The review of the global first SARS COV 2 Human Infection Challenge studies

By the UK ad hoc specialist Research Ethics Committee

Expert and lay members of UK RECs recognised to review Clinical Trials of Investigational Medicinal Products (CTIMPs) or Phase 1 studies in healthy volunteers, particularly those with experience of vaccine studies, were invited to join an ad hoc Research Ethics Committee to review SARS COV 2 Human Infection Challenge studies (HICS).  All were asked to attend two virtual HRA workshops before the first committee meeting (and all did!) and were provided with articles from both sides of the argument for further reading.  Given the pandemic lockdown, we met virtually, ensuring broad representation across the UK nations, and that applicants were easily able to attend (of huge help to our review).

The balance between benefits and harms was at the centre of review. The first HICS was to define the dose infectivity for further SARS COV-2 studies with wider therapeutic aims. Its acceptability, therefore, depended crucially on demonstrating purpose to these later studies, how they would contribute to the understanding and management of SARS COV2. The REC also wanted to be reassured that: –

  • the results could be generalised from healthy volunteers to the broader population.
  • the studies were justified when there were vaccines of greater than 90% efficacy.
  • these studies would continue to have value as new variants emerge.

Possible harms and their mitigation were the other part of this balance, not a unique consideration but of particular importance as volunteers could potentially be very sick. We looked closely at quantitative data on the risk of hospitalisation, admission to critical care, death and “long COVID”. The proposed care and rescue treatments along with the expertise and experience of the whole team were analysed in detail.

The applicants proposed using the qCOVID personal risk assessment tool to ensure that volunteers would be at the least risk from SARS COV 2 infection. We accepted  this but, while recognising the increased vulnerability of BAME individuals, we were keen that they should not be discriminated against and unfairly excluded from participation.

Robust consent procedures would be of crucial importance to ensure any volunteer understood what he or she was agreeing to and the attendant risks. To ensure this, we required a clear consenting schedule, starting with an introduction to outline the key facts about the study followed by a more detailed discussion in which the participant information sheet could be used as a template for discussion. After a break allowing the potential participant to reflect and ask others, understanding would be checked by a consent quiz before signed consent was taken using an itemised informed consent form, matched to the introductory “key facts”.  We required this process would be audio or video recorded.

The review of one further SARS COV 2 human challenge study has been completed. Both were given a favourable opinion after amendments were made.  Dissenting  voices on issues were recorded and those who dissented accepted the committee’s decision. The WHO criteria were a useful basis for deliberation, and only two criteria didn’t map well, but these were more about the process of review rather the ethical / scientific considerations. (Criterion 4, “Coordination” and  Criterion 7, “Expert Review”). These could be considered as being covered by the formation of the specialist REC by the HRA.  After review we would recommend one further criterion, specifically directing RECS to ask and consider alternative research designs as this was a major consideration for us. Could research questions be equally well answered by less intrusive field studies?

We worked in collaboration with the applicants, and we recognised that such proximity might raise the accusation of “collusion”. Every effort was made to maintain “moral distance” and all decisions were made by the committee alone.

In conclusion we have tried to make a decision in good faith, using the evidence we could ascertain and listening to all others with fair interest. We know there is controversy and disagreement within and without our committee and reasonable people may feel we have made the wrong decision but we feel we have given the issue detailed consideration. We can’t know whether the possible benefits outweigh the risks but we will required regular reports.

What might we have done differently?

Even with prior preparation, review took time and, in the context of a pandemic where there is an argument for speed, this could have hindered a rapid response to the emergency. Now the committee is established, we hope review for the various follow-on studies will be speedier and with time our procedures can be further refined and if we are “mothballed” once the pandemic has subsided, our group could be re-convened in future emergencies.

 

Authors and Affiliations:

UK ad hoc specialist Research Ethics Committee:

  • Miss Stephanie Ellis (Chair): Retired Civil Servant
    Dr Hugh Davies:  Retired Consultant Paediatrician, past Research Ethics Advisor UK Health Research Authority
    Professor Iolo Doull: Consultant Respiratory Paediatrician
    Mr Chris Foy: Medical Statistician
    Dr Leo James: Independent Pharmaceutical Physician
    Dr Lucy Kershaw: Research Fellow in Imaging Science
    Dr Simon Kolstoe: Senior Lecturer/Fellow University of Portsmouth
    Dr Tony Lockett: Medical Director
    Dr Thomas Woodcock: Retired Consultant – Intensive Care Unit
    Dr Ian Zealley: Consultant Radiologist
    Dr Kathrine Craig: Nurse, Chair Wales REC 1.
    Mrs Arlene Seaton: Retired Medical Publisher
    Dr Mauro Buraglio: Independent Consultant in Clinical Pharmacology and Clinical Development
    Dr Aaron Courtenay: Lecturer in Clinical Pharmacy
    Mr Lindsay Murray: Chartered Clinical Psychologist
    Dr Fran Silverton: Statistician and Lecturer

Competing interests: None

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