COVID-19 trial transformed treatment – and what it could do for other diseases
Oxford, June 20: Two years ago this week, the Recovery trial transformed the care of COVID patients with its dexamethasone announcement. Within four hours, the steroid was included in NHS treatment recommendations. Almost overnight, treatment of COVID patients around the world changed completely. It has been estimated that dexamethasone may have saved a million lives in the first nine months following the announcement.
Recovery, jointly led by Oxford Population Health and the Nuffield Department of Medicine, is a groundbreaking scientific machine which, from the outset, moved at unprecedented speed. Within 15 days, more than 1,000 participants around the UK had joined the trial; five weeks later, that number had risen to 10,000. In the first 100 days alone, the trial produced three groundbreaking results that would completely reshape COVID care.
From an impromptu discussion between two professors on a London bus to headlines around the world – and a baby being born at home in the midst of the pandemic – this is the inside story of Recovery, by three medics who have been part of this extraordinary journey.
The vast and unique nature of the NHS provided the perfect setting for the trial’s rapid development. Indeed, if a similar approach could now be employed for other common and important diseases, we believe it could transform the quality of evidence supporting treatments for millions more people in the UK and around the world.
Early March 2020. Despite growing concerns about the worldwide spread of COVID-19, life in the UK continued pretty much unchanged. Daily commuting, large sporting events and international travel all kept going, even after the virus began circulating within the UK and the first deaths occurred.
But in scientific circles, discussions were already under way about how to respond to this mysterious virus. Following a call for research proposals in early February, public funding for a UK-based trial was agreed on March 5.
Four days later Professor Martin Landray, an experienced clinical trialist based at Oxford Population Health, and Sir Jeremy Farrar, director of Wellcome, happened to meet on a No.18 London bus journey. Both agreed that a major public health crisis was looming.
“What we agreed on that bus trip was that the tsunami would arrive within a fortnight,” Landray later recalled. “So we had to have the trial up and running within two weeks.” On March 11, the World Health Organization declared COVID-19 a global pandemic, and on March 23, the UK imposed its first national lockdown.
Landray joined forces with Professor Peter Horby, a specialist in emerging infectious diseases at the Nuffield Department of Medicine. They recognised that COVID-19 was an entirely new disease for which no proven treatments were available. Many were making educated guesses regarding what did and didn’t work, resulting in a jigsaw of different clinical recommendations around the world, but no one knew much for certain.
And so Recovery (short for the Randomised Evaluation of COVID-19 Therapy) was established to embrace, rather than deny, these uncertainties – and to harness the best scientific methods to resolve them, rather than relying on hype or hope.
But this mantra did not land well with some people, who mistook scientific rigour and the quest for definitive answers for dangerous delaying tactics, thinking they already knew which treatments would and wouldn’t work. As Horby later recalled: “I’ve got a drawer full of letters telling me I’m killing people.”
To be successful, Recovery needed a mechanism for conducting randomised controlled trials at a scale large enough to provide conclusive evidence. Unless the number of patients involved in such a trial is large, the play of chance can mean sicker patients are more common in one group, masking any effect of the treatment being tested (in the same way you need to toss lots of coins for the number of heads and tails to be reliably balanced).
Thousands of patients had to be enlisted as soon as possible. This was no trivial task – especially given the immediate impact of the pandemic on clinical research due to staff shortages and redeployment. Healthcare workers were under unprecedented strain, and there was little room for additional research commitments.
To achieve the scale required, Recovery had to be simple, making it easy for busy frontline staff to enlist unwell patients, while at the same time adhering to high scientific and ethical standards. The trial achieved this with a disruptive yet beautifully streamlined design. In part, it relied on clinical trial methodology first used in the 1980s – a highly pragmatic approach, focused on collecting small amounts of data on large numbers of people.
But it also made use of the latest available data technology – notably, the NHS’s healthcare data collection system. Much of the data generated as part of routine NHS care is gathered centrally to help allocate resources to hospitals and disease surveillance. This information can be quickly repurposed to help scientists run clinical research, and has been instrumental in the UK’s fight against COVID-19.
Professors Landray and Horby put together a small team in Oxford, drafted a protocol and submitted it to the research regulators. On March 19 – less than a fortnight after funding had been agreed – the first patient entered the Recovery trial. The speed at which this occurred was in itself a major breakthrough from traditional clinical trials, which typically take months (and sometimes years) to take off.
Every day the trial got bigger as more hospital sites were included. By the end of spring 2020, every single acute hospital in the UK – 176 in total – was a recruiting Recovery site. Now every person admitted to a hospital with COVID-19 could be asked to participate in the trial. Within 12 weeks, Recovery had grown into a truly national endeavour.
In total, around 10% of all those admitted to hospital with COVID-19 in the UK participated in the Recovery trial over the first year. In the city of Leicester alone, well over 1,000 people had taken part by the end of 2020. By itself, this one NHS Trust randomised more patients than most of the world’s largest COVID trials.
Due to its integrated nature, the NHS provided the perfect setting for Recovery. Unlike other healthcare systems in the US and Europe, the NHS is a unified, single-payer system that does not rely on medical insurance. This means in each UK nation, primary care practices and hospital sites all work in collaboration under a common leadership structure.
Drug supplies are provided and managed nationally. Each patient has a unique identifier (NHS number) assigned to them, enabling the linkage of data recorded in different places. Most information used for hospital reimbursement, disease surveillance and clinical auditing is collected centrally for the entire nation.
These features may not have been thought up or designed to enable clinical research but serendipitously, they ended up providing the precise infrastructure that was needed to deploy large-scale randomised COVID trials at rapid pace.
The process for obtaining ethical approval of studies in the NHS is also governed by a central body, the Health Research Authority, which eliminates the need for lengthy and cumbersome approval processes at each participating institution. This could have been a major limitation for Recovery, given that it spanned more than 170 hospitals across the UK. Instead, the study was approved and regularly reviewed by a single research ethics committee, greatly streamlining the entire process.
Throughout the second half of 2020 and beyond, the desire of doctors to help with the wider medical effort against COVID-19 could, in part, be channelled into making the Recovery trial a success. Instead of every department in each UK hospital trying to work out how to best care for their COVID patients, Recovery offered the prospect of a united response: “We don’t know the answers yet, but we do know how to find out – and we’re going to do it together.”
In the first 100 days alone, Recovery produced three groundbreaking results that, almost overnight, changed COVID care around the world.
Early in the pandemic in the US, the antimalarial drug hydroxychloroquine had received emergency-use authorisation by the US Food and Drug Administration (FDA). Around the world, it was being widely touted by highly influential figures including the US president, Donald Trump, and Brazil’s Jair Bolsonaro.
But on June 5 2020, Recovery released its first result, showing the drug had no clinical benefits and hinting at the potential risk of harm. Shortly after this result was made public, the FDA revoked its recommendation. This led to an immediate impact on clinical care strategies around the world.
Owing to the extreme urgency of the situation, Recovery’s approach was to issue a press release as soon as each trial’s findings had been ratified. In every case, this was followed as quickly as possible – usually within a few days – by an open-access “pre-print” scientific paper. The fully peer-reviewed version would follow in due course.
Then on June 16 came Recovery’s landmark dexamethasone result, which concluded: “One death would be prevented by treatment [with dexamethasone] of around eight ventilated COVID-19 patients, or around 25 patients requiring oxygen alone.” This cheap steroid, widely available since the beginning of the pandemic, was now a key element of COVID treatment strategies.
(AGENCIES)
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