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Applying Patient and Public Involvement in preclinical research: A co‐created scoping review

Abstract Background Patient and Public Involvement (PPI) in research aims to improve the quality, relevance and appropriateness of research. PPI has an established role in clinical research where there is evidence of benefit, and where policymakers and funders place continued emphasis on its inclusion. However, for preclinical research, PPI has not yet achieved the same level of integration. As more researchers, including our team, aim to include PPI in preclinical research, the development of an evidence‐based approach is important. Therefore, this scoping review aimed to identify and map studies where PPI has been used in preclinical research and develop principles that can be applied in other projects. Methods A scoping review was conducted to search the literature in Medline (PubMed), EMBASE, CINAHL, PsycInfo and Web of Science Core Collection to identify applied examples of preclinical PPI. Two independent reviewers conducted study selection and data extraction separately. Data were extracted relating to PPI in terms of (i) rationale and aims, (ii) approach used, (iii) benefits and challenges, (iv) impact and evaluation and (v) learning opportunities for preclinical PPI. Findings were reviewed collaboratively by PPI contributors and the research team to identify principles that could be applied to other projects. Results Nine studies were included in the final review with the majority of included studies reporting PPI to improve the relevance of their research, using approaches such as PPI advisory panels and workshops. Researchers report several benefits and challenges, although evidence of formal evaluation is limited. Conclusion Although currently there are few examples of preclinical research studies reporting empirical PPI activity, their findings may support those aiming to use PPI in preclinical research. Through collaborative analysis of the scoping review findings, several principles were developed that may be useful for other preclinical researchers. Patient or Public Contribution This study was conducted as part of a broader project aiming to develop an evidence base for preclinical PPI that draws on a 5‐year preclinical research programme focused on the development of advanced biomaterials for spinal cord repair as a case study. A PPI Advisory Panel comprising seriously injured rugby players, clinicians, preclinical researchers and PPI facilitators collaborated as co‐authors on the conceptualization, execution and writing of this review, including refining the findings into the set of principles reported here.


| INTRODUCTION
Actively involving patients and the public in research is increasingly recognized as necessary to ensure outcomes are relevant and beneficial to the people most likely to be affected by them. This is reflected by increasing awareness of the role of Patient and Public Involvement (PPI) in research. PPI is usually defined as research 'with', or, 'by' members of the public rather than 'to', 'about' or 'for' them. 1 This definition was originally developed by the advisory group INVOLVE, which has since been integrated into the National Institute for Health Research (NIHR). 2 More recently, the NIHR definition of PPI has moved away from separating 'patients' and the 'public', now referring to PPI as public involvement in research. 1 PPI can involve patients at any stage of a research project, from identifying research opportunities to supporting the dissemination of findings to broader audiences. It can also take many forms, for example, patients and the public participating on steering or advisory committees, reviewing study protocols or collaborating as co-researchers. 3 The activities are often mapped to frameworks such as the NIHR research cycle, which describes the stages of research where PPI can be implemented: identifying and prioritizing, commissioning, designing and managing, undertaking, disseminating, implementing and evaluating impact. 1 Researchers who employ PPI in their studies have reported many benefits such as enhanced research quality and appropriateness, and additional impacts including user-focused participant information, enhanced recruitment strategies and improved dissemination of findings. 4 Within clinical research, PPI has become a relatively standard component of research practice. Key stakeholders including funding agencies, regulators and leading journals routinely acknowledge the significant role PPI has to play in improving research and frequently require researchers to provide evidence of PPI in their work. 1,5 In contrast, the role of PPI in preclinical research is less well established.
Preclinical research (meaning basic, fundamental, biomedical, translational or lab-based research) typically takes place in settings far removed from patients and the public and may seem inaccessible or obscure when compared to clinical research. While some suggest PPI may reduce waste, increase value and improve quality in preclinical research, 6,7 others caution that it may be more difficult for patients and the public to meaningfully influence research in this setting. 8,9 This divergence in opinion poses challenges for those exploring the potential for PPI in their preclinical studies. This is further compounded by a limited empirical literature base to guide the selection of applicable PPI approaches or goals. The team was aware of two existing review studies at that time which focused narrowly on specific areas of antimicrobial drug development and genomics, 10,11 but none that mapped empirical preclinical PPI literature across disciplines. Panel members agreed that a scoping review would be useful, and collaboratively developed a protocol for the study. 12 In the intervening period, another scoping review was published that explored patient engagement in preclinical laboratory research. However, this study had a more general aim and broader definition, including engagement and involvement activities, and included secondary as well as primary literature. 13 The research question for this scoping review study was how do researchers incorporate PPI in preclinical research? 12 The aims of this review were to identify and map the current empirical literature on PPI in preclinical research to identify why researchers used PPI, the volume and range of approaches used, the benefits and challenges encountered, the impacts they reported and potential applications for our own PPI strategy. We planned to synthesize the initial findings collectively as a group comprised of PPI Advisory Panel members to ensure that the findings reflected the perspectives of the entire team.
We aimed to use the review findings to inform the development of a PPI strategy tailored for a preclinical spinal cord repair project. Levac et al. 16 and provided the structure for identifying eligibility criteria, refining search strategy, selecting sources of evidence, extracting data, analysing evidence, presenting results and consulting with stakeholders. The review is reported with reference to these JBI guidelines and the Preferred Reporting Items for Systematic Reviews Extension for Scoping Reviews (PRISMA-ScR; Supporting Information: Appendix 1). 17

| Eligibility criteria
Studies were considered eligible for inclusion if they were primary empirical studies involving PPI in preclinical research settings and involved interacting with patients and/or the public directly. Only studies written in English were included due to translation costs and the risk of misinterpretation. No limitations were placed on the study location or date of publication. 'Patient engagement' 18 and 'community-based participatory research' (CBPR) 19 approaches overlap with PPI to a certain degree as they involve patients. However, there are differences relating to the definition, approach, origins and the level of ownership held by researchers and therefore, these were not considered eligible for inclusion. 18,20 Studies describing contact with representative organizations with no direct involvement of patients and/or the public were excluded. While the majority of studies would likely be clearly clinical or preclinical, it was possible that there could be some degree of overlap. In cases where the nature of the research was not immediately clear, the following question was considered: 'Does this research have an immediate clinical application?' If an immediate clinical application was identified, the study was excluded.

| Information sources and search strategy
The search strategy was developed in consultation with a specialist librarian PM who is a co-author of this review. Search terms were determined with input from advisory panel members. Recognizing the variation in terminology used to describe PPI internationally, terms relating to patient engagement and CBPR were included in the search strategy. This ensured that studies including PPI but using different terminology were captured in the search. However, they were excluded at the study selection stage if their approach was not considered to be PPI.

| Article selection
The article selection process is outlined in the PRISMA-flow diagram ( Figure 1). Records identified in the database searches were imported into EndNote and duplicates were removed by P. C. Two reviewers P. C. and M. F. conducted screening and study selection according to JBI guidelines for conducting scoping reviews. 14 In advance of commencing study selection, each reviewer independently screened the titles and abstracts of five articles before comparing the application of eligibility criteria to ensure consistency. Following this, both researchers used Endnote to screen the title and abstract of each record independently before meeting to compare results and ensure consistent application of the eligibility criteria. Discrepancies of opinion regarding studies deemed potentially eligible were resolved through discussion between P. C. and M. F. If consensus could not be reached, a third reviewer F. M. made the final decision. For full-text screening, both reviewers again completed an initial review of five studies before meeting to compare results. Both then independently reviewed the remaining full texts for eligibility, and discrepancies were resolved through discussion or consultation with the third reviewer.

| Data extraction
Two reviewers P. C. and M. F. conducted data extraction using a data extraction form developed in accordance with the JBI guidelines 14 and the study protocol. 12 The following information was extracted for each included study: (1) author(s); (2) year; (3) title; (4) country of origin; (5) the scientific discipline/context of the study; (6) who took part in the PPI component (PPI Contributors); (7) the reason for conducting PPI (PPI Rationale); (8) what researchers sought to accomplish with PPI (Aims of PPI); (9) which PPI approach was used (PPI Format); (10) how PPI was implemented (PPI Methods); (11) stages of implementation according to NIHR 1 ; (12) benefits associated with PPI; (13) challenges associated with PPI; (14) impact of PPI on study; (15) if/how PPI was evaluated; (16) elements with potential application within our preclinical PPI project.

| Narrative synthesis
One reviewer P. C. conducted a narrative synthesis of the findings according to the guidelines set out by Popay et al. 21 No quality assessment was conducted.

| PPI
Three members of the PPI Advisory Panel are PPI contributors and were involved in the project from the beginning, including project planning and protocol development stages. 12 Completed data extraction forms were circulated to PPI Advisory Panel members in advance of a scheduled meeting. The extracted data were discussed in terms of themes/trends identified by the patient partners and other panel members, aspects relevant to the spinal cord repair project, and aspects relevant to preclinical PPI more generally.
Perspectives were captured using a digital whiteboard, synthesized afterwards by P. C. and M. F., and incorporated into the discussion.

| Study characteristics
A total of 12,087 studies were identified through database searching.
Duplicates were removed and studies underwent title and abstract screening to eliminate studies that did not meet the inclusion criteria.
After this process, 54 studies remained for full-text review. After the full-text screening, nine studies were included in the final review ( Figure 1). Key characteristics of the included studies are summarized  23 Two studies were in the context of medical device development, 23,27 one in drug development, 29 one in translational rheumatology research, 22 one in asthma research, 26 one in vaccine development, 28 one in microbiology research, 24 one in autism research 25 and one in psychiatric genomics research. 30

| Rationale and aims for including PPI
The authors of the included studies discussed several rationales and aim for including PPI ( Sohy et al. 28 Outside in-inside out. Creating focus on the patient-a vaccine company perspective Belgium Vaccine development Employees at a vaccine production company.
Encouraging vaccine producers that they are vaccine 'patients' so that they can better provide input into the vaccine production process as patients rather than solely as producers. To promote the understanding that employees in a vaccine company are themselves 'vaccine patients', and to create a bridge between employees' day-to-day activities and their impact on patients.
Chalasani et al. 29 Enhancing Elberse et al. 27 Researchers and patients developed a report in collaboration with an independent advisory group that provides advice regarding public health policy to a national Minister for Health. In the report, patients articulated needs and outlined a research agenda for medical products regarding their conditions. This report was presented to the Minister for Health to inform a national research agenda for medical products.
None reported. Researchers considered building relationships in the early stages of research important for collaborating with PPI contributors throughout the project. Researchers also found it beneficial to involve patients, carers and healthcare providers in PPI, due to their knowledge and experiences of particular conditions.

Baart and Abma 30
Researchers and patients jointly submitted an action paper containing a series of recommendations for improving communication and interaction between researchers and patients, for example, redesigning the group website to make it more accessible for patients, using conferences to interact with patients and families, jointly hosting researcher/patient workshops and collaborating on publications.
None reported.
Researchers seeking to incorporate PPI should start by identifying areas of common interest between researchers and patients. Identifying common ground can serve as a basis for developing/strengthening relationships between groups of stakeholders.
Sohy et al. 28 PPI had many impacts including hosting patient-focused webinars for employees, panel discussions between researchers and patients, sending employees on visits to developing countries to see the impact of vaccines they produce and including patient-focused sections in research publications. Two studies employed PPI to meet funding body requirements. 29,30 In one study, preclinical researchers were directed by their main funding body to improve their level of interaction with patients as a prerequisite for further funding. 30 Initially, researchers described the idea that patients could be involved in preclinical research as 'impossible' and 'new-fangled nonsense'. However, they responded to this requirement by implementing a PPI programme that aimed to facilitate dialogue between scientific researchers and patients; increasing the knowledge base of the research team. Directives from national funding bodies also provided the rationale for another study, which aimed to obtain patients' perspectives on specific diseases and their currently available treatments. 29 In this study, researchers conducted PPI to ensure that patients' voices were Researchers also reported incorporating PPI to receive public input for guiding specific research projects/project outcomes. In one study, researchers conducted PPI aiming to obtain feedback on the appropriateness of a pharmaceutical research agenda for autism. 25 This was done to ensure that those potentially impacted by the outcomes of their research would have their voices represented, and would be provided with the opportunity to comment on its suitability. In another study, preclinical researchers met with patients to discuss the recruitment of PPI panel members. Researchers reported that it is more difficult to recruit PPI panel members for a preclinical research study. Therefore, meeting with patients and receiving input on the recruitment process helped design a more participant-friendly recruitment strategy for a PPI panel. 24

| Volume and range of PPI approaches
Preclinical researchers employed a variety of formats when conducting PPI (Table 3). Included formats were described as panel meetings, 29 workshops, 23  Another approach used by preclinical researchers seeking to incorporate PPI was PPI Advisory Panels. 26,30 One study on identifying biomarkers in respiratory disease used a PPI Advisory Panel, describing their approach as a 'Patient Input Platform'. 26 In this approach, patient organizations were invited to provide input into a grant proposal for the research project. Patients from these organizations were then included on multiple boards overseeing the work of the project, provided feedback on project progress and acted as collaborators with researchers on project design and dissemination strategies. 26 Researchers also conducted PPI by hosting meetings to gather input from patients. In these meetings, patients were invited to attend and provide feedback to researchers regarding their research agenda. In one study, researchers aiming to recruit a PPI panel held an open event for prospective PPI panel members to meet the research team and ask questions about the role of the panel members without committing to join. 24 In another study, a public meeting was held for people with autism, their friends and family, and people who worked with children or adults with autism. Researchers presented a promotional video describing a pharmaceutical research agenda for autism, and attendees were invited to submit feedback at the meeting or via email, to voice their opinions regarding its suitability. 25

| Benefits and challenges
The incorporation of PPI resulted in many benefits for preclinical researchers (Table 3). In one study, preclinical researchers reported improved communication skills after building relationships with PPI contributors throughout their research project. 22 Moreover, building such relationships resulted in further research opportunities which may not have come about without PPI. For example, in one study, researchers conducting PPI were invited to visit patients' homes to observe how they manage their conditions. 23 Other researchers reported that by conducting PPI with employees in a vaccine production company, staff saw opportunities for enhanced engagement such as nominating an employee to represent patient interests at company meetings. 28 PPI also benefited studies by connecting preclinical researchers with the needs of patients, potentially strengthening understanding and improving research relevance. One study reported that PPI identified areas of common ground between researchers and PPI contributors, which served as a basis for discussion and exchanging knowledge. 30 Empowerment and motivation were also benefits of conducting PPI. One study reported PPI contributors feeling empowered from contributing to the PPI process. 27 Becoming involved in research, sharing their experiences and seeing a tangible impact from their input resulted in PPI contributors identifying value from their experiences. 27 Similarly, researchers were motivated by their interactions with PPI contributors when faced with difficulties in their scientific research. 26 Studies also reported several challenges. One challenge was that PPI contributors might not represent the diverse set of views held by patients. Seven studies reported this challenge. 22,24-28,30 PPI contributors were typically self-selected to become involved in research, meaning they may not represent the viewpoints of a typical patient or member of the public but rather reflect the views of one already interested/involved in a particular aspect of the research programme. 22,24 One study refers to this as 'selective PPI' where only a limited/sympathetic viewpoint is included. 25 Similarly, researchers who included an evaluation study reported the representativeness of the PPI contributors was a limitation of their work. 22,28 Researchers also considered PPI as time and resource-intensive. 24,29 Another barrier to preclinical PPI was a lack of training and awareness of PPI methodologies. 24,25 Two studies reported difficulty in persuading researchers of the merits of PPI for preclinical research due to concerns around the ability of PPI contributors to provide a tangible impact on scientific research. 26,30 Other challenges for preclinical PPI included contributors becoming unwell, 23 and the suitability of PPI for preclinical research projects which progress slowly and require a long commitment from contributors. 26,30

| Impact and evaluation
A number of impacts were reported in the studies included (Table 4). In one study, researchers reported that PPI directly influenced their funding application and recruitment strategy for participants to provide biological samples for testing by preclinical researchers. 26 Another impact of PPI on preclinical research was by shaping research agendas, with five studies reporting this as an impact. 23,25,27,29,30 For example, two of these studies used PPI to articulate patient priorities and develop research agendas for medical products. 23,27 Finally, one group reported that PPI impacted their study by developing a series of initiatives designed to improve patient/ researcher interactions such as patient-focused webinars, panel discussions between researchers and patients and the preparation of patientfocused sections in research publications. 28 Only two studies reported formal evaluation of their PPI. 22,28 In one study, staff of a pharmaceutical company producing vaccines were surveyed (n = 743). The majority reported understanding the purpose of the PPI initiative (72%) and that it improved patient focus among researchers (65%), and 90% reported understanding the realworld impact of their work. 28 In another study, surveys designed in collaboration with PPI contributors were distributed to researchers (n = 15) and PPI contributors (n = 6) to collect feedback evaluating impact. All PPI contributors felt they had a positive impact on the research, and 73.4% of the researchers agreed. 22 No other included study conducted a formal evaluation.

| Learning opportunities for PPI in preclinical research
Included studies contained several key lessons that may be applied to PPI for preclinical research (Table 4). Researchers considered building relationships as a key enabler for preclinical PPI. 24,27,30 Due to its long-term nature, this was seen as particularly relevant for preclinical research. 27 According to one study, researchers established relationships with PPI contributors by finding areas of similar scientific interest. This served as a basis for further discussions around involvement. 30 Other considerations for relationship building were that it was most impactful at the early stages of research, 26 and that a good relationship between researchers and PPI contributors improved the quality of PPI contributions to the research. 24 Implementing PPI training was another learning point from the included studies. Two studies reported that training should be implemented for preclinical researchers conducting PPI. 22,24 One study, which evaluated their PPI, found that both researchers and PPI contributors would have preferred more training. 22 Due to their limited level of interaction with patients generally, this was identified as particularly relevant for preclinical researchers. 22,24 Specifically, researchers in one study recommended that PPI training be integrated into basic training for research students. 22 Providing PPI contributors with feedback on project progress was also important as described by three featured studies. According to the evaluation of one study, PPI contributors wanted feedback on their impact on research activities. 22 In another study, researchers reported that providing regular project feedback improved PPI contributors' understanding of the research cycle. 26 One study achieved this by publishing a summary of outputs in collaboration with PPI contributors to demonstrate the impact of PPI on their work. 29 Researchers also reported that the selection of PPI contributors was an important consideration factor.

| Limitations
This review contains some limitations. First, while this study examined preclinical research studies which used PPI, two studies could be better described as reflections by preclinical researchers on their use of PPI. 24,25 Therefore, it was difficult to compare these studies with other studies containing dedicated PPI components. However, it was important to include these studies as they describe interesting cases of preclinical PPI, and provide valuable context for researchers learning about its application. Secondly, the search strategy may have missed some studies regarding PPI. The terminology surrounding PPI remains somewhat contested, with the ongoing debate on what constitutes PPI, patient engagement, CBPR, co-production and a series of other terms describing involving patients in research. 34 While the search strategy aimed to capture as much PPI literature as possible, and an updated search was conducted in August 2021 to capture updated search terms, some eligible studies may have been missed. Subsequent to our planning and completion of this review, specific JBI guidance on involving knowledge users has been published. 35 We involved the PPI Advisory Panel members in most elements of the study, but not the screening and data extraction steps. It may be possible to further deepen involvement in future reviews by involving PPI Advisory Panel members in all stages as per the recent JBI guidance.