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.
In modern medicine most treatments, such as statins for cholesterol and anti-inflammatory drugs for rheumatic diseases, only have “small-to-moderate” effect sizes – around 10-20% reductions in the likelihood of having a bad outcome. This is comparable to the overall effect seen in Recovery with dexamethasone, although the impact in the sickest patients was larger. While effects of this size may not seem much, when used at the scale of a pandemic or in combination with other treatments with similar “modest” effects, they can have a tremendous impact on population health.
However, small trials (involving hundreds of people) are not usually sufficient to convincingly identify these beneficial treatments because of the natural differences between people. Recovery was designed to overcome this problem – each possible treatment was studied in many thousands of patients to ensure the results could be relied on, and were not just down to the play of chance.
To conclude a rollercoaster month, Recovery announced its preliminary results on the antiviral drug combination lopinavir/ritonavir in late June 2020. Like hydroxychloroquine, this drug had already been recommended by some national clinical guidelines. It was being widely used around the world based on hints of efficacy in laboratory tests, but had not yet been proven to help hospitalised Covid patients. Recovery showed the drug combination was not effective at preventing deaths in hospitalised patients, helping to redirect busy clinical staff and stretched healthcare resources towards treatments that would actually make a difference.
A disappointing but equally important result
Convalescent plasma has been tried as a treatment for various infections for more than a century, without any definitive evidence to show whether it works or not. The idea is simple and appealing: people recently recovered from an infection usually have high levels of antibodies in their blood against the pathogen responsible. By collecting that blood and separating the plasma (the antibody-containing liquid in which blood cells are suspended), antibodies can then be given to other people in the early stages of the same infection, in whom it might prevent severe disease or death.
This was one of the earliest treatments tried for Covid-19, but could Recovery find definitive proof of whether it worked?
The most influential early data came from a large US observational study – a non-randomised study comparing people who happened to receive different treatments as part of their medical care. This found that hospitalised Covid patients who received convalescent plasma with high antibody levels had a third lower chance of death than those given plasma with low antibody levels (the control group in this study). This finding was used to justify widespread use of convalescent plasma in the US, where it has been given to hundreds of thousands of Covid patients.
However, this study had serious limitations – not only was there no control group that didn’t receive any convalescent plasma, but the study was not randomised. Many factors determine which treatments different patients receive, including considerations that aren’t reflected in the medical records. For example, we know that experienced doctors often place more weight on how unwell a patient looks than individual test results. If patients receiving a particular treatment are on average sicker than those who don’t, any conclusions about the effects of that treatment could be false.
Non-randomised observational studies can’t typically find a way around this issue, so while they have many uses, they don’t reliably tell us if a particular treatment works. Yet this long-recognised limitation did not stop some misleading observational results being widely promoted and acted upon for the treatment of Covid-19.
What was needed was evidence from a study that was both randomised and sufficiently large to provide clear results. By the time Recovery had finished testing convalescent plasma in January 2021, 10 small randomised trials of the same treatment had already been reported, totalling more than 1,600 Covid patients. Yet even taken together, they were too small to tell us whether convalescent plasma reduced the risk of death by 40%, or had no effect at all. Recovery randomised 11,000 patients, increasing the statistical power more than tenfold, and showed very clearly that convalescent plasma was of no material benefit for patients with severe Covid-19.
While disappointing, this negative result was definitive enough to enable UK research and clinical practice to move on to new Covid treatment targets. In fact, Recovery subsequently showed that higher doses of human antibodies targeted specifically at the virus, but produced in the lab instead of collected from recovered patients, did reduce the risk of death in patients with low antibody levels. Other studies continue to investigate whether convalescent plasma could be effective if given at much higher doses, or very early in an individual’s Covid infection.
We now know more about Covid-19 than most older diseases
In all, Recovery has now demonstrated the effectiveness of four life-saving medical treatments for Covid-19, and given clear conclusions on six other treatments that do not work. The effective treatments, which had mostly inconclusive results in other trials, were each found to reduce the risk of death among hospitalised Covid patients by 10-20%. Since their effects are additive, given in combination they can reduce the risk of death by around 40-50% for severely ill patients, compared with the likelihood of death when the pandemic was declared in March 2020.
Because of Recovery, we now know more about the treatment of Covid-19 than most much older diseases. Recovery was part of an extraordinary response by the NHS, the National Institute for Health and Care Research, UK Research and Innovation and many other organisations that, hopefully, won’t need to be repeated soon. However, it offers a roadmap for how much progress could be made in other areas of medicine by randomising more patients in treatment trials, and integrating these trials within routine care to minimise the burden on clinical staff.
Importantly, establishing simple trials with broad eligibility criteria in all UK hospitals opened up Recovery’s research to Covid patients from disparate backgrounds, avoiding the usual under-representations. For example, the ethnic group breakdown in the dexamethasone result is very close to the overall distribution of the UK population, and also the proportions among hospitalised Covid patients. This has helped to provide practice-changing results for all patients both within and outside the UK.
Recovery has always focused on the effect of different drugs on mortality. This ensures that everyone can easily understand the answers the trial delivers: does the treatment save lives or not? Information on mortality can also be easily collected from national databases, providing additional sources of comparison for evaluating longer-term survival.
Recovery was thus able to deliver the sort of certainty that could be understood by everyone – doctors, patients and politicians alike – anywhere in the world, and be put into practice quickly.
What could Recovery mean for the future of drug testing?
The results of the Recovery baricitinib comparison in March 2022 demonstrated that, while some may try to “move on” from Covid-19, the search for new and better treatments continues. Baricitinib (another anti-inflammatory drug used to treat rheumatoid arthritis) was found to reduce death by an additional 13% on top of the mortality reductions achieved with existing treatments. Recovery was the only baricitinib trial that included large numbers of patients receiving other immunosuppressive drugs, meaning we now have more confidence about using combinations of Covid treatments in larger groups of people.
In our view, Recovery could be the catalyst for a seismic shift in the way clinical research is conducted in the UK and elsewhere. The trial has shown that, in a time of crisis, an entire country can break through the established status quo to collaborate together for a common goal, to enormous effect.
Tens of thousands of patients are admitted to hospital each year for conditions such as heart attacks, influenza, stroke and pneumonia. These diseases kill large numbers of people each year – many more than Covid-19 – yet the evidence base for treatment of some of them is now of worse quality.
Enrolling the majority of these patients into nationwide, randomised trials such as Recovery could provide definitive answers to many treatment dilemmas within months. Decisions about which treatments are better for a particular patient group are being made by doctors every day, based on limited evidence and without improving the evidence base for future patients. Instead, through a national randomised trial programme, we could all be learning with each patient who requires clinical care.
Furthermore, such opportunities for clinical research should not be limited to the UK. Recovery is now recruiting patients in six countries in Africa and Asia. By including clinically relevant common diseases and evaluating widely-available treatments, future benefits could be accessible across the world. Large collaborative trials can be managed via online resources, randomisation can be performed online, and (where available) follow-up can be facilitated through electronic healthcare records and simple questionnaires.
We also hope that governments and research funders can make it easier for similar large trials to happen – and for doctors and patients everywhere to be involved. The ball has already started rolling at the highest levels including the G7, but this transformation needs continued support.
Recovery has shown that these trials do not require complicated technology, expensive drugs or fancy laboratories. In the UK, pragmatic trials can be run at exceedingly low cost by making better use of the wealth of existing NHS clinical research and healthcare data infrastructure. Using this approach, we could achieve small but continuous improvements in healthcare that, when combined, lead to increased longevity and reduced disability, easing the strain on our health services. This would represent a major financial saving for the UK as a whole.
Recovery has also underlined the importance of embedding clinical trials in routine medical practice. Well-designed trials are carried out with patients and for patients in a healthcare system that recognises we don’t always know which treatments work, but that is committed to finding out. Through such a system we can achieve multiple, incremental improvements in patients’ health outcomes, and focus scarce medical resources on those things we know work while abandoning the many that do not.
As a result of Recovery, the chances of survival for a patient admitted to hospital with Covid-19 today are substantially better than they were two years ago. Now is the time to apply these lessons to the many other health challenges we face.