Time to STEP UP: methods and findings from the development of guidance to help researchers design inclusive clinical trials

Abstract

Background

It is important to design clinical trials to include all those who may benefit from the intervention being tested. Several frameworks have been developed to help researchers think about the barriers to inclusion of particular under-served groups when designing a trial, but there is a lack of practical guidance on how to implement these frameworks. This paper describes the ACCESS project, the findings from each phase of the project and the guidance we developed (STEP UP) on how to design more inclusive trials.

Methods

Development of the STEP UP guidance had five phases: (1) Scoping literature review, (2) ‘roundtable’ discussion meetings, (3) redesign of trials, (4) interviews and (5) guidance document development, with input from public contributors and the ACCESS team.

Results

Over 40 experts contributed to the ACCESS project—patients and the public, clinicians, NHS research staff, trialists and other academics. The scoping review identified several strategies being used to improve inclusion, mostly around recruitment settings, but there was little evaluation of these strategies. The ‘roundtable’ discussions identified additional strategies being used across the UK and Ireland to improve inclusion, which were grouped into: Communication, Community engagement, Recruitment sites, Patient information, Flexibility, Recruitment settings, Consent process, Monitoring, Training for researchers and Incentives. These strategies were used to redesign three existing trials by applying one of the three INCLUDE frameworks (ethnicity, socioeconomic disadvantage, impaired capacity to consent) to one trial each, to produce the key recommendations for the guidance. Issues around implementation were explored in stakeholder interviews and key facilitators were identified: funders requesting information on inclusion, having the time and funding to implement strategies, dedicated staff, flexibility in trial protocols, and considering inclusion of under-served groups at the design stages. The STEP UP guidance is freely available at http://step-up-clinical-trials.co.uk.

Conclusion

Researchers should consider inclusivity to shape initial trial design decisions. Trial teams and funders need to ensure that trials are given both the resources and time needed to implement the STEP UP guidance and increase the opportunities to recruit a diverse population.

Plain Language Summary

Randomised clinical trials compare one or more treatments to another to see which ones work best. Trials don’t always include people or groups who might benefit from the results: those excluded are sometimes called ‘under- served groups’. Recent work has shone a light on this and now researchers are being asked by the public, trial funders and others to design their research so that under-served groups are more able to take part.

We worked on a project to find out how to make sure everyone can be part of clinical trials. We looked at published work and held five online meetings with researchers, doctors, and patients to see what was being done already, and to think of other things that could help under-served groups take part in trials. Three groups of people, including scientists, patients, doctors and other NHS workers then  used this information to redesign three older trials using some existing inclusivity frameworks to think through the barriers for under-served groups in these trials. The three groups then talked through these trials at a 2-hour meeting, suggesting changes to the original trial plan, and discussed whether the suggestions were practical and useful. From this we came up with recommendations for how to design trials so that they have fewer barriers for under-served groups.

We interviewed people to find out the best way to put these things into practice and talk through any practical issues. Using all of this information: the recommendations and what came out of the interviews, the study team created some guidance – ‘STEP UP (Strategies for Trialists to promote Equal Participation in clinical trials for Under-served Populations)’ – for people working in trials.

Background

Research shows that participants in clinical trials are often unrepresentative of the populations that could benefit from the treatments being investigated. To help to address this, the National Institute for Health and Care Research (NIHR) INCLUDE project [1, 2] was initiated in 2017 to look at under-representation in clinical trials. It identified a range of under-served groups, which can vary across the types of studies, disease or condition being studied. This has  prompted funders and trialists to make efforts to improve the recruitment and retention of under-served groups by thinking about the way trials are designed. There has been extensive work around improving recruitment and retention to trials which may be useful in improving the recruitment and retention of under-served groups, but they did not focus on under-served populations [3,4,5]. To help researchers design more inclusive trials, there are currently three INCLUDE Frameworks [6,7,8], each aiming to support researchers to think carefully about their trials with ethnicity, people with impaired capacity to consent, and people experiencing socioeconomic disadvantage in mind. The Frameworks guide discussions around which groups of people the trial results should apply to, and how the design of the trial and the intervention might make it more difficult for any group to take part. The INCLUDE frameworks help researchers (alongside clinicians, patients and the public) to consider how elements of the trial might facilitate diverse recruitment, or create barriers and make amendments to their design accordingly.

The ACCESS project

The Medical Research Council-NIHR-Trial Methodology Research Partnership (MRC-NIHR-TMRP) Inclusivity Working Group identified that guidance on how to overcome some of these barriers to inclusion was needed. A collaborator group was formed through the TMRP working group and the UK Clinical Research Collaboration (UKCRC) network and we set up the ACCESS project (‘A collaborative study to identify the activities needed to improve representation of under-served groups in trials and understand their implementation’ – https://www.sheffield.ac.uk/ctru/completed-trials/access) funded through the NIHR CTU trial efficiency funding programme. Although there was no patient or public involvement (PPI) contributor in the ACCESS team we sought PPI throughout the project, including the development of the guidance. The ACCESS project aimed to identify how trials can be designed to make them more accessible to under-served groups.

The STEP UP guidance

This paper describes the process used to develop the STEP UP (Strategies for Trialists to promote Equal participation  in clinical trials for Under-served Populations) guidance for trialists (http://step-up-clinical-trials.co.uk). The guidance has been developed to help trial teams design trials that are more accessible to a wider range of people, including under-served groups [1]. It can be used in conjunction with other resources and guidance that aims to improve inclusion in trials such as the INCLUDE frameworks [6,7,8], or Equality Impact Assessments [9].

Developing the STEP UP guidance

Five phases made up the ACCESS project with input from the ACCESS collaborators throughout (Fig. 1); a full protocol can be found on the project website. Ethical approval for phases 2–4 was given by the School of Health and Related Research (ScHARR) Research Ethics Committee (REC) in January 2022 (Reference: 043869). Participants in all stages of the ACCESS project were invited through the ACCESS team’s contacts and networks, emails to distribution lists for trialists, and advertisements through the NIHR’s People in Research website (https://www.peopleinresearch.org). PPI members and interviewees were reimbursed for their time in line with the NIHR payment guidance [10]. Contributors at each phase are detailed in appendices (Appendices, Table 1).

Fig. 1

ACCESS project phases

Phase 1: Scoping review (October 2021-January 2022)

Methods

We conducted a scoping review of methodological research studies from the UK and Ireland to identify effective activities to improve representation of under-served groups in trials [11]. We focused on minoritised ethnic groups, socioeconomically disadvantaged groups, older people, and those with impaired capacity to consent, published between 2000–2021. These groups were chosen in line with the existing INCLUDE frameworks [6,7,8] and current work in the area [12]. Systematic searches were conducted in November 2021 using the PubMed database. Data were independently extracted by two authors (CD and KB) and narratively synthesised. The methods and findings from the scoping review have been previously reported in full [11].

Findings

Strategies

We identified seven papers discussing strategies for improving inclusion [13,14,15,16,17,18,19]. We grouped the strategies they discussed into nine domains based on a previous review of strategies (without evaluation) in this area [20]: Recruitment sites; Recruitment settings; Community engagement; Patient documentation; Communication between study team and participants; Flexibility; Incentives; Inclusion criteria; Consent process. The most common domain mentioned across the papers was the recruitment setting, with a broad range of recruitment venues reported.

Evaluation

Although some activities appeared promising in engaging under-served populations, there was little evaluation of the effectiveness of these activities on recruitment or retention of under-served groups. Formal evaluation showed a monetary incentive mentioned in an invitation letter improved positive responses overall, but not for older people or people experiencing socioeconomic disadvantage [13]. Comparisons of recruitment pathways indicated that letters from GPs were the most successful method in recruiting older populations [15, 21], but other methods might be better for recruiting socioeconomically or ethnically diverse participants [15].

Recruitment via community organisations, and via snowball sampling were reported as successful by the authors for recruiting South Asian participants [16], and talks in community venues for recruiting more diverse participants [15]. Using mixed methods, Jayes and Palmer [18] found that the Consent Support Tool (CST) successfully identifies the appropriate information to give the participant based on their aphasia and can be used in the trial consent process. Only two trials reported retention data [17, 21], with retention rates being 85% or higher in both. Kolovou et al. [17] used strategies around communication, flexibility in follow-up visits and incentives to maximise retention, and Forster et al. [14] reported that their £100 incentive may have helped with retention rather than recruitment as it was mentioned after recruitment.

ACCESS team input

A collaborator meeting was held to discuss the findings of the scoping review, to plan the format of the roundtable meetings and to identify possible contacts and networks for participants. Suggestions were made based on knowledge of other projects being conducted with the aim of improving inclusion in trials across the UK and Ireland.

Phase 2: Roundtable Discussions (3rd, 7th, 18th, 25th and 28th March 2022)

Methods

We had five online ‘roundtables’ with a total of 30 attendees (4–8 attendees per meeting) including trialists, recruiting staff, clinicians, and PPI contributors. The meetings were approximately two hours long and started with a presentation of the scoping review findings, we then facilitated an open discussion guided by the domains from the review. Activities discussed by the attendees were added to a ‘Jamboard’ during the meeting (Appendices, Fig. 1), and all participants were given the opportunity to comment on these during the meeting. The ‘Jamboards’ and notes taken by CD and KB during the meeting were combined to produce a list of suggested strategies (Table 1).

Table 1 Activities to support more inclusive trials identified by participants attending the roundtables

Findings

While roundtable discussions identified more activities aiming to promote inclusivity in trials compared to the scoping review, a gap remains in evaluating their effectiveness. Barriers to evaluation highlighted by participants were the tight deadlines in research, and the importance of recruitment, where researchers want to do everything that they can to improve recruitment, so all available strategies are adopted, implemented and usually not tested.

Several common items were discussed across all meetings. Simple language, clinician/researcher attitudes and communication with participants, and community engagement were considered important throughout. Table 1 summaries the strategies mentioned by participants at the five roundtables, ordered according to the most commonly discussed themes across the roundtables.

The importance of intersectionality was highlighted in all roundtables, where several PPI contributors considered themselves to be part of more than one under-served group. There were discussions around socioeconomic disadvantage being linked to other under-served groups, such as ethnic minorities, stigmatised populations, people with disabilities and/or mental health conditions, people in alternative residential circumstances, and that the intersection of these identities can result in health inequalities. This can create additional barriers to participating in trials, and highlighted the need for trialists to consider more than one under-served group in their trials in order to be inclusive.

Attendees had different preferences in relation to several elements of trial design. For example, in relation to the methods used for advertising the trial, some people preferred finding out face-to-face via their healthcare provider, others preferred letters from the GP, or advocated for using social media. Different consent and data collection methods were suggested for different groups. For example, some people suggested that older people might prefer a visit, and talking through the documents to remote forms of consent, but that remote data collection might be preferred to reduce clinic visits for those with less time. It is also important to note that members of an under-served group are not homogenous and can have different preferences, and that more than one method is needed across the trial stages to avoid excluding people.

Roundtable attendees also highlighted the importance of other organisations’ support in making trials more accessible. It was noted that research ethics committees (RECs) have a role to play in requesting that researchers explain how they will recruit a diverse population in the same way that they require details on other parts of the recruitment process, and more recently PPI. There appears to be variation in RECs and there was a suggestion that REC members may benefit from training around inclusion. Funding and timelines are likely to be increased when aiming for diverse populations, and pressure on recruitment timelines was reported as a barrier for researchers in doing these activities, therefore support from funders is necessary.

ACCESS team member input

ACCESS team members discussed the inclusion activities suggested at the roundtables and were reassured that a lot of the same suggestions were coming up across the five roundtables and from different stakeholders. ACCESS team members suggested looking at the demographics of the meeting attendees to see if suggestions varied by the different demographic groups. The main difference in content was the under-served groups discussed at the meeting, but the suggested implementation strategies did not differ (see appendices, Fig. 1), e.g., engagement with communities for research processes and clinical trial education, using various recruitment settings, using simple and inclusive language, appropriately trained staff and making sure PPI is appropriate and includes people from under-served groups. The ACCESS team discussed using different recruitment settings in a trial, which led to discussion around the focus of the research question, as this often determines the setting that the population can be recruited from as community-based recruitment may be less successful for studies focussing on a particular clinical population. For example, surgical trials can often only recruit those on the waiting list for that particular surgery, and cannot recruit via community groups. It is for funders and researchers to consider the scope of the research question carefully, and how this might exclude people with poor healthcare access. ACCESS team members discussed the existing pressures to recruit, which often override efforts to recruit a more diverse sample and agreed that efficiency of recruitment should be considered in light of having a more inclusive sample.

ACCESS team members decided the types of trials to be selected for the next phase of the project. To ensure a broad range of contexts were considered, it was decided that one should involve primary care as this came up a lot in the roundtable meetings, one should involve a care home as there are additional considerations around older people and mental capacity, and one should be a drug trial as that may involve additional safety and regulatory issues.

Phase 3: Redesign meetings (June 2022-October 2022)

Methods

We had three online meetings including several stakeholders (see Table 1 in appendices) to theoretically redesign three completed trials that ran in the UK and were funded by the NIHR. Three trials were chosen (Table 2) to cover different types of intervention and conditions (drug trial in diabetes, therapy for depression, and a care home occupational therapy trial for stroke) which enabled focus on different under-served groups: Ethnic minority communities, older people, socio-economically disadvantaged groups, and people with impaired capacity to consent. Prior to each meeting the study team went through an INCLUDE framework relevant to the trial, making suggestions based on the scoping review and roundtable findings, and these were reviewed by ACCESS team members. These suggestions were organised around four key questions in the INCLUDE frameworks, and elements of trial design, and circulated to attendees one week before the meeting to review in advance if they wished. Due to the time allocated for the meeting, and to reduce the burden for attendees, we did not share the patient information materials and so did not discuss these elements in detail during the redesign meetings. We had limited information on some elements of the trials, such as PPI involvement, but these were still discussed, and suggestions made where appropriate.

Table 2 PICO for trials and INCLUDE framework used for theoretical redesign

Each meeting started with a 10-min presentation on the ACCESS findings so far and the INCLUDE framework key questions, and then went through the elements of the trial. We presented the ACCESS team suggestions, allowing participants to discuss freely and make additional suggestions. KB presented the findings and suggestions, and chaired the meetings and a research assistant took notes (CD or KH). Discussion started with thinking about the population that should be included in the design and considered the eligibility criteria, which helped to think about the other elements of trial design as per the INCLUDE frameworks.

Trials and frameworks

Findings

Table 3 details the suggestions made by the ACCESS team based on previous phases of the project, and comments and suggestions from the stakeholders at each meeting. There were several common elements redesigned in each meeting, and some similar considerations, even though the focus was on different populations, under-served groups and included stakeholders with different experience.

Table 3 Redesign recommendations by trial element and by trial

ACCESS team member input

There was at least one member of the ACCESS team at each of the redesign meetings and all recommendations for redesigning the trial were presented to the ACCESS team members at a further meeting. We discussed potential implementation issues, and how some of the recommendations could be operationalised in the guidance.

In relation to who should be included in the interviews to discuss implementation issues, we agreed to include trialists that had not been included so far, and people who were involved in the roundtables who had relevant trial experience. ACCESS team members discussed the need to focus on more than one under-served group in the discussions so that the guidance could cover wider aspects of trial design.

Phase 4: Interviews and ACCESS team member meeting on implementation (December 2022-March 2023)

Methods

To explore the implementation of inclusive trial designs, we conducted 15 interviews with CTU staff, clinical trialists, community experts and researchers with experience of including under-served groups in heath research. We then held an ACCESS team member meeting to discuss issues around implementing these activities.

We explored interviewee experiences in implementing activities aimed at improving representation of underserved groups, determined if they were successful, and we focused on the facilitators and barriers to their implementation.

Findings

The key implementation issues identified in the interviews and the ACCESS team member meeting (and throughout the ACCESS work-packages) are presented in Fig. 2. During each ACCESS work package, the project team took notes of the barriers and facilitators as they were discussed in relation to each recommendation. In addition, each interviewee provided some barriers and facilitators in line with the recommendations that they had experience of. These are presented in Table 4 below and were grouped to provide the facilitators and barriers in Fig. 2.

Fig. 2

Facilitators and barriers to implementing strategies to improve inclusion identified in interviews

Table 4 Table of key recommendation and implementation considerations

ACCESS team member input

Following interviews, we had a collaborator meeting to specifically discuss implementation issues based on the ACCESS team’s knowledge and experience. Table 4 presents the key findings on implementation from the roundtable and redesign meetings in relation to the key recommendations, from the interviews and from the ACCESS team member implementation discussion.

To present the guidance the ACCESS team agreed on an infographic to highlight the main recommendations and a full report of the findings.

Phase 5: Development of the STEP UP guidance

Findings complied into guidance document (April–May 2023)

KB combined all the ACCESS findings into a guidance document, starting with the key recommendations from the redesign meetings and incorporating the findings on implementation.

Review of guidance (April 2023)

ACCESS team member input

The ACCESS team reviewed and commented on the first report, with the main feedback that it needed to be streamlined and more focussed to make it more accessible. They also reviewed all document drafts throughout the guidance development and provided resources and examples for the guidance.

Deep End PPI panel meeting

The Deep End PPI panel (https://sites.google.com/sheffield.ac.uk/dera/home/dera-ppi-group) is a diverse group of PPI contributors from GP catchments in the most deprived areas of Sheffield. KB attended a Deep End PPI panel to go through the guidance and discuss the panel’s feedback. The panel thought it was a useful and important piece of work. All panel members liked the recommendations, and the panel thought that ‘using simple language’ was the most important thing for researchers to work on. They expressed that a lot of the recommendations were obvious to them and wondered why trials were not being done that way already. The panel members were keen to hear the results and wanted to share the website and recommendations with other research teams they were working with.

Developing the STEP UP guidance website and other materials (March-November 2023)

KB contacted a creative healthcare agency (COUCH Health) in March to discuss the possibility of working with them to create a website and other dissemination materials. We discussed the project, the findings and they proposed making a report, a website and an associated infographic. KB initially sent the project details, and following the ACCESS team member and PPI feedback, sent the full report of findings.

COUCH Health initially suggested names for the guidance that represented the final version of the guidance (as opposed to naming it after the ACCESS project), this was reviewed by the ACCESS team and ‘STEP UP’ (Strategies for Trialists to promote Equal Participation in clinical trials for Under-served Populations) was decided on. They then developed an initial outline, and two drafts of the report and an infographic, all of which were sent to the ACCESS team for review, as well as the mock up website. This was finalised and produced by the company in November 2023.

Discussion

The guidance

The guidance can be found online (http://step-up-clinical-trials.co.uk) and is split into 6 sections: Recruitment and setting, Stakeholder engagement, Communication, Flexibility, Researcher training and hiring strategies, and Data collection. There are specific recommendations for designing trials in each section, and includes comprehensive and practical advice for implementation. Clinical trials are embedded in multiple layers of context, and as such trialists should think about community level factors, and the setting of the trial or the included population which may limit the inclusion of some groups. Although our scoping review focussed on four under-served groups, more groups were included during the other stages of the project and each trial will need to consider the included trial population and the under-served groups relevant to them, which can vary across trials and settings. As noted in our discussions around implementation, this can be a difficult task as information about the population is not always readily available, but discussion with clinicians working in the area, and the use of routine data [23] are potential methods of identification.

Although this guidance was developed for a UK and Ireland setting, we think much of the considerations could translate to other countries and settings. We included input from experts and PPI contributors who come from other countries and/or are UK immigrants, but they would not necessarily know the clinical trial landscape in their home countries. Although we are unsure of the availability of funding to resource these recommendations, particularly in Low- or Middle- Income Countries (LMICs) settings, we do think trialists in other countries could use the recommendations as well. Whilst the barriers and solutions to improving inclusivity in clinical trials are likely to be context-specific, the underpinning principles in this guidance may be transferable to other international contexts. For example, determining the appropriate trial population, engaging the right stakeholders, enhancing communication, and reducing the overall burden on potential participants through flexible recruitment, data collection methods, and reimbursement would be beneficial for researchers globally. Additionally, providing relevant training on equality, diversity, and inclusion tailored to each country's context could help researchers address issues related to minority populations in their regions.

There are many wider systemic issues that affect the inclusion of under-served groups, including resource limitations and a lack of monitoring and reporting of diversity in trial populations. These complex issues require addressing at multiple levels. This practical guidance is intended for researchers when making decisions at the design stage of a trial.

Using the guidance

We encourage trial teams to use this guidance to change the way they have been designing trials to increase the inclusivity of their trials. Relevant resources are listed in the guidance, and there is a section on the Trial Forge website around improving inclusivity in trials (https://www.trialforge.org/trial-forge-centre/diversity/). By using the guidance in the early stages of designing a trial, the trial can be costed appropriately, and protocols can incorporate the strategies that may help in the recruitment of under-served groups. Our identification of the implementation issues can help to plan and manage the strategies recommended. To make the recommendations more accessible for people designing trials, we have produced an infographic which is available on the website and included in supplementary material highlighting the key considerations. In addition to being used in the design of trials, these recommendations may need to be monitored and there may be a need for amendments during the management of a trial.

It is important to note that there are relationships between factors of recruitment, study engagement, and retention that may be at play, and efforts to improve recruitment may impact on engagement and retention which should be considered.

Limitations

Although there was little methodological evidence identified in the scoping review, we have identified strategies/activities to support more inclusive trials through working with a wider range of members of trial teams and patients and the public. To determine their effectiveness, evaluation will be needed.

The funding for this project was limited and so we had to make some decisions around the best way to use this resource. In relation to the scoping review, the search was limited to one database (PubMed) and we focussed on methodological evidence from the UK and Ireland and focussed on four specific under-served groups. This search could have been widened to include other under-served groups, and evidence from outside the UK and Ireland, but we thought the searches would lead to too many papers to sift through in this project, and the aim was to produce guidance for researchers in the UK and Ireland.

We involved a wide range of stakeholders in the research but we did not ask for detailed background from our PPI contributors and therefore do not know if there was representation from, for example, gender minorities or LGBTQAI + individuals. From the information provided by contributors, we had representation from people with multiple chronic conditions, serious mental illness and mental health conditions. We did not seek to include experts from other areas that may have been useful, such as sociologists, political scientists or economists, though we did include patients and the public, clinicians, NHS research staff, trialists, trials methodologists, and an interdisciplinary group of academics with other sources of substantive expertise. Two of three chosen trials had representation from the original trial team. Although this may have led to us not knowing about specific implementation issues for one trial, this was a theoretical ‘redesign’ and implementation issues were readily discussed in each meeting.

The future

During the project, we identified activities and strategies being used to support more inclusive trials, but these were not necessarily being shared widely. Reporting these approaches will help to diffuse good practice amongst trial teams. It would be helpful for trial teams to report on the implementation and effectiveness (i.e. do evaluations) of the strategies being used to try to improve inclusion of under-served groups, and CTUs may need to support site staff to do this. However, some of these recommendations may not lead to increased recruitment but will increase the level of understanding and improve the decision making for a wider range of potential participants, which could ultimately aid retention. This is an important ethical consideration and perhaps a moral obligation as well.

Evaluating the recommended strategies.

Several strategies recommended in the guidance can be evaluated through a ‘study within a trial’ (SWAT), and SWATs aiming to improve the recruitment or retention of under-served groups are a priority for the Trial Forge SWAT Network. There are existing SWATs in the SWAT repository (https://www.qub.ac.uk/sites/TheNorthernIrelandNetworkforTrialsMethodologyResearch/SWATSWARInformation/Repositories/SWATStore/) relevant to activities suggested in the guidance and could be adapted to focus on under-served groups and existing SWATs looking at the use of videos (e.g. SWAT 15) and translated videos (e.g., SWAT 205), that can be adapted for use in other trials.

QuinteT Recruitment Intervention (QRI) methods [24] aim to optimise recruitment and informed consent in randomised controlled trials (RCTs), and these could be adopted to make improvements to the recruitment of under-served groups.

Translation was considered an important topic for evaluation as CTUs are including costs for this at present, and we are not sure of the impact of this. The first step to this could be to survey CTUs on their current use of translation and interpretation, and assessing whether this improves recruitment of ethnic minorities.

Across the ACCESS project, there was a recommendation to simplify the language used, and to make sure staff communicate appropriately to improve trust, understanding, acceptability and recruitment, but there is a gap in research relating to ‘recruitment conversations’ in relation to under-served groups.

CTUs are introducing strategies to improve recruitment of under-served groups, and evaluations of these strategies need to be conducted to ensure we are making the right changes to trials, and ultimately widening the inclusion to trials.

Conclusion

We created the STEP UP guidance to help trialists design trials that are more inclusive. The guidance was developed with ethnic minorities, older people, people with impaired capacity to consent, people experiencing socioeconomic disadvantage, people with physical and mental health conditions, and other under-served groups in mind, and we hope the recommendations (where possible) will be applied across all trials and populations, making trials more accessible to not only the groups we focused on, but to other under-served groups too.

Supplementary Information.