key: cord-0804226-nvjd81q9
authors: Williams, Eloise; Craig, Kathrine; Chiu, Christopher; Davies, Hugh; Ellis, Stephanie; Emerson, Claudia; Jamrozik, Euzebiusz; Jefford, Monica; Kang, Gagan deep; Kapulu, Melissa; Kolstoe, Simon E.; Littler, Katherine; Lockett, Anthony; Lozano, Elena Rey; Messer, Janet; McShane, Helen; Saenz, Carla; Selgelid, Michael J.; Shah, Seema; Smith, Peter G.; Yamazaki, Naho
title: Ethics review of COVID-19 human challenge studies: a joint HRA/WHO workshop
date: 2022-02-14
journal: Vaccine
DOI: 10.1016/j.vaccine.2022.02.004
sha: 9cbdeffee42c5b4fa45203553894fb850baa00a2
doc_id: 804226
cord_uid: nvjd81q9

This report of a joint World Health Organization (WHO) and United Kingdom (UK) Health Research Authority (HRA) workshop discusses the ethics review of the first COVID-19 human challenge studies, undertaken in the midst of the pandemic. It reviews the early efforts of international and national institutions to define the ethical standards required for COVID-19 human challenge studies and create the frameworks to ensure rigorous and timely review of these studies. This report evaluates the utility of the WHO’s international guidance document Key criteria for the ethical acceptability of COVID-19 human challenge studies (WHO Key Criteria) as a practical resource for the ethics review of COVID-19 human challenge studies. It also assesses the UK HRA’s approach to these complex ethics reviews, including the formation of a Specialist Ad-Hoc Research Ethics Committee (REC) for COVID-19 Human Challenge Studies to review all current and future COVID-19 human challenge studies. In addition, the report outlines the reflections of REC members and researchers regarding the ethics review process of the first COVID-19 human challenge studies. Finally, it considers the potential ongoing scientific justification for COVID-19 human challenge studies, particularly in relation to next-generation vaccines and optimisation of vaccination schedules. Overall, there was broad agreement that the WHO Key Criteria represented an international consensus document that played a powerful role in setting norms and delineating the necessary conditions for the ethical acceptability of COVID-19 human challenge studies. Workshop members suggested that the WHO Key Criteria could be practically implemented to support researchers and ethics reviewers, including in the training of ethics committee members. In future, a wider audience may be engaged by the original document and potential additional materials, informed by the experiences of those involved in the first COVID-19 human challenge studies outlined in this document.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has had an extraordinary impact on global public health and socioeconomic stability (1, 2) . It has claimed millions of lives and placed extreme strain on health care systems worldwide (3, 4) . Human challenge studies, in which research participants are deliberately exposed to infectious pathogens, have played a significant role in vaccine and therapeutic development and the study of host-pathogen interactions (5) .

However, human challenge studies are not usually undertaken with a novel pathogen in the midst of a pandemic. The COVID-19 pandemic galvanised the global scientific community, resulting in several rapid advances including the availability of highly efficacious vaccines within a year of the identification of SARS-CoV-2 (6) . With these developments, the scientific justification for COVID-19 human challenge studies has evolved, with the potential aim of human studies shifting from first generation vaccine development to other purposes such as i) testing next generation vaccine candidates and therapeutics; ii) determining immune correlates of protection to be used as surrogate endpoints in future trials; iii) improving understanding of the pathogenesis of, immune response to, and transmission of SARS-CoV-2;

and iv) characterizing vaccine responses to variants of concern. This report of a joint World Health Organization (WHO) and United Kingdom (UK) Health Research Authority (HRA) workshop reviews the early efforts of international and national institutions to define the ethical standards required for COVID-19 human challenge studies during the pandemic as well as the experience of researchers who are now conducting such studies. This workshop took place in July 2021 following the initial enrolment of participants to two COVID-19 human challenge studies.

In May 2020, the WHO published an outline of key criteria for the ethical acceptability of COVID-19 human challenge studies (WHO Key Criteria) (7) . This document aimed to provide guidance to scientists, research ethics committees, funders, policy makers, and regulators in deliberations regarding SARS-CoV-2 challenge studies by identifying (especially salient) conditions that would need to be satisfied in order for such studies to be ethically acceptable.

The WHO Working Group for Guidance on Human Challenge Studies in COVID-19 was tasked with developing this guidance and was formed as a sub-working group of the International Working Group on Ethics and COVID-19. Additional expertise was co-opted for this working group, including experts involved in a pre-existing WHO initiative to develop broader guidance on ethical issues in human challenge studies.

Eight interconnected ethical criteria were highlighted as key considerations to be addressed for COVID-19 human challenge studies (in addition to other usual research ethics criteria and local requirements) (7) . In brief, SARS-CoV-2 human challenge studies:

1. Must have strong scientific justification.

Must have a reasonable expectation that the potential benefits of the study outweigh the risks, particularly in comparison to alternative scientific methods.

3. Should be informed by consultation and engagement with the public as well as relevant experts and policy makers. 4 . Should involve close coordination between researchers, funders, policy makers and regulators.

5. Should undergo appropriate site selection to ensure research is conducted in places where it can be performed to the highest scientific, clinical and ethical standards. 6 . Should ensure that participant selection criteria limit and minimize risk. 7. Should have expert review by a specialized independent committee.

In mid-2020, the National Health Service (NHS) HRA formed a Specialist Ad-Hoc Research Ethics Committee (Specialist REC) to consider UK applications for ethics review of COVID-19 human challenge studies. The Specialist REC was formed of eighteen experienced members from existing RECs from a range of professional backgrounds and nationalities (twelve from England, three from Scotland, two from Wales and one from Northern Ireland). The committee included twelve expert members (people with relevant formal qualifications or professional experience that can help the REC understand particular aspects of research proposals), three lay members (people who reflect the currency of public opinion and are not employed in health or care professions or whose primary professional interest is not healthor care-related research) and three lay "plus" members (lay people who are not and have never been i) health care professionals; ii) involved in the conduct of clinical research other than as a participant; or iii) a chairperson, member or director of a health service body or body which provides health care), with this balance of lay and expert members required by law under clinical trial regulations (8) . The UK Specialist REC was recognised by UKECA (United Kingdom Ethics Committee Authority). The HRA provided this group of Specialist REC members with specific training, the development of which was informed by the WHO Key Criteria.

The UK was the first and remains the only country in the world to commence COVID-19 human challenge studies (9) . The UK Specialist REC reviewed and approved "A Dose Finding Human

Strain" (COHVIC), the first SARS-CoV-2 human challenge study. This study was led by researchers from Imperial College London in partnership with hVIVO (a contract research organization that specialises in human challenge studies) and funded by the Royal Free Hospital NHS Foundation Trust. COVHIC is a virus characterisation study. Using controlled doses, the aim of the study was to discover the minimum amount of virus that causes SARS-CoV-2 infection in 50% of those challenged. The study was conducted sequentially in small ≥ groups of healthy young people, aged between 18 and 30 years. Up to 90 volunteers were planned to be involved (10) . This study was submitted to the Specialist REC as separate elements, including the screening process to select potential participants (11) and the dose finding procedure (10) . The screening process was reviewed in November 2020 when it 

Overall, the workshop participants agreed that the WHO Key Criteria document is a valuable tool providing an ethical framework for the review of COVID-19 human challenge studies. In particular, lay members of the panel who were not previously familiar with human challenge studies found that having an international reference document available to navigate the complexities of ethics review for this scientific research approach was useful and reassuring.

By contrast, some participants with previous experience with human challenge studies indicated that they were already comfortable reviewing COVID-19 human challenge studies and aware of the need to address requirements such as those enumerated in the WHO Key Criteria.

The HRA approach of creating the UK Specialist REC for COVID-19 Human Challenge Studies as a dedicated national committee for the assessment of COVID-19 human challenge studies to ensure rigorous and timely review is in accord with criterion seven of the WHO Key Criteria (7) , which recommends the formation of specialized independent committees with high levels of expertise. In addition to individuals with relevant expertise, the UK Specialist REC also included a significant proportion of lay members. This composition ensured the committee had broad representation, including relevant experts as well as people from outside the healthcare sector who reflected the currency of public opinion. In addition, in order to reduce potential bias in favour of human challenge trials, the committee was purposively designed to include members who did not have human challenge study review experience. This composition was selected to ensure the panel included members who would be open to critiquing proposed human challenge studies. In order to provide appropriate background on human challenge studies to members without human challenge study experience, the HRA developed a specific COVID-19 human challenge studies training module informed by the WHO Key Criteria. The UK Specialist REC members all acknowledged that this training was particularly valuable for both education and team building in the early preparatory stages after the committee was established. Now that the UK Specialist REC and HRA training materials have been deployed, this committee will be able to rapidly review future COVID-19 human challenge studies and will contribute to enhanced local capacity for human challenge study review for future pandemic preparedness.

The Specialist REC had a number of important priorities that needed to be balanced during the assessment period, including training of committee members, rigorous ethics review of available information, and timely assessment to avoid undue delay in starting potentially beneficial research. To expedite the review of the study, the project was separated into discrete elements for assessment, including review of the screening procedure, dose finding procedure, and the protocols to evaluate potential interventions (therapeutics/vaccines).

The UK has a well-established regulatory system comprising over 60 coordinated committees, approximately 1000 trained members and a variety of expert committee members, researchers and regulators with significant experience in human challenge studies established over decades (over 350 human challenge studies have been conducted to date in the UK).

Therefore, the generalizability of the UK's experience to other settings may be limited.

However, given the urgency, risk, and uncertainty involved, a highly experienced and wellresourced setting was arguably one of the best environments for the first COVID-19 human challenge studies. This setting aligns with the recommendations of criterion five in the WHO Key Criteria, which states that these studies should be situated where the research can be conducted to the highest scientific, clinical and ethical standards (7) . As the only country in which COVID-19 human challenge studies have been performed, insights from the UK Specialist REC experience will be valuable for RECs who may review similar studies in other settings, or in the context of a pandemic with a new pathogen in the future.

Overall, researchers observed that the WHO Key Criteria built confidence and provided reassurance regarding the potential international acceptability of COVID-19 human challenge studies. It also provided consensus guidelines regarding the key ethical elements to be addressed in study design and preparation for ethics review. The researchers found that interactions with the UK Specialist REC provided a forum for debate and promoted confidence in the study design and protocols, in addition to providing robust ethics review.

The structure and facilitatory model of the UK research ethics committee reviews enabled timely review of initial submissions and amendments in the face of a rapidly changing scientific and public health landscape. By separating the review of the study into separate elements, including review of the participant screening procedure, dose finding procedure, and protocols to evaluate drugs/vaccines, there were multiple opportunities for meetings between researchers and the UK specialist REC, with three rounds of review undertaken for both the COHVIC and the COV-CHIM01 studies in total. These meetings provided additional opportunities for amendments to be presented and discussed and the risks and benefits of the studies to be reassessed as the scientific and public health settings of the pandemic evolved. This facilitatory and highly researcher-facing participatory structure represents a model of good practice for ethics review of certain novel, complex or sensitive study designs, particularly where the associated scientific and public health settings pertaining to the study are rapidly evolving. inform key scientific, clinical and public health questions (19) . Compared to field studies, human challenge studies provide a level of control that is impossible to achieve in the field. COVID-19 human challenge studies could also provide a platform for future vaccine candidates to be directly and rapidly compared to licensed vaccines, rather than undergoing large-scale comparative field studies. It is important to note that comparative field studies are rarely performed. Because vaccines are usually made by different companies, comparative field studies entail significant commercial risk and are therefore not a priority of commercial companies. While the expense involved in conducting large field studies is prohibitive to most independent researchers. It is also difficult to compare efficacy between field trials conducted by different investigators due to differences in trial design, population, public health settings and timing of the studies. Although COVID-19 human challenge studies offer a potential method to directly compare vaccines, a significant potential barrier to this work would be the feasibility of accessing a healthy, unvaccinated population to recruit for these studies in the UK, for example. It is expected that studies that aim to recruit a vaccinenaïve population would require additional community engagement and consultation work to be performed and significant revision of the current recruitment strategies. COVID-19 human challenge studies could enable optimization of future vaccination strategies through the i) assessment of the durability of protection by challenging participants at predefined timepoints after natural infection or vaccination to inform the use and optimal timing for booster vaccine doses; ii) to compare novel vaccination schedules, such as heterologous vaccine combinations; and iii) assessing the incremental benefits of new vaccines compared to a baseline of previous vaccination/immunity. Finally, COVID-19 human challenge studies could be used to study vaccine efficacy against circulating SARS-CoV-2 variants of concern using challenge strains made using these variants (8, 15) . Importantly, it must be acknowledged that there would be inevitable delays to commencing COVID-19 human challenge studies with novel variants of concern due to the lead time required to select and Scientific progress has also enabled researchers to further mitigate risk to potential participants by utilizing real-time data of clinical outcomes in the proposed participant population (i.e. previously healthy young adults naturally infected in the UK) in risk assessments via the QCovid algorithm (20, 21) . Such quantitative assessments can inform participant screening (to estimate individual absolute risk for hospitalization or death) and, if required, therapeutic interventions to reduce the likelihood of progression of disease in patients with COVID-19 (e.g. monoclonal antibodies (22, 23) , corticosteroids (24, 25) , nonsteroidal immunomodulatory agents such as tocilizumab and baricitinib (26) (27) (28) (29) and specific antivirals such as molnupiravir (30, 31) ). Some REC members with prior experience in human challenge studies reflected that malaria human challenge studies (in malaria naïve participants) could be perceived as higher potential risk to participants than COVID-19 human challenge studies in the planned study population of healthy young adults. It is inevitable that SARS-CoV-2 will continue to evolve, as will the scientific understanding of individual and public health impacts of COVID-19, including preventative and therapeutic interventions.

Human challenge studies will require regular reassessment and, in some cases, redesign to ensure that they meet the rigorous ethical standards demanded of research involving healthy volunteers.

Future steps may include the development of COVID-19 human challenge studies in additional settings. In preparing for future ethics review of COVID-19 human challenge studies internationally, the workshop members identified several ways that the WHO Key Criteria could be adapted to improve implementation and engagement. In particular, the requirements outlined by the WHO Key Criteria could be made more accessible to a wider audience by i) translating the document into further languages; ii) producing associated documents to target specific audiences (e.g. lay people, media and policy makers); and iii) the addition of implementation materials (e.g. case studies) for multiple stakeholders (including research ethics committee members and researchers) as annexes. Initial training in the review of COVID-19 human challenge studies was identified as a valuable part of preparation for the UK Specialist REC. The addition of case studies to the WHO Key Criteria informed by the UK Specialist REC experiences would help provide material for this training and will provide examples and scenarios for appropriate local or national resources to be created by groups in other countries preparing to review COVID-19 human challenge studies.

There has been explosion of scientific discovery related to COVID-19, with human challenge studies being a potentially valuable component of ongoing research to improve our understanding of this important infectious disease. This workshop provided an opportunity to assess the performance of the WHO Key Criteria in practice and learn from the experience of the UK Specialist REC that reviewed the first COVID-19 human challenge studies, along with COVID-19 human challenge researchers. Overall, the experience of workshop members suggested that the WHO Key Criteria was useful in a real-world setting by supporting researchers and research ethics committees including in the training of ethics committee members. There was broad agreement that the WHO Key Criteria represented an international consensus document that played a powerful role in setting norms and delineating the necessary conditions for the ethical acceptability of COVID-19 human challenge studies. Importantly, given the rapid pace of scientific discovery related to COVIDchallenge studies will require regular reassessment to ensure that conducting research involving the intentional exposure of healthy volunteers to SARS-CoV-2 is justified.

The ethics review structure implemented by the UK HRA for the review of the first COVID-19

human challenge studies represented a model of good practice for ethics review of novel, complex and sensitive study designs. The two key elements of this structure included i) the formation of the Ad-Hoc Specialist REC for COVID-19 Human Challenge Studies, comprised of a specifically selected panel with broad and unbiased representation that was provided with specialized COVID-19 human challenge study training; and ii) a facilitatory review structure with studies separated into discrete elements, reviewed over multiple sessions, that both expedited the review and delivery of the study and accommodated the dynamic responses required in the context of the rapidly evolving scientific and public health landscape.

In future, a wider audience may be engaged by the original WHO Key Criteria document through supplementation with additional materials and ancillary documents, informed by the UK Specialist REC experience. The availability of international guidance as well as capacity building based on the UK experience may help to promote public confidence in this important type of research in other settings.

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☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work

The authors declare no conflicts of interest.

Medical Research Council (GNT2005380).

All authors attest they meet the ICMJE criteria for authorship.