and discussing confidentiality during initial contact in a SWAT involving community health advisor volunteers.\u003c/p\u003e\n\u003cp\u003eIn summary, in terms of the guidance, the solution offered at the consensus building forums was to include public and patient partners in the SWAT team to help identify and avoid these issues. Of 103 included SWATs, just 17 (17%) reported PPI involvement.\u003c/p\u003e\n\u003cp\u003eEthical considerations 7 and 8 focused on RECs experience of SWATs. Five (6%) SWATs encountered challenges raised by the REC during review\u0026mdash;two were conducted and three were abandoned post-ethics. One of these, SWAT 141, focused on pre-host trial screening to assess whether patients\u0026apos; guided self-reflection on their illness could enhance recruitment. The committee requested detailed information in the intervention arm participant information leaflet (PIL), including specifics about required involvement (time, location, travel), and asked for control arm participants to receive a PIL and provide written informed consent for completing an anonymous questionnaire. Another, SWAT 107, also focused on pre-host trial screening recruitment, testing an animation on general clinical trial information and key concepts. The committee requested additional information for the protocol and a PIL for SWAT participants, along with informed consent for intervention arm participants. There was some confusion in the REC response due to the lack of distinction between SWAT and host trial recruitment. In another conducted SWAT, where the intervention was a theoretically informed newsletter, the team was asked to send the newsletter to the control group as well, affecting the timing for outcome measurement. The last two SWATs were replications of SWAT 24. While one aimed to replicate SWAT 24 (a factorial design) within a single host trial, changes requested by the ethics committee, labelling the intervention email and letter as coercive, led the trial team to consider it no longer worth testing (personal communication).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRECRUITMENT\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e(including ethical principle 9)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRespect for persons emerged in our consensus building forum and was debated at length, primarily when discussing informed consent. The ethical principle requires the informed consent of prospective research participants, unless conditions for a waiver of consent apply. However, requiring informed consent can cause problems for many, if not most, SWATs. SWATs are typically about trial processes that will happen in one form or another regardless of the SWAT, are low risk, and knowledge of participation in a SWAT might influence how participants interact with it, undermining the evaluation. \u0026nbsp;SWAT investigators typically request that host trial participants are not consulted or informed about the SWAT.\u003c/p\u003e\n\u003cp\u003eOur consensus building forum participants had differing views on this. In one of the forums there was a desire to give SWAT participants a choice, not about whether to participate in the SWAT, but about whether to accept or refuse an intervention. Of course, this is likely to result in the intervention changing, which is problematic from a SWAT design and implementation perspective. This discussion originated around the use of monetary incentives (shopping vouchers) to enhance retention:\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026ldquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003eOffering payment doesn\u0026apos;t mandate that people accept it. (\u0026hellip;). Again, it\u0026rsquo;s very paternalistic.\u0026rdquo; (Participant 10, PPI partner, meeting 2, chat).\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cem\u003e\u0026ldquo;\u0026hellip; making you feel respected, trusted... and not (e.g.) taken for a cheapskate or someone who would only be motivated by money, and not inclined to do something that is socially valuable unless there was money involved.\u0026quot; (Participant 4, Ethicist, meeting 1, chat)\u0026rdquo;. \u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe discussion highlighted that not all incentives will be perceived in the same way by everyone. One forum participant suggested that offering a choice either in whether to receive the incentive, or the type of incentive, would give SWAT participants some autonomy of their participation:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cem\u003e\u0026ldquo;(\u0026hellip;)is there any way that people could have a choice over what gift voucher they receive or what... if we\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003ere calling it an incentive (inaudible) it might not be, whatever incentive they receive, I\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003em thinking that if it was a large trial, you might also get the additional information about which is the best way of... you know, what type of voucher or what type of financial reward, or if it may not even be financial, it might be something completely different, is most likely to result in people... I don\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003et know, completing the questionnaires.\u0026rdquo; (Participant 8, PPI Partner, meeting 1)\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThree solutions emerged from the consensus building forums, two by the forum participants and one by the authors. Firstly, it was suggested to include a blanket consent at the time of host trial consent, i.e. a general description of SWATs and that when taking part in the host trial, participants might also take part in a SWAT:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cspan dir=\"RTL\"\u003e\u0026ldquo;\u003c/span\u003e\u003cem\u003eI just think there\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003es the risk of making research so laborious that this kind of work doesn\u0026rsquo;t get done [..]In the States they did update the common rule in 2018 exactly because RECs were totally overwhelmed\u0026hellip; with all these kind of research requests and they introduced the concept of broad consent. [..] But I think it\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003es important that people are aware, that they\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003ere informed you know, it might not be an individual consent, I\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003em thinking of one trial in particular, but there was a notification given to patients and they were all told that their particular facility may or may not be randomised to an intervention and the IRB\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003es [Institutional Review Board which is a research ethics committee in the US]) approved that. Individual consent wasn\u0026rsquo;t obtained but\u0026hellip; there was notifications provided to everybody about a pragmatic cluster randomised trial.\u0026rdquo;\u0026nbsp;\u003c/em\u003e(Participant 4, Funder, meeting 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe second suggestion was to fully debrief SWAT participants about the purpose of the SWAT and what was involved when the SWAT is completed:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026ldquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003e(\u0026hellip;) it\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003es no different, really, to a blinded clinical trial where you might tell people what arm they\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003ere on at the end and which IMP [investigational medical product] they received. I suppose in that sense it is justifiable ethical, as long as you\u0026rsquo;re transparent at the end of the study.\u003c/em\u003e\u0026rdquo; (Participant 6, Sponsor Representative, meeting 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors added to this the best time to inform participants of the SWAT findings would be together with information about the host trial results, as it is current best practice to do so(23, 24). Additionally, the authors suggested having public and patient partners on the SWAT team as an essential part of working towards a solution to the concerns raised, to ensure SWAT participants\u0026rsquo; right to autonomy is respected.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe SWAT literature provides an overview of current practice. Out of the 90 SWATs that reported needing ethical approval, the majority (50; 56%) did not seek explicit consent from participants. Twelve (13%) reported seeking consent from SWAT participants or legal guardians, 16 (18%) described consent to be given indirectly (e.g. the SWAT was described in the host trial PIL; \u0026nbsp;SWAT participants consented to receive SMS text messages in the host trial which were part of the SWAT intervention; return of a questionnaire was taken to indicate consent), two (2%) included consent for both SWAT arms after ethical review (SWAT 107 and 141), and the remaining 12 (13%) did not report whether consent was collected or not from participants or legal guardians. Two (2%) SWATs reported obtaining consent from doctors and volunteer community health advisors in addition to patient consent. One SWAT described collecting consent indirectly as the intervention involved use of text messages and participants consented to be contacted this way for the host trial. It was unclear if this SWAT had ethics committee approval or not.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the 50 SWATs that did not seek consent, 27 provided a justification for not doing so, nine had the need for consent waived by the research ethics committee, six SWATs were described as low risk, three declared they were not withholding information, in seven SWATs participants were not aware of taking part in a SWAT, and in two SWATs the host trial consent was described to encompass the SWAT. Additionally, one SWAT was described as low risk but also described collecting consent indirectly. SWATs without consent were observed across many countries.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn summary, practices vary, but our consensus building forum participants were open to host trial consent without the need for separate SWAT consent from participants, with the caveat that they are informed at some point that their data has been included in a SWAT.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA COLLECTION (including ethical consideration 10)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn terms of the principle of justice there was a discussion around whether SWAT interventions target the\u0026nbsp;parts of the host trial population that it needs to target:\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026ldquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003e(\u0026hellip;)... so you\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003ere deliberately trying to incentivise people who are not responding to the survey, (\u0026hellip;) , maybe there are certain groups who the financial incentive doesn\u0026rsquo;t have a big impact for, so this question of looking at who\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003es responding, I think it\u0026rsquo;s particularly important, because (\u0026hellip;) those principles that get reviewed at the ethics committees, justice is maybe one of the ones that doesn\u0026rsquo;t get as much attention as the consent or the risks and benefits, [..].\u0026rdquo;\u0026nbsp;\u003c/em\u003e(Participant 2,Trialist/Methodologist, meeting 1)\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAdditionally, the overall issue of the inclusivity and appropriateness of SWATs for the population being investigated emerged. \u0026nbsp;Issues can involve e.g., whether all participants have a mobile phone (or a particular brand of mobile phone) or whether the theory underlying the SWAT intervention is generalisable to all or only some of the population:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026ldquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003e(\u0026hellip;) whether there are, then, any implications or concerns about fairness, equality of respect, which I would also include as justice, by the way. I wouldn\u0026rsquo;t just see justice as a purely distributive matter. I think we should be attending to more relational understandings of justice as well \u0026ndash; are people treated as equals, are people related to as equals. You know, it\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003es unlikely that there\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003es a huge problem here, but if the behavioural theory that has informed the thing had been developed. In one very narrow population, then there might be concerns.\u0026rdquo;\u0026nbsp;\u003c/em\u003e(Participant 4, Ethicist, meeting 1)\u003c/p\u003e\n\u003cp\u003eThe authors have tackled this issue in the guidance document for SWATs, recognizing that the generalisability of evidence relies on the representativeness of the sample of participants involved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eANALYSIS (including ethical consideration 11)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProtection of the host trial was discussed extensively with many issues arising for the design stage. However, protection of the host trial also emerged at the analysis stage. In terms of justice, it was highlighted that in other countries subgroup analysis is becoming a requirement:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026ldquo;\u003cem\u003eIn Canada there is now increasing requirement to include Sex and Gender-Based Analyses (SGBA+). I wonder how often studies look at sub-analyses?\u0026rdquo; (\u003c/em\u003eParticipant 2, Trialist/Methodologist, meeting 1, chat)\u003cem\u003e. \u0026nbsp;\u003c/em\u003eHowever, due to the generally restricted sample size in SWATs, any subgroup analysis will probably have to be done at the pooling stage. In Trial Forge Guidance 4 the authors suggest SWAT teams make their data available for subgroup analysis and to describe who took part in the SWAT(25).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEND OF SWAT/HOST TRIAL/DISSEMINATION (including ethical principles 12 and 13).\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe principle of justice prevails here. Justice requires that when the trial is complete research participants have reasonable access to any beneficial treatment identified. In SWATs it may appear convenient to overlook the principle of justice when participants are unaware of their involvement. However, such behaviour is neither ethical nor in line with best practice. During consensus building forums there was a proposal to treat SWAT participants similarly to those in host trials where participants are provided access to the intervention treatment. In SWATs this intervention could be a monetary incentive, supplementary information through a newsletter, or something entirely different. Only seven (7%) of the SWATs we identified reported to have (n=4) or plan (n=3) to inform SWAT participants of the SWAT results. \u0026nbsp;The authors included this point as a final step in the process of a SWAT/host trial and dissemination\u003cem\u003e.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026ldquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003e(\u0026hellip;), much like giving patients with placebo/standard of care, the opportunity/access to intervention treatment that is done in many drug treatment trials.\u0026rdquo;\u0026nbsp;\u003c/em\u003e(Participant 14, Trialist/Methodologist, meeting 2, chat)\u003c/p\u003e\n\u003cp\u003eThere was a general call to educate RECs and other review bodies about SWATs in the consensus building forums and to help other SWAT teams by letting them know which RECs have experience of a specific SWAT protocol to achieve consistency in the review process. As educating RECs and other review committees about SWAT is not quickly achievable, we have developed this general information about SWATs as part of this guidance. SWAT teams can then submit this text at the time of review (see TFG5 guidance). Participants in the consensus building forums also suggested updating the SWAT registry entry to show which RECs had approved SWAT evaluations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cspan dir=\"RTL\"\u003e\u0026ldquo;\u003c/span\u003e\u003cem\u003eI know the REC that had reviewed the SWAT initially had a bit of pushback and it was then that we had to go back and say,\u0026nbsp;\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026ldquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003eWell, this has been approved before.\u0026rdquo; That was a point that I\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003ed scribbled down at the start, you know, if the SWAT repository or whatever\u0026hellip; it would always be quite good to know what ethics committees had actually reviewed what SWATs. I think if I was putting an application in now for a SWAT, I\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003ed want to reference that because that\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003es happened, I\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003ed want to say,\u0026nbsp;\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026ldquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003eThis has actually been approved by X, Y, Z.\u0026rdquo; If I see that sometimes in a REC, I\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003em like,\u0026nbsp;\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026ldquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003eWell, okay, that\u003c/em\u003e\u003cem\u003e\u003cspan dir=\"RTL\"\u003e\u0026rsquo;\u003c/span\u003e\u003c/em\u003e\u003cem\u003es how many people have thought that this was all right previously.\u003c/em\u003e\u0026rdquo; (Participant 2, TM, meeting 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn relation to respect for communities the suggested solution was also to include PPI partners on the SWAT team for the REC to be confident that someone similar to SWAT participants has been consulted about all aspects of the SWAT and the intervention.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrengths and limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis guidance has been developed for randomised SWATs as these constitute the majority of SWATs (NI SWAT Repository). While this does not mean the guidance is not relevant to SWATs using other designs, it will likely exclude ethical challenges specific to these designs. Consensus building forum participants were based exclusively in the global north, in addition, the majority were based in either Ireland or the UK. However, this also reflects the literature where all 103 SWATs included were conducted in the global north and most in either Ireland or the UK. Hence, this reflects a limitation of the area of research rather than a study-specific limitation per se.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAlthough SWATs are generally low risk and low burden to participants this does not mean ethical standards for research do not apply. While similar in many ways to other research studies, SWATs have important differences that have implications for their ethical conduct. We anticipate this guidance will not only guide all relevant parties in the ethical conduct of SWATs but also provide education about SWATs, their purpose, limitations, and the need for these studies in making clinical trials more efficient, particularly making replication of SWATs possible so the evidence for target interventions can increase.\u003c/p\u003e"},{"header":"Abbreviations","content":" \u003cp\u003e REC Research Ethics Committee\u003c/p\u003e \u003cp\u003eSWAT Study Within A Trial\u003c/p\u003e \u003cp\u003ePIL Participant Information Leaflet\u003c/p\u003e \u003cp\u003ePPI Patient and Public Involvement\u003c/p\u003e \u003cp\u003eUK United Kingdom\u003c/p\u003e \u003cp\u003eHRA Health Research Authority (United Kingdom)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was given by the Clinical Research Ethics Committee of the Cork Teaching Hospitals, Ireland (ECM 4 (m) 20/09/2022). Verbal consent was collected from all attendees at the start of each consensus building forum.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors agree to the publication of this paper.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll materials are available in supplementary files in this paper. The transcripts of the consensus building forums generated and analysed during the current study is not publicly available due it containing information that could compromise participant consent (but are available from the corresponding author on reasonable request).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCW receives consulting income from Cardialen and Eli Lilly \u0026amp; Company. ST is an Editor-in-Chief of Trials. MB is a Senior Editor with Trials and received unrestricted grants from Moderna unrelated to this work. The other authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding for this work was received from the Health Research Board - Trials Methodology Research Network (HRB-TMRN) under the working group award scheme (HRB-TMRN 2021-1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFS, RC, MC and ST conceived the idea for the project. HB, FS, \u0026nbsp;RC, MC, EM, MB, AP, KG, CW, HG, PH and ST contributed to the initial design and development of the project. HB, FS and ST drafted the manuscript and guidance document, and this was revised with input from all authors. All authors have read and approved the final manuscript and guidance document.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank our contributors in the consensus building forums who gave their time to enable this work. Special thanks are due to Dr Darren Dahly who contributed to the initial stages of the project.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; information (optional)\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDesai M. Recruitment and retention of participants in clinical studies: Critical issues and challenges. Perspect Clin Res. 2020;11(2):51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShiely F, Murphy D, Millar SR. Clinical research nurse predictions of trial failure, recruitment and retention: a case for their early inclusion in trial design. 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Trial Forge Guidance 2: how to decide if a further Study Within A Trial (SWAT) is needed. Trials. 2020;21(1):1\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArundel CE, Clark L, Coleman E, Doherty L, Parker A, Torgerson DJ. Challenges and solutions to the implementation of studies within a trial: The experiences of the PROMETHEUS programme. Res Methods Med Health Sci. 2023;4(1):16\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShiely F. Effects of a multi-trial programmable animation platform on the efficiency and success of pre-screening and subsequent recruitment to a randomised trial. Protocol for a Study within a Trial (SWAT). 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BMJ open. 2022;12(3):e057019.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAuthority HR. Publication and dissemination of research findings 2023 [ \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.hra.nhs.uk/planning-and-improving-research/best-practice/publication-and-dissemination-research-findings/\u003c/span\u003e\u003cspan address=\"https://www.hra.nhs.uk/planning-and-improving-research/best-practice/publication-and-dissemination-research-findings/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArundel CE, Clark LK, Parker A, Beard D, Coleman E, Cooper C, et al. Trial Forge Guidance 4: a guideline for reporting the results of randomised Studies Within A Trial (SWATs). Trials. 2024;25(1):183.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Trial methodology, SWAT, Study Within a Trial, methodology guidance, research ethics, Trial Forge","lastPublishedDoi":"10.21203/rs.3.rs-5073175/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5073175/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRandomised trials often struggle with recruitment, retention, and delays, impacting both finances and patient care. To improve trial processes, trialists can do Studies Within A Trial (SWATs) that compare trial process alternatives. Although SWATs are recognized by funders, there are differences in how they are implemented, such as different consent requirements in the UK and Ireland. This complicates SWAT conduct, raises ethical considerations, and highlights the need for standardised, ethical approaches to SWATs. The purpose of the current study was to devise guidance to address this.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe used existing systematic reviews, searched PubMed and the SWAT register, and contacted SWAT teams known to the authors to identify relevant randomised SWATs. We extracted information on any challenges in the SWAT approval process, as well as challenges implementing the SWAT. We held three consensus building forums, all including representatives from nine key stakeholder groups representing a broad range of roles in trials. We presented participants with two SWATs to start conversation on perceived ethical issues. Consensus building forums were recorded, transcribed, and analysed using NVivo, focusing on ethical principles, challenges, and solutions.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe developed guidance on ethical considerations applicable to randomised SWATs. The guidelines cover all stages of a SWAT, from development and SWAT team selection to communication of results.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eStudies Within a Trial are generally perceived to be low risk and low burden to participants. However, there are still variation in ethical standards applied to these studies by researchers, sponsors and ethics committees. In addition, SWATs are uniquely distinct from trials, presenting specific for their ethical conduct. These guidelines will be helpful to anyone planning or reviewing SWATs in understanding these differences and their ethical implications and provide a practical guide for the ethical conduct of SWATs.\u003c/p\u003e","manuscriptTitle":"Trial Forge Guidance 5: ethical considerations in randomised Studies Within A Trial (SWATs)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-15 11:51:32","doi":"10.21203/rs.3.rs-5073175/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2025-02-16T20:55:02+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-12-17T14:21:47+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-25T12:00:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-23T13:48:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2024-09-11T14:48:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"eed87bad-d1aa-4ae8-8cac-c11310770827","owner":[],"postedDate":"January 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-04T16:39:22+00:00","versionOfRecord":{"articleIdentity":"rs-5073175","link":"https://doi.org/10.1186/s13063-025-08958-9","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2025-08-02 16:04:56","publishedOnDateReadable":"August 2nd, 2025"},"versionCreatedAt":"2025-01-15 11:51:32","video":"","vorDoi":"10.1186/s13063-025-08958-9","vorDoiUrl":"https://doi.org/10.1186/s13063-025-08958-9","workflowStages":[]},"version":"v1","identity":"rs-5073175","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5073175","identity":"rs-5073175","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}