Dr. Kerry Nield PhD
Dr. Juergen Dobmeyer MD
Dr. David Cook PhD.
Disclaimer
This article represents the opinions of the authors and does not represent the opinions of any business or entity for which the authors work or have worked.
One of the central tenets of healthcare provision is that all patients have the right to expect equal treatment. Unfortunately, much as we might wish to offer the best treatments to all, there are only finite resources available and so it is necessary to balance the needs of different patients to ensure their fairest distribution. This is a difficult balancing act, but over the years we have developed approaches to ensure such judgements are as objective and as equitable as possible. In the UK, the National Institute for Health and Care Excellence (NICE1) is responsible for doing this, but the approaches taken by NICE are not unique and similar methods are used by healthcare systems around the world.2
Non-pharmaceutical interventions such as the imposition of societal restrictions, ‘lockdowns’, aim to have clinical outcomes i.e., a reduction in COVID-19 cases and deaths. However, unlike almost all other medical inventions these have not been subjected to the normal assessments used to test their effectiveness and worth.
So, what if lockdowns were a new treatment, ‘Lockdown™’, would we use it?
Three important areas are considered by authorities before a new therapeutic is recommended for use:
1. Efficacy and cost effectiveness
2. Safety and the Benefit/Risk profile
3. Lost opportunity cost
Efficacy and cost effectiveness of Lockdown™
Firstly, let’s be explicit about what Lockdown™ is. Lockdown™ is the use of societal restriction applied to the general population based purely on geography, (e.g. a country), with the aim of limiting general social contact between individuals as a way of minimizing the spread of SARS-CoV-2 within that population.
In order to assess the cost effectiveness of a treatment, health technology assessors such as NICE use the concept of a ‘quality adjusted life year’ or QALY.3 QALYs capture the idea that quality of life is important, not just its extension. A treatment may produce more QALYs if it gives patients a shorter length of high-quality life than one that gives them a longer period of low-quality life.
Before we can assess cost effectiveness, we first need to estimate the efficacy of Lockdown™ and to do this we must decide on what outcome(s) is most important; our ‘primary clinical endpoint’. The main aim of Lockdown™ is to prevent deaths associated with COVID-19 and so we shall use this. This endpoint is objective, easily countable and broadly comparable between countries and regions.
Normally treatment efficacy would be determined by extensive clinical testing, something to which Lockdown™ has not been subjected. However, what if we treated the prior use of Lockdown™ by countries and states as clinical trials? Can we use these ‘trials’ to estimate the efficacy of Lockdown™?
From a design perspective, and in contrast to gold-standard double-blind, placebo-controlled trials, the trials of Lockdown™ were single-arm, unblinded, open-label studies. They were single-arm studies because there was only one treatment (Lockdown™) without a direct comparator, and unblinded and open-label because everyone knew who got the treatment and what the treatment was.
The problem with this kind of study is it leads to the problem of assumed efficacy.
This is because the use of the treatment always leads to the outcomes we observe. So, in the UK, following the use of Lockdown™ in March 2020, SARS-CoV-2 infections declined and overall, there were approximately 41,000 deaths attributed to COVID-19.4 But, how do we know that this was due to Lockdown™? How do we know that crossing our fingers and hopping on one leg wouldn’t have produced the same result? How can we separate correlation from causality?
This can only be done by comparing the use of Lockdown™ with other, alternative approaches.
One way to do this is to compare Lockdown™ to a theoretical ‘no treatment’ scenario in which SARS-CoV-2 infection is allowed to run unchecked through the population. Such comparisons can be made using computer modelling but are fundamentally flawed as they assume that the alternative to Lockdown™ is doing nothing. In practice, Lockdown™ is used in addition to less ‘invasive’ measures, such as physical distancing and hand sanitizing, which themselves can have significant impacts on the spread of viruses like SARS-CoV-2.5 So, comparisons to theoretical no-treatment scenarios are likely to substantially over-estimate the efficacy of Lockdown™.
Ideally, to get a grip on the likely efficacy of Lockdown™ we would compare its use with other strategies. Luckily, Rabail Chaudhry and colleagues have done just such an assessment looking at the impacts of government actions on COVID-19 mortality across several different geographies.6 They concluded:
Rapid border closures, full lockdowns, and wide-spread testing were not associated with reductions in the number of critical cases or overall mortality.
They did however note that Lockdown™ may produce a more rapid decline in viral transmission rates, an observation supported by more recent analysis by the UNCOVER Group.7 So, it appears that Lockdown™ can accelerate the rate of decline of SARS-CoV-2 infection, but its impact on deaths due to COVID-19 is likely modest. Why might this be?
To understand the impact of an infectious disease on mortality we can use the infection fatality rate (IFR). The IFR represents the proportion of people who would die in a population infected with a given pathogen; the higher the IFR the more deadly it is. For SARS-CoV-2 the IFR is not fixed and increases substantially with age and for those with underlying health conditions (‘co-morbidities’).8, 9, 10 The most recent estimates of the Global IFR for SARS‑CoV-2 is 0.15‑0.2% for the whole population.10 For those under 70 it is only 0.03‑0.04%, which is similar to swine flu.10, 11
So, the substantial risk of death due to SARS-CoV-2 infection is mainly present in a minority of the population who likely have other medical conditions. This could explain why, despite Lockdown™ potentially accelerating the decline in viral infection,6, 7 it only has a modest impact on COVID-19 related deaths.6 A more rapid decline in infections in individuals who are unlikely to die due to COVID-19 has minimal impact on deaths, whilst those with underlying health issues may, ironically, end up in situations such as hospitals where they are more likely to be infected,12 perhaps increasing their likelihood of developing COVID-19.
Overall, although computer models can suggest a significant impact of Lockdown™ on COVID-19 related deaths, in reality it is only likely to be modest.
David Miles and colleagues3 have done an extensive analysis of the cost effectiveness of Lockdown™ in the UK using QALYs. This analysis demonstrated that even when compared to high mortality (no treatment scenarios), the huge economic cost of its use (approx. £190 billion) means Lockdown™ would not be considered cost effective. In more realistic scenarios, the cost per QALY is many multiples of what is normally considered economically viable.
Therefore, based solely on the usual criteria for cost effectiveness in the UK, Lockdown™ would not be recommended for use as an intervention.
Benefit/Risk of lockdown
QALYs and costs are not the only considerations in assessing whether a therapy should be used. Because most pharmaceuticals carry with them potential side-effects, it is important to have evidence that the benefit to the patient outweighs the potential negative impacts of the treatment…the “pill cannot be worse than the ill”.
As discussed above, the benefits of Lockdown™ are mainly to the more elderly population however, the side effects affect all individuals treated with Lockdown™ and are actually likely most impactful in younger people and children.13
In other words, the use of Lockdown™ risks substantial harm to individuals who are unlikely to receive any benefit from treatment.
For Lockdown™ some of the adverse events are now becoming clear. Most concerning are the impacts on mental health, which can lead to depression and suicide:14, 15
“Social isolation, anxiety, fear of contagion, uncertainty, chronic stress and economic difficulties may lead to the development or exacerbation of depressive, anxiety, substance use and other psychiatric disorders in vulnerable populations…”15
The safety burdens associated with Lockdown™ are substantial, diverse, and long-lasting, meaning the benefit/risk profile is extremely unfavourable. If it were approved, Lockdown™ would carry “black box” warnings on its label with respect to likely adverse events, indicating that its use comes with significant risks.
Lost opportunity cost of Lockdown™
There are only finite resources within any healthcare system and so a decision to invest in one treatment may result in an inability to do something else. This is called the ‘lost opportunity cost’. If we accept the tenet that all patients are entitled to be treated as equitably as possible, then this means we should not invest in a treatment for one group of patients to the disproportionate disadvantage of another.
This is best understood by an analogy; imagine we have a new treatment for cancer, but to use this treatment we had to stop all hip-replacement operations. We might even prove that the loss of QALYs to (non-essential) hip-replacements was less than the (life-extending) gain in QALYs to cancer patients. Regardless, such a treatment would not be recommended because the fact that patients needing a hip-replacement can no longer receive treatment makes the lost opportunity cost unacceptable.
In scenarios where COVID-19 patients overwhelm the healthcare system, a focus on limiting the number of COVID-19 patients benefits everyone. However, it is now clear that Lockdown™ has had a substantial impact on the ability of the healthcare system to meet the needs of non-COVID-19 patients. In the UK alone, government analysis suggests that due to individuals not seeking medical help or the late diagnosis of cancers, there may be as many as 75,000 non-COVID-19 related deaths directly attributable to the use of Lockdown™ in March 2020.16 Also, as with our analogy above, even ‘non-essential’ operations are aimed at improving the quality of life for individual patients and so the loss or delay of these procedures translates into a significant loss of QALYs for those affected.
Overall, the lost treatment opportunities for non-COVID-19 patients mean a substantial reduction in QALYs for patients across many different indications. Understanding all of these impacts will take years because they will be spread over such a wide number of people, but they will be significant and in some cases life-limiting. Overall, the lost opportunity costs associated with Lockdown™ could substantially outweigh any benefits gained.
Final thoughts
As recent European experience demonstrates, the benefits of Lockdown™ are transient. Once treatment finishes, infection rates pick up, leading potentially to the need for more Lockdown™. So, to be effective, Lockdown™ would need to be used chronically. However, the huge expense, poor safety profile and substantial lost opportunity costs, make Lockdown™ extremely unlikely to be recommended for use, especially as a chronic intervention. If Lockdown™ is to be used, it should only be as a therapy of last resort, a point made by Dr David Nabarro, the WHO’s special envoy on COVID-19.17 Although the WHO have modified this position to some extent,18 it is still clear that Lockdown™ should only be used with great caution.
The use of quarantine and physical measures to limit the spread of infectious disease is well established and so it is not the fundamentals of Lockdown™ that are the issue. The problem with Lockdown™ is its blanket deployment based on geography rather than risk.
We would not give everyone in society a course of chemotherapy in order to treat cancer, we’d focus on those who needed it. For COVID-19 we now have a much better understanding of who is at risk. For the majority of the population the risk is low and only really significant in the more elderly population or for those with underlying health issues.8, 9, 10 So, a focused or ‘Precision Medicine’ approach to using Lockdown™ would mean using societal restrictions to protect vulnerable individuals.19 Such focused efforts are not without their own problems and challenges, not least ensuring that the rights of at-risk individuals are respected, but given the issues associated with Lockdown™ we should at least explore alternatives. Either that or accept that the negative consequences to individuals and society of the use of Lockdown™ will live well beyond the COVID-19 pandemic and could dwarf it in their significance to public health.
About the authors
Dr. Kerry Nield Ph.D has a BSc (Hons) in Human Genetics from University College London and a PhD in Molecular Genetics from the University of Manchester. She has over 17 years’ experience in clinical research and drug development, primarily within the biotech sector.
Dr. Juergen Dobmeyer MD is a Clinical Research Physician with over 25 years global experience in drug development & clinical research. The focus of his activities is translational clinical development in rare diseases, haemato-oncology and development of antimicrobials. Juergen is a European Union Marie-Curie Experienced Researcher Alumnus, a board-certified physician with licence to practice and training in immunology, infectious diseases, and oncology
Dr. David Cook Ph.D has a BSc (Hons) in biochemistry from University of Bath and a PhD from Imperial College London. He has over 20 years of industrial experience in the development of new drugs from new research ideas, through clinical development to the support of marketed products.
References
2 Xcenda, February 27, 2020. A tale of 2 frameworks: impact of ICER and NICE updates on future HTAs and market access.
3 Miles D, Stedman M, Heald A. Living with COVID-19: balancing costs against benefits in the face of the virus. National Institute Economic Review 2020;253:R60-R76.
4 The official UK Government website for data and insights on Coronavirus (COVID‑19).
5 Chu DK, Akl EA, Duda S et al. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis. Lancet 2020;395(10242):1973-87.
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7 Li Y, Campbell H, Kulkarni D et al, for the Usher Network for COVID-19 Evidence Reviews (UNCOVER) group. The temporal association of introducing and lifting non-pharmaceutical interventions with the time-varying reproduction number (R) of SARS-CoV-2: a modelling study across 131 countries. Lancet Infect Dis 2020.
8 CDC Coronavirus 2019 (COVID-19) Pandemic Planning Scenarios.
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12 Heneghan C, Howdon D, Oke J, Jefferson T. The ongoing problem of UK hospital acquired infections. The Centre for Evidence Based Medicines, October 30, 2020.
13 Ladhani S, Viner RM, Lynn RM et al. Lockdown measures reduced the risk of COVID-19 but had unintended consequences for children. BMJ Opinion August 6, 2020.
14 Pell R, Fryer E, Manek S, Winter L, Roberts ISD. Coronial autopsies identify the indirect effects of COVID-19. Lancet Public Health 2020;5(9):e474.
15 Sher L. The impact of the COVID-19 pandemic on suicide rates. QJM: An International Journal of Medicine;113(10):707-12.
16 Direct and Indirect Impacts of COVID-19 on Excess Deaths and Morbidity: Executive Summary. Department of Health and Social Care, Office for National Statistics, Government Actuary’s Department and Home Office. 15 July 2020.
17 https://californiaglobe.com/section-2/who-official-urges-world-leaders-to-stop-using-lockdowns-as-virus-control-method/
18 https://globalnews.ca/news/7398396/coronavirus-lockdown-who-reality-check/
19 Smith JD, Spiegelhalter D. Shielding from COVID-19 should be stratified by risk. BMJ 2020;369:m2063.
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