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Beyond recruitment: good participatory practice enhances the impact of research in a pandemic In a health emergency, clear, two-way communication between researchers and a broad spectrum of stakeholders is essential to establishing trust—a prerequisite for meaningful uptake of new treatments and vaccines. Barthalomew Wilson, Katharine Wright, Robert Taylor and Elizabeth Higgs

rust is crucial to the medical research Good participatory practice: layers of trial stakeholders enterprise. Absence of trust in Tresearch and researchers—whether Trial participants among the medical establishment, potential Community: family, friends, schools, colleagues, peers, trial site staff, local religious institutions, traditional participants, or the wider public—can Trial participants leaders, elders, youth groups, women’s groups, faith- disrupt and delay the conduct of studies. Community based leaders, local healthcare service providers, local Of greater consequence in a pandemic, stakeholders hospitals it can have a negative effect on the public Broader Broader stakeholders: Local NGOs, local policymakers, acceptability and, hence, the uptake stakeholders local media, medical professionals, broader healthcare providers, local universities, foundations, funders of research results, including the new National treatments and vaccines needed to respond stakeholders National stakeholders: national NGOs, national effectively to novel pathogens. Lack of scientists, parliamentarians, ministries of health, media, regulatory bodies, ethical review committees, funders, trust, in other words, risks undermining Regional, sponsors global the fundamental rationale for undertaking stakeholders Global stakeholders: international NGOs, trial sponsors research in the first place. and networks, WHO & UNAIDS, international In the case of a global pandemic such as organizations COVID-19, lack of trust has consequences— for the people who refuse novel Fig. 1 | The multiple layers of stakeholders in clinical research; researchers tend to pay too much interventions because they lack confidence attention to the two outer circles and not enough to the three inner circles. NGOs, non-governmental in the process by which they have been organizations; WHO, World Health Organization; UNAIDS, Joint United Nations Programme on HIV/AIDS. developed, and for everyone, in prolonging Adapted from ref. 4. the enormous disruption to normal life engendered by the pandemic. In fact, the first goal of the new US COVID-19 strategy is to “restore trust with the developed further4–6, these practices communities to be placated, but as integral American people”1. allow researchers to bring in all trial parts of the research team. stakeholders as essential members of the Building trust research team, which makes research a GPP in practice How is trust created—especially in the genuinely joint enterprise. What does this mean in practice? Below we stressful, time-pressed, and fearful climate Implementing GPP requires effort, provide three examples to illustrate the role of a global pandemic? Much has been resources, and expertise, and the list of GPP can play in clinical research, and give written in recent years about the need for stakeholders is both multi-tiered and some high-level, pragmatic advice about ‘trustworthiness’ on the part of those asking long (Fig. 1). It is nonetheless essential, how to implement GPP in clinical research. others to trust them2. Trust is not the default on both moral and practical grounds. condition, and it is even harder to build The moral case for working in respectful Ebola trials in Liberia. When the USA and without a solid foundation of trust before a partnership with stakeholders has been Liberia forged the Partnership for Research crisis hits. It is something that researchers made elsewhere7. In practical terms, if a on Ebola Virus in Liberia (PREVAIL) in must earn over time through the attitudes, substantial part of a population does not October 2014, to confront the West African values, and practices that they bring to trust that a trial is scientifically rigorous Ebola outbreak, the environment for clinical their work. and is conducted by people working for research in Liberia was extraordinarily A core element in creating the public good, the trial can grind to a difficult. The very name of the disease environments of trust is found in ‘good halt amid rumors and recriminations; evoked enormous fear, rumors were rife, participatory practice’ (GPP) that allows even if the trial is completed, the research and trust in researchers—both foreign all stakeholders—a broad spectrum that results might simply be ignored. Sometimes and domestic—was almost nonexistent. includes both those able to affect the distrust is rooted in a grim history of Community and national leaders were not conduct of the research and those liable oppression and betrayal8. Sometimes it is at all inclined to support the conduct of to be affected by it—to contribute to just the result of the latest social-media research on human subjects in the midst accomplishing a trial’s research aims. rumor9. Either way, the solution is for of a disastrous epidemic. With roots in community engagement for those who plan, fund, and conduct However, PREVAIL launched its first research into human immunodeficiency clinical research to see the broad group vaccine trial in February 2015 and brought virus in the 1980s3 and subsequently of stakeholders not as a set of disparate it to a successful conclusion. That and

Nature Medicine | VOL 27 | March 2021 | 367–371 | www.nature.com/naturemedicine 369 comment | FOCUS comment | FOCUS other PREVAIL trials would not have been from the nationally recognized traditional the emergency use authorizations that possible without the Liberian-led social leader Queen Juli Endee (https://www. followed13,14 took patients, care providers, mobilization, community engagement, youtube.com/watch?v=tHbLDsXX20w). and other important stakeholders by and communication (SMC) team that surprise. From the pandemic’s earliest developed and executed a comprehensive The RECOVERY trial in the UK. The days, the public-health message for people roadmap to bring stakeholders into the UK Randomized Evaluation of COVID-19 diagnosed with COVID-19 has been to trial. The SMC team convinced key leaders Therapy (RECOVERY) trial recruited 12,000 isolate at home, and to not seek further to allow the trial to begin, maintained participants from 176 different hospitals in treatment until symptoms become severe. bidirectional communication channels with its first three months10. Through a multi-arm Without messaging to prepare the way, affected communities and stakeholders, adaptive design, it identified dexamethasone it was difficult for people to understand actively identified problems and rumors, (a widely used anti-inflammatory steroid) that the option to seek out a new effective corrected misinformation, and conducted as an effective treatment for COVID-19 in outpatient treatment might be open to them. media campaigns and other innovative patients requiring oxygen or ventilation, Moreover, hospitals and other medical outreach efforts. and it produced promising provisional facilities were not at all ready to safely Many factors contributed to that results for the monoclonal antibody administer the requisite lengthy infusions success. In the broadest terms, PREVAIL tocilizumab (already licensed for to a large group of infectious patients. The was conceived from the beginning as rheumatoid arthritis) in patients in the result has been that in the USA, these drugs a genuine partnership. Some initial intensive care unit. New national guidance are currently underutilized. That problem distrust flowed from a lingering history in the UK now calls for eligible patients to might have been prevented had a phase 2/3 of foreign exploitation, corruption, and routinely be offered dexamethasone11 and trial been completed, as had been planned lack of transparency and accountability. It to be considered for tocilizumab12. Equally in the US COVID-19 research agenda therefore mattered that Liberian doctors, importantly, the RECOVERY trial showed Accelerating COVID-19 Therapeutic government officials, and community that other candidate therapeutics, such as Interventions and Vaccines (led by the members were not just ‘informed’ about convalescent plasma, are not effective in US National Institutes of Health)15, which PREVAIL but actually became an integral treating COVID-19. included robust GPP efforts such as Rise part of the research team—they no longer Several factors contributed to the rapid Above COVID16, Community Engagement were outsiders being asked to trust a group deployment, enrollment, and uptake of Alliance Against COVID Disparities17, of foreign researchers. The SMC team then results for the RECOVERY trial, including and Combat COVID18. forged and strengthened more partnerships pre-existing integration of clinical-research with a broad range of stakeholders, infrastructure with clinical services provided Implementing GPP: a pragmatic including communities, to change negative through the National Health Service. overview perceptions in the broader population National political leaders and medical To bring stakeholders into the trial process into positive relationships by engaging authorities publicly supported participation from the beginning, we suggest that those local expertise. in clinical trials, and that support was then responsible for planning and funding trials Two more specific examples illustrate widely reported through the media. Other take three early steps to implement GPP. the SMC team’s activities. First, early key stakeholders were also engaged early in First, identify all stakeholders. Second, listening sessions with community members the process, including the Health Research make a detailed roadmap for how GPP will revealed that the word ‘trial’—which Authority, which facilitated rapid processes be integrated into the trial from the design the local community thought of as an for ethical review and approvals by the phase onward to engage those stakeholders. experiment done on animals—should be National Health Service. Because the full Third, identify specific people to develop replaced with the more acceptable ‘study’. array of stakeholders had been engaged and implement the roadmap, making sure This was a small point, but an important appropriately from the beginning, the study they have the operational authority and one that could have easily been missed was approved quickly and was given priority budget to do so. without the listening phase. for implementation so that enrollment went The roadmap itself can be separated Second, on the basis of recommendations smoothly. Notably, when new treatment into three phases covering the life of the from community leaders, ‘trackers’ were guidelines appeared based on the research, trial. Below, we highlight key aspects of the nominated by the local community to join they were efficiently communicated, roadmap that relate to engagement with the study team to support study participants. and immediately changed practice. community stakeholders and participants. These trackers were instrumental in Other parts of the roadmap will need to achieving an enviable follow-up rate of Monoclonal antibody trials in the include plans to engage with the other more than 98%. Equally importantly, they USA. Not engaging stakeholders from regional and national stakeholders described also became local community liaisons, the outset can lead to public confusion, above. Building trust with a diverse group educating the wider community about the underutilization of the countermeasures of stakeholders is not an event but a process trial and communicating problems back to studied, and other problems. For example, that requires extensive dialog, transparency, the SMC team. For example, they were able surprising results from industry-sponsored time, and two-way communication. to alert the study team to the stigma faced phase 1 dose-escalation trials conducted by trial participants that in some cases led in the USA showed that the monoclonal During trial design. The over-riding to their being evicted from their homes, and antibody bamlanivimab (LY-CoV555) purpose of many early GPP activities is to were able to inform the study team about reduced hospitalizations and visits to the listen and learn, to inform development and circulating rumors and misinformation. The emergency department due to COVID-19, implementation of the protocol. Among SMC team then addressed these problems and that REGN-COV2, a combination other tasks, planners must map community with targeted messaging and broader sharing of two monoclonal antibodies, reduced groups and identify trusted formal and of trial information through community medically attended visits. But those informal leaders; identify trusted sources meetings and radio spots, including jingles positive results were so unexpected that of information; identify community beliefs

370 Nature Medicine | VOL 27 | March 2021 | 367–371 | www.nature.com/naturemedicine FOCUS | comment FOCUS | comment and attitudes about clinical research; map All the while, a monitoring and evaluation Published online: 15 March 2021 the communication channels through which mechanism for community-participation https://doi.org/10.1038/s41591-021-01271-3 people receive and act on information; and activities should be established and understand the target population’s major implemented, and the findings should be References 1. US Government. Te White House https://www.whitehouse.gov/ health concerns, which may not be the used to revise GPP strategies. wp-content/uploads/2021/01/National-Strategy-for-the-COVID-19 disease the trial is about. -Response-and-Pandemic-Preparedness.pdf (2021). A second set of pre-enrollment activities Closing the trial. How the trial ends can 2. O’Neill, O. Int. J. Philos. Stud. 26, 293–300 (2018). 3. Fauci, A. S. Acad. Med. 64, 115–119 (1989). aims to open clear, two-way communication have a major impact on the degree to 4. Te Joint United Nations Programme on HIV/AIDS. UNAIDS channels with various community groups which people will accept the intervention https://www.unaids.org/en/resources/documents/2011/20110629_ and other stakeholders. Some of these under study, and on prospects for future JC1853_GPP_Guidelines_2011%20OK (2011). 5. Hankins, C. World Health Organization https://www.who.int/ channels are formal; for example, a research in the same community. The key blueprint/what/norms-standards/GPP-EPP-December2016.pdf community advisory board, designed to outcomes must be carefully communicated (2016). provide information and feedback from to different stakeholders, using various 6. World Health Organization. https://www.who.int/docs/default- source/science-division/research/blueprint-good-participatory- various groups within the community, media, in order to maximize access to practice-for-covid-19-clinical-trials---a-toolbox.pdf (2020). should be created with defined procedures new interventions and implementation of 7. Wright, K. & Parker, M. Nat. Med. 26, 308–309 (2020). governing membership and responsibilities. study findings. If healthcare providers are 8. Washington, H.A. Medical Apartheid: Te Dark History of Medical Experimentation on Black Americans from Colonial Times to the Some are informal, such as opening to incorporate any new interventions into Present (Doubleday, New York, 2006). informal dialog with leaders of subgroups standard practice, the necessary resources— 9. Neil, S. J. D. & Campbell, E. M. AIDS Res. Hum. Retroviruses 36, within a population. Some will rely on mass financial, human, and infrastructure—must 545–549 (2020). communication with the population as a be in place. 10. National Institute for Health Research. https://www.nihr.ac.uk/ case-studies/the-uks-fagship-covid-19-treatment-trial-the-rec whole or with specific target audiences. To overy-trial/25358 (2020). use these channels effectively, the study team GPP from the start 11. NHS England. https://www.england.nhs.uk/publication/ should develop culturally adapted messages In a pandemic, it might be tempting to covid-19-therapy-corticosteroids-including-dexamethasone- and-hydrocortisone/ (2020). and materials to support the trial, with input imagine that there is simply no time to 12. Department of Health and Social Care, Te Scottish Government, from appropriate stakeholders. consult a wide group of stakeholders. That Welsh Government & NI Department of Health. https://www. would be a mistake. Minimizing deaths cas.mhra.gov.uk/ViewandAcknowledgment/ViewAttachment. aspx?Attachment_id=103745 (2021). During the trial. Once active recruitment and accelerating the end of the pandemic is 13. U.S. Food & Drug Administration. https://www.fda.gov/ and follow-up begins, the research the goal of emergency-response research. But news-events/press-announcements/coronavirus-covid- team needs to continue to fully engage the trust that flows from full implementation 19-update-fda-authorizes-monoclonal-ant ibody-treatment-covid-19 (9 November 2020). stakeholders and maintain a dialog about of GPP is essential to the successful 14. U.S. Food & Drug Administration. https://www.fda.gov/news- study activities, using the bi-directional development of new interventions that will events/press-announcements/coronavirus-covid-19-update- communication channels already actually be used by the target populations. fda-authorizes-monoclonal-antibodies-treatment-covid-19 (21 November 2020). established. Local people should be In short, beginning with the end of 15. National Institutes of Health. https://www.nih.gov/research- recruited to serve as communicators, the pandemic in mind, one must begin training/medical-research-initiatives/activ (2020). mobilizers, and study-participant trackers. with GPP. ❐ 16. Rise Above Covid. https://www.riseabovecovid.org/en/ (2020). The community advisory board should get 17. National Institutes of Health Community Engagement Alliance. 1 2 https://covid19community.nih.gov/ (2020). regular updates from study leadership— Barthalomew Wilson , Katharine Wright , 18. U.S. Department of Health and Human Services. and the study team must ensure that Robert Taylor3 and Elizabeth Higgs4 ✉ https://combatcovid.hhs.gov/ (2020). feedback from the community is in fact 1Partnership for Research on Vaccines and Infectious 19. Hall, W., Jamieson, A. & Wardle, G. https://wellcome.org/sites/ default/fles/advancing-epidemics-rd-2019.pdf (Wellcome 2 used to guide trial conduct and address Diseases in Liberia, Monrovia, Liberia. Nufeld Trust, 2019). new or ongoing problems. Social analytics, Council on Bioethics, London, UK. 3National which continuously brings together Institute for Allergy and Infectious Diseases, National Acknowledgements data from multiple communication Institutes of Health (Contractor), Rockville, MD, For E.H. and R.T.: the opinions expressed are the authors’ own and do not necessarily represent the views of the USA. 4National Institute of Allergy and Infectious channels, is becoming increasingly National Institutes of Health. helpful in discerning population attitudes, Diseases, National Institutes of Health, Rockville, knowledge, and rumors, particularly MD, USA. Competing interests during large outbreaks and pandemics19. ✉e-mail: [email protected] The authors declare no competing interests.

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