How to set up a trial in nine days
The COVID-19 pandemic has seen some extraordinary medical feats and achievements, which are being rightly celebrated. Researchers at Oxford University have been at the forefront of global efforts, including the first human trials of a COVID-19 vaccine, and the world’s biggest trial of potential COVID-19 treatments, RECOVERY.
The Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial has recruited more than 10,000 patients in 176 hospitals in just two months - truly incredible figures for that timescale, making it the fastest ever recruiting individually randomised controlled trial. From conception to launch took just nine days! The trial is being co-led by Professor Peter Horby from the Nuffield Department of Medicine (NDM) and Professor Martin Landray from the Nuffield Department of Population Health (NDPH), and is testing existing drugs, all with well-known side effects and confirmed safety, on hospital inpatients with suspected or confirmed COVID-19.
Each participant is randomised via a secure 24/7 web-based system. Participants receive either the usual standard of hospital care, or one of four drugs - lopinavir-ritonavir, normally used to treat HIV, the steroid dexamethasone (or alternative corticosteroids), used in a wide range of conditions to reduce inflammation, hydroxychloroquine, which is mainly used as an anti-malarial drug and the antibiotic azithromycin. The study allows a second randomisation for patients with progressive COVID-19, who receive the usual standard of care or tocilizumab, an immunosuppressive drug. The researchers will be able to fairly compare each of the treatments with usual standard of care and work out which, if any, make a difference. The trial design is flexible and as new treatments are suggested or become available, it can be adapted to accommodate them. Indeed, azithromycin, tocilizumab and most recently, convalescent plasma (CP) arms were added after the trial began recruitment; CP is about to be offered on top of the main first line randomisation options.
As an ‘Urgent Public Health Research Study’, RECOVERY qualified for a £2m grant from UK Research and Innovation and the Department of Health and Social Care, through the National Institute for Health Research. There were many factors that made this trial happen so fast, as NDPH Associate Professor Ed Juszczak explains ‘A lot of it comes down to the global importance of the research question, but also the single-mindedness and professionalism of the large number of staff on the trial. Some people have even delayed or come out of retirement to help!’
Months and years to hours and days
‘For this trial, the timeline has been re-written. All of the UK Chief Medical Officers and the NHS England Medical Director have broadcast that this trial is a national priority, that it has to happen, so everything has been sped up remarkably. That’s been fundamental to its success,’ said Juszczak. ‘The timescales have gone from months and years to hours and days, which is just phenomenal, and shows you what is possible.’
Rather than joining a queue for decisions from ethics committees and regulators, or individual hospital Trusts, the decisions have gone through quickly, though Juszczak is keen to point out that reviews were appropriately robust.
One example of the urgency is the frequency of the external and internal meetings. The trial management group meets daily. The Data Monitoring Committee, which would usually meet every six to twelve months, is meeting fortnightly. The Trial Steering Group, which would usually meet similarly often, is meeting every week. Statistics team meetings are also very frequent.
Streamlining the protocol
Clinical trials can be complicated with one, sometimes two primary outcomes, a number of secondary outcomes, corroborating information, and clinical or process outcomes. The RECOVERY Trial protocol has been streamlined and simplified and has one primary outcome – mortality within 28 days – with just a few clinical and process outcomes, such as need for ventilation and duration of hospital stay.
The consent process has been optimised, with the patient information sheet just two pages and covering the key points that patients need to know. Data collection is focused so that it takes just five minutes, on average, to randomise a patient (excluding the consent process). The treatment processes mirror care pathways which are already happening, so it is second nature to the medical staff on the ground. Likewise a lot of data being used in the trial are from routine sources, minimising the burden on hospital staff and so reducing the likelihood of errors.
Data on patient outcomes are being provided through NHS DigiTrials, a new service that is being developed by a consortium of partners to enable more efficient clinical trials. Recognising the urgent need for rapid access to outcomes data by COVID-19 researchers, the NHS DigiTrials team have made it possible for researchers to link trial data with NHS data sources.
‘The key to success is coming up with an important clinical question, following a clear care pathway that is already embedded within the NHS, and collecting much of the data from routine sources, keeping the input from hospital staff to a minimum. It has to be as simple as possible, and relevant to clinicians and patients,’ said Juszczak.
Additionally, the protocol is adaptable and flexible, as the situation is changing all the time. The study can act as a blueprint for other researchers around the world wanting to replicate the research, even if the drugs investigated are not the same, or there are not as many available. Juszczak explained that even if only one drug is available, the RECOVERY Trial protocol can still be used and patients randomised into receiving that drug or the usual standard of care. As Juszczak says, in the midst of a global pandemic, every patient counts and every patient should be offered the opportunity to take part.
Rapid IT testing and single-mindedness
Juszczak, his clinical counterpart Professor Richard Haynes, and the team of IT specialists, trial managers, statisticians and communications specialists working on the trial have had their work cut out delivering the trial with the chief investigators. A randomisation system would normally take months to develop, test to destruction (including security against hacking, resilience for multiple users, glitches and inconsistences), and be approved for release. In fact, the three software developers took just 72 hours to initially come up with the key IT systems (randomisation, clinical and administrative databases), and within a week they were pretty much tested and finalised. The trial managers have also being working around the clock to set up all the trial sites in record time, and the trial website was built and launched in just five days. In addition, the team have been managing continual attention from local, national, and international media.
‘Of course, normally, you’d be working on a number of projects, but we have dropped everything and thrown everything at it. The staff were working around the clock, which isn’t sustainable long-term, but now recruitment has taken off, we can all start to breathe a sigh of relief,’ said Juszczak.
Their work isn’t over, as the protocol is continually evolving, and more treatments, and therefore randomisation arms may need to be added.
Collaboration is vital
The RECOVERY Trial is being coordinated by the two clinical trials units within NDPH - the National Perinatal Epidemiology Unit Clinical Trials Unit (NPEU CTU) and the Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU) - who took up the challenge of starting a trial in less than two weeks. Both units routinely carry out clinical trials, although normally with very different target groups.
The RECOVERY Trial draws on the strengths of both units. The NPEU team lead the IT systems side of the trial, with CTSU specialists harvesting routine data sources. CTSU also provides longstanding expertise in streamlining clinical trials to make them more efficient and cost-effective. Trial managers were pulled in from CTSU; statisticians were recruited from both teams. Juszczak says the result was ‘amazing, with instant bonding and everybody knowing exactly what they needed to do and getting on with it’, despite everyone being at home.
The trial is delivered in hospitals by a network of investigators, clinicians and nurses in hospitals across the UK, supported by the National Institute for Health Research Clinical Research Network. They work directly with the participants without whom the trial couldn’t happen.
‘It’s been fantastic sharing practice and skills and seeing everybody supporting each other. The teamwork, learning about different ways of doing things, learning from each other and being so completely focused on this fight against COVID-19 has been fantastic. We’ve been given a (hopefully!) once-in-a-career opportunity to do something to really make a difference nationally and internationally. To see people grasp it with such enthusiasm, such dedication, and such absolute skill, resourcefulness, energy and motivation is really humbling,’ said Juszczak.
The darker side of it all, of course, is that COVID-19 is an international crisis, and every patient in the trial is a potential casualty, something that Juszczak says hammers home the grim reality of the situation and the pressure to get a result on the research team and medical staff. He feels he has to look at the positives, however.
‘It’s been a magnificent collaboration, and it will change the way we work together going forwards. I think we will work differently, closer together, and we will share even more of what we do and how we do it. This has been an exemplar of what is possible. Together we can hopefully change clinical practice and make history’.