As members of the Trial Management Team of the Daily Contact Testing for COVID-19 schools and colleges trial, and the independent chair of the Public Health England (PHE) Research Ethics and Governance Group (REGG) that reviewed the trial, we have read the letter by Gurdasani et al, about the trial with care. [1,2] We welcome discussion about this important and timely trial, especially as government ministers have since stated that the trial results will inform policy for the autumn. [3]

This cluster-randomised controlled trial is comparing Daily Contact Testing (DCT) using rapid lateral flow device (LFD) antigen testing, with 10 days of quarantine for close contacts of a person testing positive for covid-19. Within the trial, 202 secondary schools and colleges have been randomised to either the DCT intervention or to a control arm.

The study tests two main hypotheses: that DCT will increase school attendance compared with the control arm, and that the level of transmission of covid-19 in schools and colleges in the DCT intervention arm is not inferior to (i.e. not higher than) the control arm. The trial protocol was reviewed prior to participant recruitment by PHE’s REGG group and given a favourable opinion on 11 March 2021 (R&D 434). This approval is confirmed in the trial registration which was made within six weeks of recruitment in accordance with Department of Health and Social Care policy. [1] PHE REGG is an established ethics committee with a track record of supporting public health research including studies of covid-19. [4] To meet the most exacting standards for safety, the study is also overseen by an Independent Data Monitoring Committee who have met weekly throughout the course of the study. We would like to reassure the authors that, as is standard for such committees, they will intervene should the data indicate increased harm to participants in either arm.

The first major theme of Gurdasani and colleagues is the ethical basis for the study. They contend that the researchers have failed in their ethical and scientific responsibilities under Good Clinical Practice. The basis of this statement rests on the assertion that there is not equipoise regarding the study hypotheses. In other words, they feel confident in their knowledge of which arm of the trial will perform better. The data they cite to support this view come from a modelling paper whose authors conclude that in a school-like setting, a combination of twice-weekly mass testing along with DCT “can allow lower prevalence and lower numbers of school days missed, if both uptake and adherence are high.” [5] While Gurdasani et al clearly disagree with this, the existence of disagreeing opinions is evidence for, rather than against, the presence of equipoise. 

Similarly, the authors of the modelling paper rightly highlight uptake and adherence as key components of real world effectiveness. While superiority may be clear from a purely scientific or mechanistic perspective, equipoise may still be present if patients or the public are unwilling to adhere to a “gold standard” intervention. In such a situation it may well be the case that an alternative intervention is more effective overall if adherence and uptake is sufficiently higher in comparison with the gold standard. This “human factor” element is common to most healthcare situations, and must also be considered when determining whether sufficient equipoise is present to justify a trial. We believe that this condition is clearly met for this trial.[6]

Gurdasani et al also raise concerns around the validity of the DCT intervention itself, and the performance of LFDs to identify infectious individuals. There are two trials underway which explore the performance of DCT, our own and one open to members of the general public. [7] These studies will gather evidence for the performance of LFDs used for DCT, given that the current (recently extended) exceptional use authorisation does not allow LFDs to be used for self-test at home by contacts of positive index cases. [8] These trials are in part driven by the Scientific Pandemic Influenza Group on Modelling (SPI-M) models which indicate that DCT could reduce the growth rate of transmission compared to self-isolation. [5] They are further supported by a study of over 1 million covid-19 cases and their contacts in the Test-and-Trace programme which has estimated that approximately 90% of infectious individuals can be detected by LFD. [9] The Department of Health and Social Care have submitted to the Medicines Healthcare products Regulatory Agency (MHRA) a request for a variation to the current exceptional use authorisation, to allow LFDs to be used in DCT, and this is under review alongside the two trials.  These studies are in fact the very processes that will guide further assessment by the MHRA of the use of these devices. 

This trial is employing the rigors of a randomised controlled trial to understand whether these predictions are supported. We are sure that Gurdasani and colleagues will support the importance of advancing our understanding of the relative efficacy of quarantine and its alternatives, especially in light of the impact that lockdown and quarantine have had on young people’s mental health, well-being and education. [10] It is the opinion of both the research team and members of PHE REGG that these additional factors also contribute to the establishment of sufficient equipoise to justify this trial at this time.

Another major theme we find in the concerns regarding this trial is the impact of the Delta variant, and whether this alteration in the viral epidemiology warrants a re-review by the research ethics committee prior to continuation of the trial. The protocol of this trial as originally presented for ethical review foresaw the overwhelming likelihood of the epidemiological landscape changing even over the short course of this study. Changes in the transmission and possible disease impacts of SARS-CoV-2 were anticipated, including increasing community protection from vaccine uptake, which will also affect transmission and effects. For these reasons, the conduct of the study has always been subject to national public health policy. Additionally, the trial has specified that schools and colleges enrolled would continue to follow public health policy. Directors of Public Health and Local Authorities retain oversight over local areas, and can direct a pause of the study if they deem this appropriate. These arrangements were considered satisfactory by the REGG.

Similarly, the DCT schools and colleges trial protocol submitted to the REGG did not specify any restriction on recruitments based on variants. Rather, at the launch of the trial these were excluded in accordance with government policy. This policy changed in early June, in the light of increasing prevalence of the Delta variant and increasing knowledge about it, and in recognition that the potential value of DCT as evaluated in the trial would be lost without assessing its performance in the context of such variants. At the time of this change, the schools and colleges in the study were advised of the policy change. 

Schools and colleges continue to follow broader risk mitigation strategies under government guidance, and have undertaken specific risk assessments. We have sought parent and teacher involvement and feedback throughout the design and conduct of the study. We join with the letter’s authors in agreeing that there are multiple potential ways to control the transmission of covid-19 in schools and colleges. Interventions that have potential benefits must be robustly evaluated to determine real world, rather than theoretical, effectiveness. To that end, we continue this study to answer the critical question of whether DCT offers a safe and well-adhered to alternative to full quarantine for our young people in education. 

Tim Peto, Principal Investigator DCT Schools and Colleges Trial, Nuffield Department of Medicine, University of Oxford, UK

Martin J Llewelyn, Independent Chair Trial Steering Committee DCT Schools and Colleges Trial, Department of Global Health and Infection, Brighton and Sussex Medical School, Brighton, UK

Simon E. Kolstoe, Chair PHE Research Ethics and Governance Group (PHE REGG), School of Health and Care Professions, University of Portsmouth, Portsmouth, UK

Bernadette Young, Investigator, DCT Schools and Colleges Trial, Nuffield Department of Medicine, University of Oxford, UK

Competing interests: none declared. 

References:

1. ISRCTN registry. Daily contact testing schools and colleges trial. 2021. https://www.isrctn.com/ISRCTN18100261.
2. Gurdasani, D et al Daily Contact testing trials in schools are unethical and extending them to include the delta variant puts everyone at risk. BMJ opinion.  2021 Jun 17
3. https://www.theguardian.com/education/2021/jun/28/ministers-set-to-end-automatic-isolation-for-pupils-in-england
4. Harris RJ, Hall JA, Zaidi A, Andrews NJ, Dunbar JK, Dabrera G. Effect of Vaccination on Household Transmission of SARS-CoV-2 in England. N Engl J Med. 2021 Jun 23 
5. SPI-M-O. SPI-M-O: Statement on daily contact testing, March 3, 2021 https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/976324/S1146_SPI-M-O_Daily_contact_testing.pdf
6. Smith LE, Potts HWW, Amlôt R, Fear NT, Michie S, Rubin GJ. Adherence to the test, trace, and isolate system in the UK: results from 37 nationally representative surveys. BMJ. 2021 Mar 31;372:n608. doi: 10.1136/bmj.n608. PMID: 33789843; PMCID: PMC8010268.
7. https://www.gov.uk/guidance/daily-contact-testing-study
8. https://www.gov.uk/government/news/following-a-satisfactory-review-mhra-extends-authorisation-of-nhs-test-and-trace-lateral-flow-devices June 17, 2021.
9. Lee LYW, Rozmanowski S, Pang M, et al. SARS-CoV-2 infectivity by viral load, S gene variants and demographic factors and the utility of lateral flow devices to prevent transmission. Clin Infect Dis 2021.
10. Ford T and Gunnel D Mental health of children and young people during pandemic BMJ 2021; 372:n614