Gathering evidence may save lives and money 

Operation Moonshot, as it has already been observed, is too expensive to miss. [1] For an estimated £100 billion, it proposes to provide 10 million point-of-care tests a day to “support economic activity and a return to normal life.” [2]

I urge the policymaker, health and research communities to take a moment to consider. These are vast sums of money—two-thirds of the annual NHS budget—being directed towards unproven technologies with the potential to fail because of poorly considered or unintended consequences.

It would be unthinkable for a government and health service to buy a new medicine (or vaccine) and make it available to an entire population without clearly understanding its safety, and clinical and cost effectiveness.

The same level of evidence should be applied to SARS-CoV-2 testing.

To illustrate the consequences of inaccurate test results, already apparent in the current system, consider the following example. The child of a care home worker develops a runny nose, fever and sore throat. The child is tested for SARS-CoV-2 and the result is negative, but it is a false negative (thought to occur in up to 29% of tests). [3] The child returns to school and the carer returns to work. Both unwittingly continue to transmit SARS-CoV-2 to classmates and vulnerable care home residents, perpetuating the spread of the pandemic. 

The consequences of false positives may be less serious from a health perspective because compliant individuals would self-isolate, but these results have economic consequences due to lost productivity and household earnings.

So population SARS-CoV-2 testing does not help us sidestep the need to balance health and wealth: the same balance is inherent in false negatives and false positives. And since for any given test reducing its false negative rate inevitably increases its false positive rate, and vice versa, it is unlikely a single test can achieve the desired balance.

While the ambition to develop test technology is laudable, and its potential as a pandemic exit strategy is clear, I call on the UK government, the Department of Health and Social Care, and the National Institute for Health Research to ensure the tests are rigorously investigated, and propose the following steps.

First, modelling should assess if widespread testing has the potential to be effective and cost-effective, taking account of the variability in (and thereby determining minimum/ maximum threshold levels for): 

• SARS-CoV-2 prevalence
• false negative and false positive rates
• the time it takes to receive test results, since the effect of a delayed true positive is the same as an immediate false negative
• individual behavioural responses to positive and negative results, since we know the public will not always modify behaviour [4]
• whether the test is conducted at home, since individual responses may vary depending on whether the result is seen only by the individual or a copy is available for external verification. 

Second, and informed by step one, those developing the tests should be required to demonstrate that: 

• sensitivity and specificity thresholds have been met using prospective studies of people with unknown SARS-CoV-2 status and where result interpretation replicates final intended use
• the test adds diagnostic value to the clinical information already available at the time of testing, namely symptoms and signs. 

This is not only because there is no point in using a test if all the diagnostic information is available by asking a few questions, but also because there may be subgroups where a test adds more value—for example in children with less specific or fewer symptoms.

Finally, if the test meets the above criteria, its safety, clinical and cost effectiveness should be investigated in large, adequately powered, randomised controlled trials, and soon, before further mass testing becomes part of usual care and public and healthcare equipoise regarding its effectiveness is lost. 

The research and commercial communities are rising to the challenge of identifying clinically and cost-effective treatments and vaccines for SARS-CoV-2, now the challenge is to produce the same level of evidence for its diagnosis. [1,5,6]

Alastair Hay, Professor of Primary Care, University of Bristol. 

Competing interests: AH is a co-investigator on a Pfizer supported study investigating the burden of vaccine preventable illness in adults with lower respiratory infection and has received supplies from BioMerieux who provided point of care test machines for a recent study. The study purchased the testing kits and returned the machines to BioMerieux at the end of the study.

References:

1. Abbasi K. Covid-19: Shooting for the moon. BMJ 2020;370:m3509. doi: 10.1136/bmj.m3509
2. Iacobucci G, Coombes R. Covid-19: Government plans to spend £100bn on expanding testing to 10 million a day. BMJ 2020;370:m3520. doi: 10.1136/bmj.m3520
3. Arevalo-Rodriguez I, Buitrago-Garcia D, Simancas-Racines D, et al. False-negative results of initial rt-pcr assays for covid-19: A systematic review. medRxiv 2020:2020.04.16.20066787. doi: 10.1101/2020.04.16.20066787
4. A M. UK MP with coronavirus admits making parliament trip: POLITICO; 2020 [Available from: https://www.politico.eu/article/margaret-ferrier-coronavirus-rules-breach-train-trip-after-positive-test/ accessed 23/10/2020.
5. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;395(10236):1569-78. doi: 10.1016/s0140-6736(20)31022-9 [published Online First: 2020/05/20]
6. Group TRC. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. New England Journal of Medicine 2020 doi: 10.1056/NEJMoa2021436
7. Pfizer and Biontech announce vaccine candidate against Covid-19 achieved success in first interim analysis from phase 3 study [https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against]