A rapid review of community engagement and informed consent processes for adaptive platform trials and alternative design trials for public health emergencies

Background : Public Health Emergencies (PHE) demand expeditious research responses to evaluate new or repurposed therapies and prevention strategies. Alternative Design Trials (ADTs) and Adaptive Platform Trials (APTs) have enabled efficient large-scale testing of biomedical interventions during recent PHEs. Design features of these trials may have implications for engagement and/or informed consent processes. We aimed to rapidly review evidence on engagement and informed consent for ADTs and APTs during PHE to consider what (if any) recommendations can inform practice. Method : In 2022, we searched 8 prominent databases for relevant peer reviewed publications and guidelines for ADTs/APTs in PHE contexts. Articles were selected based on pre-identified inclusion and exclusion criteria. We reviewed protocols and informed consent documents for a sample of large platform trials and consulted with key informants from ADTs/APT trial teams. Data were extracted and summarised using narrative synthesis. Results : Of the 49 articles included, 10 were guidance documents, 14 discussed engagement, 10 discussed informed consent, and 15 discussed both. Included articles addressed ADTs delivered during the West African Ebola epidemic and APTs delivered during COVID-19. PHE clinical research guidance documents highlight the value of ADTs/APTs and the importance of community engagement, but do not provide practice-specific guidance for engagement or informed consent. Engagement and consent practice for ADTs conducted during the West African Ebola epidemic have been well-documented. For COVID-19, engagement and consent practice was described for APTs primarily delivered in high income countries with well-developed health service structures. A key consideration is strong communication of the complexity of trial design in clear, accessible ways. Conclusion: We highlight key considerations for best practice in community engagement and informed consent relevant to ADTs and APTs for PHEs which may helpfully be included in future guidance. Protocol: The review protocol is published online at Prospero on 15/06/2022: registration number CRD42022334170.


Introduction
Public health emergencies (PHEs) caused by novel or re-emerging pathogens present a significant threat to the health and security of people around the world [1][2][3] .In the wake of the COVID-19 pandemic, preparing for effective responses to these events remains a priority for governments and international agencies such as the World Health Organisation (WHO) 3,4 .Clinical research is central to the response 3,5 , particularly during novel infectious disease outbreaks where no known medical countermeasures exist 2 .During a PHE, rapid recruitment of large numbers of research participants are likely to be needed to produce results that can be used during the active phase of an outbreak 1,3,6,7 .As illustrated in the H1N1 pandemic where no clinical trial evidence was available to inform treatment 1 , the time needed to establish clinical trials must be optimised to avoid missing outbreak peaks.Learning the lessons from H1N1, COVID-19 saw important advances to rapid production of evidence related to vaccines and therapeutics.These advances reflect innovation to the ways in which clinical research was designed and conducted during PHEs.In particular, the use of alternative design trials (ADTs) and adaptive platform designs (APTs) have advanced the potential for clinical research to produce timely evidence for public health and clinical responses to emergency events [7][8][9][10][11] .
Adaptive designs draw from knowledge gained during the trial to inform and amend subsequent actions pre-defined by the study protocol, for example, amendments in doses or target study populations 12 .APTs are guided by a single master protocol which enables the comparison of several treatments/vaccines against a single control aimed at standardizing study procedures across participating sites and contexts in order to minimize the duplication of efforts, streamline ethical review and achieve adequate, and diverse participation when time is of the essence 9 .A prominent feature in APTs is the ability to drop arms for futility or harm as trial data emerges, and also to introduce new treatment arms as new products become available for evaluation 8,13,14 .Examples of this type of trial include the PRINCIPLE primary care trial 15 , TOGETHER 16 , REMAP-CAP 17 , RECOVERY 18 treatment trials, and SOLIDARITY which used an adaptive platform to evaluate new COVID-19 therapeutics or vaccines in multiple sites and often in multiple countries around the world 19 .The RECOVERY trial, where recruitment is integrated with healthcare through the UKs National Health Service hospital network, has further been described as a pragmatic APT in that therapies are tested for effectiveness in routine healthcare practice 20 .ADTs include seamless phase I/II/III trials aim at efficiency through combining RCT phases in a single protocol 21 , and stepped wedge trials, which may introduce trial arms sequentially.Another ADT is the ring-vaccination cluster-randomised controlled trial design, which was used to randomize rings of individuals in close proximity to index cases for vaccination in West Africa during the 2013-2016 Ebola epidemic 21 .
Engagement and informed consent are essential elements of clinical trials, important within their own right, but also mutually supportive 22,23 .For this review, we use the term engagement to include Good Participatory Practice (GPP) 24 , Patient and Public Involvement (PPI), consultation, dialogue and information giving/gathering activities, with a range of public, community members and stakeholders, which are used to support, enable and strengthen clinical trials throughout their lifecycle.Guidelines for strong ethical practice for clinical trials, including those conducted during in PHEs, highlight the importance of engagement with communities, patients and publics throughout the conduct of clinical trials and the duty of care that researchers have to ensure that, prior to obtaining signed individual informed consent, participants have been provided with sufficient time and opportunity to consider participation, based on being provided adequate understanding of the research without coercion 23,[25][26][27] .It is currently unclear what, if any, specific considerations are provided for engagement and informed consent processes for ADTs and APTs during PHEs.This rapid review is part of commissioned project from the WHO Ethics and Governance Unit.It aims to summarise guidance, reports and evidence on implementation of engagement or informed consent practices for ADTs and APTs during PHEs.We describe how challenges raised by the PHE context and the need for expeditious evaluation of new/repurposed therapies and vaccines were addressed.Based on this we make suggestions towards further research and consider implications for guidelines related to ADTs and APTs during PHEs.

Methods
We aimed to rapidly review evidence on engagement and informed consent for ADTs and APTs during PHE to consider what (if any) recommendations can inform practice by asking the following questions: 1. What specific considerations, if any, are given to engagement and informed consent for ADTs and APTs during PHEs in prominent guidance documents?
2. How have stakeholders been engaged for ADTs and APTs during PHEs?
3. How has informed consent been undertaken for ADTs and APTs during PHEs?
4. What is the empirical evidence for the success, pitfalls and outcomes of engagement and informed consent approaches reported for ADTs and APTs during PHEs?
As is common for rapid reviews, our approach comprises a systematic literature search, screening and selection of studies, a narrative synthesis and dialogue with knowledge users 28 .The review protocol is published online at Prospero (published on 15/06/2022): registration number CRD42022334170.

Eligibility criteria
Articles were included if they met all of the following criteria: • Articles documenting or describing stakeholder/public/ community/ patient engagement/involvement and/or informed consent to support ADTs and APTs during PHEs -which comprise platform, cluster-randomised ring-vaccination, stepped-wedge, pragmatic, seamless multi-phase and adaptive design trials.
• Article type: Primary empirical studies, guidelines policy frameworks, programme reports, conceptual/ discussion papers, commentaries and letters to the editor • Language: English language.
• Date: any date Articles were excluded if they met all of the following criteria: • Articles describing engagement and informed consent for non-ADT/APTs (e.g.RCTs), or trials in non-PHE (HIV, TB, Malaria, cancer, asthma, obesity, heart disease etc.), or articles reporting on research during PHEs with no content on engagement or informed consent • Article type: Evidence reviews • Language: Non-English language.
• Date: no exclusion based on date

Information sources and search strategy
We searched the following data bases from their earliest inclusion to July 2022: Ovid Medline, Ovid PsycINFO, Ovid EMBASE, Ovid Global Health, Scopus, Web of Science (All Databases), medRxiv and Google Scholar using a structured search strategy.The search strategy was developed in Ovid Medline and refined for each database (see Extended data 29 ).
Search terms for four domains were developed based on team experience in the field and drawing on key references 30 .The domains were linked with Boolean operators as follows: Supplementary searches were conducted of relevant core journals, snowball searching to check reference lists of included articles, and recommended sources were requested via expert networks.Grey literature was accessed through relevant websites (e.g.WHO, NIHR, RECOVERY trial, REMAP-CAP, PRINCIPLE etc.).Further, we used the following two strategies to further supplement our search on ADTs and APTs during PHEs.The first was a hand search for protocols, participant information sheet and informed consent form for eight prominent adaptive trials for COVID-19.These trials were selected because they are the largest COVID-19 trials in terms of recruitment.They comprise six adaptive platform trials and two large non-adaptive platform trials for comparison.The second strategy comprised holding discussions with engagement and communications leads for two prominent trials (REMAP-CAP and RECOVERY).
Selection, data extraction and synthesis Using the criteria above, the principal reviewer (AD) screened titles and/or abstracts of retrieved articles for inclusion/exclusion.A second reviewer (AB) independently screened a sample of 10% to identify any systematic screening errors.Full text articles were subsequently reviewed by the principal reviewer, with 10% independently reviewed by a secondary reviewer (IO).Disagreements between the principal and second reviewers were resolved through re-review and discussion.
The principal reviewer (AD), IO and AB extracted data using pre-defined and piloted data extraction sheets to capture details about the type of article, type of adaptive trial, PHE, engagement and consent approaches, and recommendations.Guidance document identified during the search were grouped together to address question 1.The remaining articles and documents were imported into NVIVO14 (QDA MINER LITE could be used as an open-access software alternative for our approach) and thematic approach based on the extraction criteria was used to describe the guidance documents and approaches for engagement and informed consent.

Results
After removing duplicates, database searches (including Google Scholar) and supplementary (back-and-forth citation) searches yielded 469 articles for title and abstract screening.Sixty-four articles were identified, for full text review and from this 15 were rejected because they did not fit the inclusion criteria.Of the 49 documents included in the review, 10 were classified as 'guidance documents' because they presented guidance, a framework or related content related to engagement and/or consent to clinical research during PHEs.The remaining 39 comprised 14 articles on engagement, 10 on informed consent, and 15 discussed both concepts within a context of APTs during PHEs.Considerations for community engagement and informed consent for ADTS and APTS during PHES in included guidance documents.
Table 1 summarises ten prominent guidance documents identified in the review.Of these, one gave guidance relevant to Ebola trials 32 , three for COVID-19 [33][34][35] , four referred to outbreaks or PHEs in general 2,3,23,27 , and two gave general guidance for engagement in clinical research but not specific to PHEs 36,37 .These documents highlight the value of ADTs or APTs and the importance of community engagement but do not provide specific guidance for engagement practice or informed consent for these novel trial designs in PHEs.Of the 10 guidance documents reviewed, 4 gave specific guidance for informed consent ADT/APTs in PHE contexts 3,23,32,34 .

Community engagement
Guidance documents highlight constraints to engagement in the context of PHE, including the urgency for action, the extent to which lay members of the public can inform complex biomedical research 3 , and the extent to which local communities can influence decisions on multi-country standardised master-protocols of the sort used in platform trials during PHE contexts 35 .Despite these constraints, researchers have a moral duty to deliver community and stakeholder engagement throughout the lifecycle of clinical trial 3,27,33 .Prominent aims of community engagement include understanding community norms, values and traditions 3,27,35 ; identifying research priorities/questions 23,33,35 informing trial designs 2,23,33,35,36 ; assessing acceptability 3,23,27,32 and feasibility 27,33 of trial designs; listening and respond to community concerns 23 ; and shaping public facing trial documents such as informed consent forms 2,33,35 .
Guidance documents highlight the importance of documenting communications or engagement plans 2,23,33,35,37 , and including these in funding applications 3,33 and trial protocols 2,23,33 .Community Advisory Boards and/or Patient and Public Involvement (PPI) groups are recommended for gaining diverse perspectives from affected communities and informing trial implementation 2,3,35,38 .Practical guidance on how to work with CABs/ PPI groups included regarding working online with these groups during social distancing measures 33,38 .No guidance is given specifically on engagement with CABs and PPI groups for APTs during PHEs.
Throughout the implementation of clinical trials, documenting, monitoring and evaluating engagement activities and outcomes is recommended 23,35,36 .Active CAB engagement can help to monitor community tensions, views and rumours, and advise on how to appropriately respond to them through contributing to culturally sensitive communications 2,33,35 .This engagement is aimed at ensuring the trial is responsive to community views 36 and support study accrual and follow-up 2 .Little guidance is offered on engagement specific to the closure of adaptive platform trials in PHE settings.For clinical trials in general, several guidelines recommend stakeholder/community involvement in dissemination of results 2,23,33,35,36 , and in including stakeholders in the planning and implementation of exit strategies 2,35 .

Informed consent
Guidance provided includes need for Ethics Review Committee capacity strengthening 3,32 , for innovative approaches (for example using audio-visual aids) to be used to support individual informed consent 32 , for individual as well as 'community gatekeeper' (e.g. in West African countries) consent for ring vaccination cluster randomised trials 23 .For vaccine trials informed consent should inform participants that they can be unblinded when efficacious vaccines become available 34 .Consent processes and materials should be developed in collaboration with community stakeholders 2,3,27,35 .Guidance is also given on deferred, waived consent and consent by proxy in PHE contexts for all trials 2,3,23,27 .The following constraints to informed consent were highlighted: understanding complex (adaptive) trial designs 3,32 , differentiating between care and research 3,27 , and challenges raised by the PHE context, for example, fear, lack of alternative options, disruption, family separation, lack of access to basic resources and services 3,23,27 .

Community engagement for ADTs and APTs during PHEs
Of the 29 included articles, 22 were discussion papers reporting expert views, opinions or experiences, 5 were reports of primary empirical research using qualitative (focus groups and interviews) and quantitative methods (public survey), and 2 were trial reports with no empirical data on engagement (Table 2).The majority of papers considered clinical research conducted during the Ebola epidemic in West Africa (16 of 29) and COVID-19 (9 of 29).The term "community engagement" was used most widely (19 of 29), and "social mobilisation" was also used [39][40][41] .Public engagement and/or involvement was used for COVID-19 practice 14,42,43 [45][46][47] and ADTs such as the cluster-randomised ring-vaccination trials were considered more acceptable 46,47 .Against a backdrop of public distrust of research and researchers 39,44,45,48 , early engagement in West Africa reportedly promoted acceptability and buy-in for trial participation 40,45 , and the incorporation of community views into decision-making about trial design and implementation 45 .Early community engagement was described as important for informing respectful entry into the community 40,45 , providing an understanding of traditional practices in disease transmission and changing attitudes 2,3,45 , and for appreciating that community health priorities did not always match health challenges explored in trials 44,49 .Early engagement also informed social and cultural sensitivity 40 , for example, in guiding the need for individual and community consent 46 , and through guiding trial-related consenting, communication and messaging 39,40,44,45 .
Community engagement aimed at raising awareness and understanding of trials was described as being key to strengthening relationships, trust and support for trials 40,44,46,[50][51][52] .Explaining the purpose and procedures of research and providing accurate information was considered important to address rumours and misconceptions 40,45,47,49,51 which could cause stigma and fear 39 and consequently slow down recruitment 44,49 .Rumours were described as being based on a lack of accurate information on Ebola and research in the community 45,47 and, in settings where research was led by foreign researchers, mistrust, based on a history of colonial oppression 44 .In Liberia, for example, research participation was likened to guinea-pig experimentation 45 .Trial information was shared with communities through community meetings and question and answer sessions 39,40,45 , engaging leaders including traditional healers 39,40,[44][45][46]50,51 and working with nurses to relay messages 39 , and through distributing information materials 40 . Engagment with community members also enabled researchers to select appropriate sites for research clinics to minimise stigma 45 and undertake disease surveillance and trace contacts 40 .Engagement strategies which were reported to strengthen retention of trial participants included ensuring that feedback from the community on rumours informed community engagement messages, that messages were given by hospital nurses, the use of local dialects was used and employing local 'trackers' to follow-up with trial participants 39 .

COVID-19 APTs
For COVID-19, included articles primarily address APTs delivered in high income countries with well-developed health services and structures (Table 3).A publication of the RAPID trial explicitly stated that no PPI was conducted because of funding limitations and COVID-19 restrictions 53 .However, other reports and personal communication with trial personnel illustrate multi-stakeholder engagement in APTs 6,10,14,43,[54][55][56] .
In its trial protocol, PRINCIPLE (Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses), a UK national primary care platform trial for investigating repurposed therapies for COVID-19 treatment of older people in the community at high risk of complications, describes that prior to implementation, a panel of seven members of the public from the target recruitment age were offered an opportunity to review trial outcomes and design 15 .
The trial team report innovative approaches to inclusive recruitment among socioeconomically deprived and minority ethnic communities.These efforts included targeted efforts to reach diverse audiences in many languages through local and UK national media channels 55 .They also conducted an online public survey to assess public acceptability of using contact data derived from COVID-19 tests to recruit participants 42 .
High level health and political stakeholder discussions were described as key to the successful and rapid implementation of the RECOVERY, SOLIDARITY, REMAP-CAP and UPMC Remap-Covid COVID-19 therapeutic trials 6,43,44,54,56 .Given the lack of validated therapies and the urgent need for research at the early stages of the COVID-19 pandemic, clinicians were engaged to facilitate the RECOVERY and SOLIDARITY trials and to have clinical interventions to offer very sick patients guided by protocol 6,57 .An internal report by the RECOVERY's communication team describes consultation with the department's pre-existing Public Advisory Panel about the trial, and the subsequent establishment of a RECOVERY-specific panel 58 .REMAP-CAP and RECOVERY clinical trial teams described regular and extensive communications and interviews with local and mainstream media, where trial principal investigators were often directly involved.PPI groups and advisory panels also contributed to reviewing consent forms and animations, drafting communications to trial participants and advocating for trial participation through several media initiatives (LM Hayes (REMAP-CAP investigator), personal communication, 10 th May 2022; and A Whitehouse (RECOVERY communications lead), personal communication, 18 th June 2022).

Acceptability of ADTs and APTs
Empirical studies have highlighted general acceptability of ADTs and APTs among key stakeholder groups.A qualitative study among international health and research staff found support for adaptive/alternative designs and highlighted the importance of trial-specific early engagement to promote collaboration, incorporating community insights into decision-making, reflecting cultural values and norms, encouraging transparency, fostering trust and relationships and addressing rumours and fears 59 .
Two empirical articles considered a hypothetical Influenza-like pandemic scenario to inform clinical research preparedness for the Platform for European Preparedness Against Re-emerging Epidemics (PREPARE).PREPARE hosted an EU-wide primary care network as well the REMAP-CAP network.These studies were conducted to inform clinical research preparedness regarding public acceptability of APT designs and alternate models of consent that may be better suited to a pandemic context.These studies identified broad support for APTs 60,61 .Publics generally supported the need for research during pandemics, a moderate proportion expressed willingness to participate, and publics shared their preferences on different approaches to informed consent 60 .Regarding adaptive designs, participants considered it less important to understand the scientific design considerations and more important to know what the implications of the adaptive designs on their participation, including on risks, benefits and burdens 61 .Qualitative approaches offered members of the public and health stakeholders a greater opportunity to share their views on adaptive trials 61,62 .Whilst a few participants felt that dropping or introducing new trial arms may convey uncertainty on the part of researchers, members of the public generally supported the need for more streamlined enrolment procedures, consent waivers for very low risk studies, and the use of routinely collected medical data for research purposes 61 .Dimairo et al., in their qualitative study report clear support for adaptive trials from UK health and research stakeholders but that educative sessions would be required to address general unfamiliarity with adaptive methods 62 .

Informed consent for ADTs and APTs during PHEs
Of the 25 included articles, 17 were discussion papers reporting expert views, opinions or experiences, 4 were reports of primary empirical research using qualitative (focus groups and interviews) and quantitative methods (public survey), and 4 were trial reports with no empirical data on engagement (Table 4).The majority of papers considered clinical research conducted during the Ebola epidemic in West Africa (10 of 25) and COVID-19 (12 of 25).

Ebola 2014-2016 ADTs
Included articles provided rich descriptions of informed consent challenges and approaches 39,41,[45][46][47]50,51 . A comon challenge reported for RCTs in general and also for therapeutic and vaccine ADTs was the complexity of research concepts and procedures and difficulties communicating these, including among participants with low literacy 3,39,48,50 .Vulnerability, No description given • Face-to-face signed consent required • The 5 drugs (in each arm) are named in the consent and the risks associated with each drug stated

•
The ICF describes procedures to participants for when the trial is "interrupted" by the researcher • "If the study is interrupted you will be notified and the study doctor will take all the measures for your treatment to be continued by the attending team (your referral) in order to continue your treatment with no harm to you" The

•
Online consent, with patient information leaflets, pictorial aids and the opportunity to call trial staff for more information.
• Phone consent also possible • Participants informed that procedures may differ for some arms and that they will be contacted to discuss this where appropriate

•
No other relevant details about the adaptive nature of the trial is provided in the consent form REMAP-CAP: Randomized, embedded, multifactorial adaptive platform trial for community-acquired pneumonia 2020. 17 description given

•
Participants were given the consent form and time to read and then a time was arranged to discuss with the researchers by phone.
• Participants would then send the signed form.• If they regain capacity, such participants should be provided with information about the trial (ideally prior to discharge, but otherwise as soon as possible thereafter), what their rights are and how to exercise them, but it is not necessary to obtain their written consent.
• For children aged <16 years old consent will be sought from their parents or legal guardian.
• ICF updated with trial findings (effectiveness of dexamethasone) • Information given about all treatment arm drugs and their possible side-effects and risks

No description given
Options for consent comprise: • Self-consent online  comprehension of trial concepts and therapeutic misconceptions (a phenomenon where research participation is motivated by individual participants' overestimation of the therapeutic or protective properties of experimental interventions 68 ) were described as challenges to autonomous, informed consent.Fostering culturally sensitive consent processes and an understanding of trial procedures through consultation with the community was recommended 59 .Lengthy information sheets and informed consent forms may also present a barrier to full understanding of trial processes and to trial enrolment 3,5,60,61,[69][70][71] .The context of public health emergencies, where disruption, fear and confusion are common, was also described as presenting challenges for informed consent 41,45,51 and potential for therapeutic misconceptions 45,51 .Alirol and colleagues described this as 'situational coercion' 48 , and whilst this may result in increased trial participation, it could potentially lead to long-term public mistrust in research 61 .For some trials, because of the PHE context, ethics review committees granted consent waivers 45,51 and community members who wished to decline research participation could self-identify through wearing bracelets 45 .Where informed consent was required by a community leader and the individual participant, trial staff used a combination of storyboards and flipcharts 39,50 in group and individual meetings in an attempt to convey trial information to potential trial participants 39,46,47 .Trial participation also raised community hopes of protection from vaccination, and for ring vaccination trials where community members desired immediate in preference to the delayed vaccination, randomisation into immediate or delayed vaccination was done prior to consenting to avoid selection bias 46 .

COVID-19 APTs
COVID-19 trial reports provided short descriptions of their informed consent approaches 17,72,73 : For the REMAP-CAP trial, written or verbal consent was obtained for all patients or from their surrogates 17 ; for the CATCO trial, consent was obtained a priori or deferred 72 ; and for the RECOVERY trial, written informed consent was obtained from all patients or from a legal representative if they were too sick 73 .
A key issue for informed consent to APTs relates to the information that is provided regarding trial-specific adaptations and the optimal level of detail about trial design.In a PHE, streamlined consent processes and simplified consent forms are important for rapid enrolment 70,71,74,75 .Potential challenges to simplified informed consent processes are unfamiliarity of research stakeholders with APTs 62 and the possibility of therapeutic misconceptions, argued to be heightened in PHE contexts 3,60,61,76 .Some articles call for clarity in informed consent forms and processes as a means of mitigating against therapeutic misconception 59,69,77 and Palzzani, in her ethical discourse, highlights the importance of giving complete, non-paternalistic information and verifying the participant's understanding 69 .For APTs, Palazzani recommends a dynamic consent process emphasising that participants should be informed about; the trial design, its adaptive nature and the possible addition and removal of trial arms based on efficacy and futility respectively, how it differs from traditional trials, and implications for participation 69 .Further, she recommends that re-consenting should inform participants of any new beneficial treatment uncovered since the initial consent was conducted 69 .Formative research for clinical research in PHE from high income countries highlighted that publics prioritised information on the implications of adaptive designs on their participation, including on burdens, risks and benefits of research participation, over theoretical explanations of the study design 61 .
Of Informed consent information sheets and assent forms (for minors) reviewed for 6 large COVID-19 APTs (Table 3), five provided information to patients that they would be randomised into one of several therapeutic arms, giving descriptions about potential adverse effects for each trial therapy 15,16,18,56,64 .One of the information sheets stated that participants would be notified if trial arms were 'interrupted' 16 and another stated that "The study looks at its results as it goes and uses the results so that new patients in the study have a better chance of getting better treatments" (Assent Information form acquired from the REMAP-CAP 17 research team).Of the remaining 5 APT information sheets, none provided information that new trial arms could be added.For the COVID-19 (TICO/ACTIV-3), Murray et al., 74 describe the use of "modular consent forms" with separate appendices for each trial arm giving detailed information to participants about the intervention they were randomised to.This presumably negated the need to give detailed information to participants on all trial interventions, thus shortening the informed consent form.This approach also eased the process of adding new trial arms, given that details for participants were added to the ICF and protocol as an appended module.REMAP-CAP described the adaptive nature of the trial in their public facing website.
In PHEs there is a need to minimise and mitigate against infection during the informed consent process.Mitigating strategies, such as social distancing, isolation, and the need for research staff to wear PPE were described as barriers to communication during the consenting process for Ebola 48 as well as COVID-19 trials 69,70,75 .For COVID-19 APTs, face-to-face approaches were used for some studies as well as other innovative remote approaches 16,17,66,67 .Remote consent approaches, though logistically challenging to implement 69 , have been recommended to minimise infection 69,70 , and with ethical approval, trials have embraced this approach both online 15,18,67 and by phone 15,17,64 .
For REMAP-COVID, after screening, patients were introduced to the trial in a one-on-one 'teleconferencing' call with a trial staff member 56 .Declaration of informed consent was then facilitated through a software platform facilitating signing and countersigning.Face-to-face support was also provided for consenting where it was needed and the team anecdotally report that remote consent was most effective when combined with bedside engagement, though they provide no detail of how this was assessed 56 .Questions were raised in the literature about informed consent being administered by 'treating' clinicians with limited consent training (as opposed to trained research clinicians) in 'pragmatic' trials such as RECOVERY 20 and about the validity of online and remote approaches in confirming with certainty, the identities of consent signatories 78 .While RECOVERY provided mandatory online training for clinicians, Casey et al., suggest that in 'pragmatic adaptive platform trials' consent processes could be supported by community consultation and information 20 .Woods et al., provide a detailed description and comparison of different approaches of obtaining written consent whilst minimising the risk of infection through face-to-face, taking a photo of the form and using Docusign software 75 .The review has highlighted several innovations in modifications of consent processes to address PHE challenges, but no study described systematic methods to explore their effectiveness and / or the specific challenges related to APTs in this context.
Optimising recruitment and informed consent processes to enable rapid recruitment is a common theme to discussion articles on COVID-19 and on GHEs in general particularly for low risk studies involving repurposed drugs with good safety profiles 60,61,70,71,78 .For incapacitated patients, deferred consent, or consent by proxy by family members or legal representatives has been recommended and approved by ethics committees, with a further recommendation that patients can later be consented during therapeutic windows 5,75 .Monach et al., describing the range in trial candidates, from RCTs exploring different doses of drugs with known safety profiles and off-label drugs with a well-described safety profile, to investigational drugs with unknown safety profiles, recommends a nuanced approach to consent 71 .For low risk trial candidates, waivers (opt-out) they argue, can be considered, whilst opt-in oral and written consent is more appropriate for higher risk trial candidates with unknown safety profiles.Specific issues as they relate to APTs were not considered in these articles.

Discussion
In this review of community engagement and informed consent for ADTs and APTs in PHEs, we found that current guidance documents place strong emphasis on the importance of community involvement in conducting trials, but little specific guidance on what this means in practice for ADTs and APTs.
Based on reported experiences of conducting clinical trials in public health emergency contexts, important lessons have been learned regarding how community engagement and informed consent processes can be optimised.There is a gap in consistent reporting of these experiences and lessons, in particular as they relate to the novel aspects of trial design and the implication for participants.Based on this review, we highlight key considerations for best practice in community engagement and informed consent relevant to ADTs and APTs for PHEs which may helpfully be included in future guidance.

Key considerations for engagement In ADTs/APTs in PHEs
Pre-trial engagement is important for gaining understanding of community norms, values and traditions which might have a bearing on the way in which a trial may be implemented, assessing trial acceptability and feasibility by the community, and drawing community insights to inform design selection 3,23,27,32 .This demonstrates respect for populations, aims at nurturing trust in research and acknowledges that the perception of social value of research can vary between local stakeholders and research stakeholders, particularly in international research collaborations 79 .The review has identified a range of approaches that reflect good practice for GPP/ engagement in alternative design trials for Ebola 34,45,46,50,52,80 and also for multi-site, multi-country COVID-19 trials delivered according to a master trial protocol 6,42,43,55 .However, we found limited description of pre-trial engagement that could meaningfully impact study design or implementation.The exception was qualitative work that considered public views of APTs and consent for pandemic relevant research that was conducted for PREPARE, a clinical research preparedness infrastructure 60,61  GPP-EP guidelines emphasise the importance of public acceptability of trials 2,3,23,32,35 .The dynamic nature of APTs delivered in PHEs mean that engagement regarding acceptability and social value should continue throughout the trial's lifetime.First, adaptive trials, by design, aim at validating therapies/vaccines throughout their implementation.Thus, if they are successful, as they proceed new alternatives for addressing the health problem emerge.That social value, "a necessary component of acceptability" 79 , is related to the availability of alternatives to address the problem, and implies that as validated alternative therapies/vaccines emerge, the social value of the trial changes correspondingly.Secondly, given the longer timescales of adaptive trials (for example, RECOVERY celebrated its third anniversary in March 2023), the emergence of efficacious vaccines and dynamic biological factors including virulence, endemicity and heard immunity change over the trial's lifetime, and therefore, correspondingly, so does the disease's impact on populations.So, while continuous engagement throughout conventional RCTs may be important to re-assess acceptability and social value as new therapies may emerge and the disease evolves, arguably this is more important for adaptive trials because of their longer timeframes within a dynamic epidemic context, and because continuous identification of new therapies and vaccines as trials progress is at the heart of their design.Considerations for guidelines to inform engagement during the implementation of adaptive platform trials might include: how to engage communities when an arm is stopped for futility or efficacy; engaging communities for the introduction of new arms; and re-assessing social value as validated therapies/vaccines emerge.
While several guidance documents underscore the importance of planning respectful exit strategies through consultation 2,33,35 and appropriate ways of sharing trial results, in order to maintain trust and respectful ongoing partnerships 2,3,23,27,33,35 , the review yielded no descriptions of how this was done for any adaptive or alternative trial.

Key considerations for informed consent in ADTs and APTs in PHEs
We highlight three important questions about informed consent forms and processes for ADTs/APTs in PHE contexts.Firstly, given the greater complexity of ADTs/APTs 62,69 , what level of detail on the adaptive/alternative nature of trials should informed consent forms convey; secondly, how effective are remote and online processes in achieving informed consent and ensuring the validity of participant identity; and lastly, for pragmatic APTs, how can modified consent processes be improved and 'treating' clinicians be supported further to administer informed consent which minimise therapeutic misconceptions 68 ?Palazzani emphasises that participants should be informed about the adaptive nature of the trial 69 and research among European publics highlighted their preference to understand the implications of the adaptive nature of the design for them regarding the risks, burdens and benefits 61 .Balancing the need to avoid PHE contexts precipitating research exceptionalism through enabling reduced quality processes, including in informed consent 81 , with the need for the rapid ethical evaluation of therapies and vaccines, requires careful navigation.Casey and colleagues argue that tight regulation would have prevented the implementation of RECOVERY in the USA, but that the protocolisation of research integrated into care in the UK minimised the wide clinical use of unproven therapies like hydroxychloroquine 20 .On one hand, over-complicated information materials, consent forms and processes can impede research 60,61,70,71 , while therapeutic misconception, on the other, can lead to long-term mistrust in research 61 .
In the context of placebo controlled COVID-19 vaccine APTs, Singh and colleagues' guidelines specify that when authorized vaccines become available, participants should be offered an opportunity for unblinding and vaccination with the authorized vaccine or the investigational vaccine if proven to be efficacious 34 .However, the review revealed no empirical articles on consent for COVID-19 adaptive vaccine trials.Questions of relevance to these trials pertain to participation in trials during national roll-out of approved vaccines, and include: a) how have (or should) consent forms conveyed potential restrictions to participant freedom, for example, to travel or work, when they opt for vaccine trial participation instead of nationally provided vaccines; b) how do consent processes address the tension between encouraging uptake of nationally provided vaccines and recruiting trial participants; and c) how should consent processes and ICF content change with the evolving public health regulations in different countries.

Strengthening practice and evidence for what works
We identified some examples of good practice based on published reports and personal communication with those leading prominent APTs during COVID-19.However, there were many other platform trials delivered during the pandemic -one review identified 58 COVID-19 platform trials by May 2021 30 .Given this large number, the scarcity of engagement reports in the literature is surprising.There is a need for norms and guidance related to minimum standards for reporting of GPP-EP practices.In particular, reporting ways in which trial adaptations were communicated with trial participants and at which junctures would help to inform best practice in this work.Addressing this gap would further enable researchers to be accountable to their peers and broader publics in describing how public acceptability of research was determined; how public views were taken into account; how public input was incorporated into trial design and implementation; and if some views could not be incorporated, what were the reasons for the decisions taken.
Our review revealed novel approaches to informed consent aimed at broadening participation whilst minimising transmission, but no empirical studies explored what content informed consent forms adaptive platform trials should contain, nor the effectiveness of the novel delivery and consent training approaches.There was also no empirical evidence on the effectiveness of online or remote consent approaches and support materials (leaflets, animations etc).Further research is needed aimed at strengthening these areas.Given the significant challenges of conducting research on research, particularly during emergency events, we recommend that pragmatic, rapid operational approaches to evaluation are adopted and included in trial protocols.This planning is needed well in advance of emergency events.

Strengths and limitations
To our knowledge, this is the first review that considers the practice of community engagement and informed consent for novel trials conducted during PHEs.This review is timely given the rich learning that has happened through unprecedented investment in and delivery of clinical research during COVID-19.Further learning could have been gained by expanding our review to include oncology and critical illness clinical research, where adaptive trials and relevant aspects such as consent waiver/ deferral are more commonly encountered.We maintained our focus on PHE contexts, however, due to their specific features, including the urgency for rapid research responses and the unavailability of existing known medical countermeasures during these events.Our search was comprehensive and covered peer-reviewed and grey literature.We also drew on consultations and information for COVID-19 trials.Further information to inform key outcomes to this review may have been gathered through a greater focus on grey literature and talking to research teams.Given time constraints to conduct this work, we selected a rapid review methodology.One member of the research team identified included citations and extracted data, with 10% of the data double coded.This may have introduced error in the research process.Further, limiting our inclusions to English language papers only may have introduced bias in reporting.

Conclusion
COVID-19 witnessed a step change in the delivery of clinical research during PHEs.These advances led to identification of effective medical countermeasures to save lives during the pandemic.Prominent clinical trials such as RECOVERY, SOLIDARITY and REMAP-CAP received widespread media coverage and investigators and their teams played significant and active roles in engaging the public with research.These breakthroughs demonstrate the added value of novel trial designs that enable rapid and responsive clinical research integrated into health emergency response.It is vital that lessons learned from these advances inform guidance for rapid research in future events, including for strong and consistent best practice for community engagement and informed consent.
In our review, we identified a gap in current guidance documents to steer best practice for community engagement and informed consent for ADT and APTs during PHEs.We also found some description and evaluation of practice that can inform future guidance.To advance best practice and be accountable to collaborators and communities, trial teams must report on their engagement and informed consent practices for ADTs and APT in PHEs.

Byron Bitanihirwe
The University of Manchester, Manchester, England, UK This is a compelling review focused on identifying existing guidance, reports and evidence related to informed consent and community engagement for alternative design trials (ADTs) and adaptive platform trials (APTs) during public health emergencies (PHEs), mainly in relation to COVID-19 and the Western Africa Ebola epidemic.The authors conducted a meticulous and comprehensive interrogation of 8 electronic databases as well as grey literature to answer this question.Based on the 49 articles that met inclusion criteria, the authors found that while current PHE clinical research guidance documents appreciate the significance of ADTs and APTs in addition to the importance of community involvement in conducting trials, there unfortunately remains a lack of specific guidance as to what this means in practice for both these forms of trials.Another key finding from the rapid review involved the existing gap in reporting of experiences associated with conducting clinical trials during PHEs and how these experiences relate to novel aspects of trial design, particularly in terms of community engagement and informed consent processes.It follows that each of these findings are crucial especially as one considers aspects of best practice for optimising large-scale testing of interventions during PHEs based on lessons learned from previous trials.
Overall, this is a well conducted and timely study (with clearly identified limitations) that draws attention to a pressing public health challenge, especially as emerging pandemics/epidemics spread faster and further.
Are the rationale for, and objectives of, the Systematic Review clearly stated?Yes

Are sufficient details of the methods and analysis provided to allow replication by others? Yes
Is the statistical analysis and its interpretation appropriate?

Not applicable
The authors have provided information on engagement and informed consent processes at such a granular level that it would be of immediate benefit to individuals planning ADTs/APTs should a PHE unfold tomorrow (and more universal guidance is not yet available), and they have successfully catalogued concrete considerations with which clinical researchers and their partners could begin developing, over a longer term, more comprehensive guidance on best practices going forward.
Are the rationale for, and objectives of, the Systematic Review clearly stated?Yes

Are sufficient details of the methods and analysis provided to allow replication by others? Yes
Is the statistical analysis and its interpretation appropriate?Not applicable

Are the conclusions drawn adequately supported by the results presented in the review? Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: A medical anthropologist, I have worked as a researcher and policy analyst/advisor in the field of public health emergency management for over 20 years, with a focus on community resilience, community engagement, whole community approaches to disaster management, behaviorally realistic emergency planning, and crisis and emergency risk communication.
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
a) Community engagement and related terms; OR b) Informed consent and related terms; AND c) PHEs declared by the WHO (as defined by International Health Regulations 31 ); AND d) Adaptive platform trials (comprising flexible arm designs and, to diversify the review to include studies conducted in sub-Saharan Africa, stepped-wedge designs, cluster-randomised ring-vaccination designs, and seamless phase I/II and II/III designs.
No other information given in relation to the adaptive nature of the trial PANORAMIC: Platform Adaptive trial of NOvel antiviRals for eArly treatMent of COVID-19 In the Community 66 .No description given Either face-to-face, or by telephone.

•
Written or verbal consent, in accordance with local legislation, was obtained for all patients or from their surrogates.Written informed consent from all eligible contacts using a printed information sheet.•For illiterate participants ICFs were read in the local language and a fingerprint was taken in place of a signature • Eligible contacts and were informed of the outcome of the randomisation at the end of the informed consent process to avoid selection bias None 25.Horby et al., was obtained from all patients or from legal representative if participants were too sick None

article Main focus of article PHE APT/ADT Key finding on content relevant to engagement Objective of engagement and approach
16. Salerno et al.,

article Main focus of article PHE APT/ADT Key finding on content relevant to engagement Objective of engagement and approach
27.Gobat et al.,

focus of article PHE ADT/APT Informed consent approaches and findings Recommendations
None 23.Angus et al.
and APT protocols that explicitly mentioned use of CABs and PPI panels (Re: PRINCIPLE).In a public health emergency the time to engage publics in design aspects is exceptionally tight.To enable pre-trial engagement in these contexts, strong engagement and communications practices need to be built into the infrastructure for these research platforms.Further, ground work for building CABs and public engagement links should be established between emergency events for rapid activation during readiness for research response.This work can and should include building a suite of public-facing communications tools that can be adapted to explain different aspects of ADTs or APTs relevant to PHEs.Capacity development materials for a wide range of stakeholders, including CABs or PPI groups would also be of value.

rapid review of community engagement and informed consent processes for adaptive platform trials and alternative design trials for public health emergencies
22. Participants in the Community Engagement and Consent Workshop, Kilifi, Kenya, March 2011: Consent and community engagement in diverse research contexts.J Empir Res Hum Res Ethics.2013; 8(4): 1-18.PubMed Abstract | Publisher Full Text | Free Full Text 23.CIOMS: International ethical guidelines for health-related research involving humans.Council for International Organizations of Medical Sciences, 2016.Konnyu K, Cushman R, et al.: Evidence summaries: the evolution of a rapid review approach.Syst Rev. 2012; 1: 10.PubMed Abstract | Publisher Full Text | Free Full Text 29.Harriss E, Davies A, Ormel I, et al.: A . 2023.http://www.doi.org/10.17605/OSF.IO/D9F8C 30.Vanderbeek AM, Bliss JM, Yin Z, et al.: Implementation of platform trials in the COVID-19 pandemic: A rapid review.Contemp Clin Trials.2022; 112: 106625.PubMed Abstract | Publisher Full Text | Free Full Text 31.Mullen L, Potter C, Gostin LO, et al.: An analysis of International Health Regulations Emergency Committees and Public Health Emergency of International Concern Designations.BMJ Glob Health.2020; 5(6): e002502.PubMed Abstract | Publisher Full Text | Free Full Text 32.World Health Organization: Ethical

issues related to study design for trials on therapeutics for Ebola Virus Disease: WHO Ethics Working Group meeting 20-21 October, summary of discussion
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