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A new research organisation aims to apply the RECOVERY trial approach to clinical trials in common diseases. Emma Wilkinson reports. Recruiting to clinical trials can be slow, bureaucratic, and time-consuming for clinicians and patients. Yet RECOVERY—the clinical trial launched in April, 2020, to find treatments for COVID-19—seemed to challenge accepted wisdom, having signed up more than 47 000 patients, and quickly identifying effective therapies for a new disease. Megan Plowright, a clinical research fellow in infectious diseases at Sheffield Teaching Hospitals NHS Foundation Trust, says that RECOVERY removed many of the factors that make recruiting to a clinical trial burdensome. It was noticeably easier than other trials she was recruiting for at the same time. “The patient information leaflets are really easy to read. It's two sides of a piece of paper and then we have a chat to them about any extra questions that they've got and there's links to the website if they're more interested.” Similarly, the consent form did not require the clinician to hunt out additional information and needed just one signature. The simplicity of the trial design—aided by the fact that the patient takes the medicine while in hospital—has helped to recruit from a wide demographic she says. “Because we've needed treatments, it's become a really routine part of clinical care. Everybody who is suitable is offered the RECOVERY trial.” © 2022 Mai.Chayakorn/Shutterstock2022

Similarly, the consent form did not require the clinician to hunt out additional information and needed just one signature. The simplicity of the trial design—aided by the fact that the patient takes the medicine while in hospital—has helped to recruit from a wide demographic she says. “Because we've needed treatments, it's become a really routine part of clinical care. Everybody who is suitable is offered the RECOVERY trial.” © 2022 Mai.Chayakorn/Shutterstock2022 Now, RECOVERY's lead Martin Landray aims to extend the approach that he believes was the key to the trial's success to trials for other diseases through the announcement of a not-for-profit organisation called Protas. The goal is to design and deliver large, inclusive randomised clinical trials, working in collaboration with industry, medical charities, patient groups, academic researchers, and front-line clinical teams. Sanofi have committed £5 million and other partners will be announced soon, Landray says. The key to a successful trial is the correct design, those behind Protas say. At the very start of the pandemic, Landray published a paper about the “magic of randomisation”, pointing to trials had changed the landscape of cardiology and breast cancer treatment in the 1980s, which had very simple protocols.

Now, RECOVERY's lead Martin Landray aims to extend the approach that he believes was the key to the trial's success to trials for other diseases through the announcement of a not-for-profit organisation called Protas. The goal is to design and deliver large, inclusive randomised clinical trials, working in collaboration with industry, medical charities, patient groups, academic researchers, and front-line clinical teams. Sanofi have committed £5 million and other partners will be announced soon, Landray says. The key to a successful trial is the correct design, those behind Protas say. At the very start of the pandemic, Landray published a paper about the “magic of randomisation”, pointing to trials had changed the landscape of cardiology and breast cancer treatment in the 1980s, which had very simple protocols. Since then, clinical trials have become a hundred times more expensive despite advances in technologies that should make them more efficient, he believes. “We cannot afford either in pure financial or in health or society terms to continue doing trials the way we're doing them. With the common diseases, we need trials that really robustly answer whether a treatment might have a modest effect in something that affects a lot of people and that requires a new way of thinking.”

cannot afford either in pure financial or in health or society terms to continue doing trials the way we're doing them. With the common diseases, we need trials that really robustly answer whether a treatment might have a modest effect in something that affects a lot of people and that requires a new way of thinking.” Landray thinks that each trial should start with a blank piece of paper. Protas intend to focus on the most common diseases: heart, lung, and respiratory disease, arthritis, cancer, depression, and dementia. The first year or two will be careful planning between Protas and Sanofi around which drugs and which patients. “I don't know when we start the first trial, but I wouldn't anticipate starting the first big trial with Sanofi or any others, until the back end of next year, possibly even in 2024”, says Landray. So, which aspects of trial study design will Protas try to correct? Landray points to a US Food and Drug Administration analysis of more than 2000 registered COVID-19 trials, which found that only 5% of trials were randomised and sufficiently powered. There was no hope of producing an answer “because there was no coin toss”, he says. Other issues include collecting information for the sake of it and gathering the same basic information multiple times, making it burdensome for doctors.

So, which aspects of trial study design will Protas try to correct? Landray points to a US Food and Drug Administration analysis of more than 2000 registered COVID-19 trials, which found that only 5% of trials were randomised and sufficiently powered. There was no hope of producing an answer “because there was no coin toss”, he says. Other issues include collecting information for the sake of it and gathering the same basic information multiple times, making it burdensome for doctors. “There are many ways in which one has to shape the trial to be doable for both the patients and accessible for the patient and for the clinicians”, he says. That is also the only way to get a diverse mix of patients and it means those facilities not attached to large universities or medical schools, but who see an awful lot of patients, can participate, Landray says. The not-for-profit is a very deliberate decision, he says. “The world doesn't need another organisation syphoning money out of complexity. But this is not about driving down costs, for the sake of it. This is driving down costs, because they're not necessary, and driving up the quality of the results.”

e, Landray says. The not-for-profit is a very deliberate decision, he says. “The world doesn't need another organisation syphoning money out of complexity. But this is not about driving down costs, for the sake of it. This is driving down costs, because they're not necessary, and driving up the quality of the results.” Plowright says in her experience patients are put off by studies requiring lots of follow-up and extra visits for checks such as blood tests. “That rules out a large section of society and then your trial isn't really applicable to the population you're treating.” However, she notes the other benefit was that the outcome in RECOVERY was very simple, which allowed those running the trial to see the differences in mortality very quickly, but might not be applicable in other disease areas. “When you've got something where you've got no treatments, that's exactly what you need”, she says. “But for diseases that are more common and we already have lots of treatments for like heart disease and cancer, you can't necessarily take that exact same model and just transplant that, but there are really good things that we can take from it”.

where you've got no treatments, that's exactly what you need”, she says. “But for diseases that are more common and we already have lots of treatments for like heart disease and cancer, you can't necessarily take that exact same model and just transplant that, but there are really good things that we can take from it”. Part of the impact Protas will have, says Landray, is through transparency, making protocols and recruitment figures publicly available. Even if Protas manages to do 20 trials in a year— which would be a lot, he points out—by providing an exemplar it can have a bigger impact. He agrees with those who note that RECOVERY was in a unique situation with a novel pathogen being talked about on every page of every paper and every social media feed and, compared with most diseases, the triallists did not have to wait long for important clinical outcomes to become apparent. “The one rare instance it was completely acceptable for doctors and everybody else to say we don't know what we're doing. Actually, in reality, there are so many other areas of medicine where choices about how we treat particular or don't treat particular diseases are not well informed.”

al outcomes to become apparent. “The one rare instance it was completely acceptable for doctors and everybody else to say we don't know what we're doing. Actually, in reality, there are so many other areas of medicine where choices about how we treat particular or don't treat particular diseases are not well informed.” Charlotte Summers, professor of intensive care medicine at the University of Cambridge and chief investigator of HEAL-COVID, a trial investigating treatments that might benefit patients with COVID-19 after discharge, said they had taken a similar approach in terms of a simple trial design that is adaptable. “We've based it on RECOVERY, a similar philosophy but for a post-hospital space. This is exactly the approach we should be taking”, she says. “We have managed for the first time during the pandemic to embed research in routine clinical care in the acute setting. To transform research in other diseases, dementia for example, that have previously been thought too difficult to tackle in the same way, is an incredibly attractive notion.” Patient safety is of course vital and ethical principles must remain intact, she stresses “but the standards required and the bureaucracy that has grown around trials, compared to routine patient care, is out of kilter”.

eviously been thought too difficult to tackle in the same way, is an incredibly attractive notion.” Patient safety is of course vital and ethical principles must remain intact, she stresses “but the standards required and the bureaucracy that has grown around trials, compared to routine patient care, is out of kilter”. None of the vital research done in the National Health Service during the COVID-19 pandemic, including RECOVERY, would have been possible without a decade of investment in the infrastructure through the National Institute for Health Research, she adds. “We cannot and should not go back to business as usual. We need positive disruption and change.” Kazem Rahimi, professor of cardiovascular medicine and population health at the University of Oxford, said while there are certainly efficiency savings to be made in clinical trials and that better use of digital technologies has the potential to be transformative, RECOVERY was a special case that will not scale across the board, particularly for new medicines or devices. The expense of clinical trials has become a major barrier preventing effective treatments reaching patients, he agrees. “We should bear in mind there is no magic bullet in clinical trial efficiency. Rather, it will be the synthesis of several small changes that will make a big difference.” He added that it is often the misinterpretation of regulations that leads to clinical trials being designed inefficiently, which must be addressed.

. “We should bear in mind there is no magic bullet in clinical trial efficiency. Rather, it will be the synthesis of several small changes that will make a big difference.” He added that it is often the misinterpretation of regulations that leads to clinical trials being designed inefficiently, which must be addressed. Rhian Gabe, professor of biostatistics and clinical trials at the Wolfson Institute of Population Health, Queen Mary University of London, also believes that wider use of digital technologies could make it easier for patients to participate and that better use of electronic health records will help to ease the data collection burden; however, this also has its challenges in terms of bias and missing information, an issue that researchers are working on. “But this will all take investment, we need funding in data science and methodological statistical experience and that will take time.” The Medicines and Healthcare products Regulatory Agency are currently consulting on proposals for legislative changes for clinical trials. “People have been talking about streamlining clinical trials for years and the pandemic showed us we can do it. There are a huge amount of positives to take away.” For Landray's paper on the magic of randomisation see N Engl J Med 2020; 382: 674-78For the FDA analysis report see Nat Rev Drug Discov 2021; 20: 254-55For more on on legislative changes see https://www.gov.uk/government/consultations/consultation-on-proposals-for-legislative-changes-for-clinical-trials For Landray's paper on the magic of randomisation see N Engl J Med 2020; 382: 674-78

For Landray's paper on the magic of randomisation see N Engl J Med 2020; 382: 674-78For the FDA analysis report see Nat Rev Drug Discov 2021; 20: 254-55For more on on legislative changes see https://www.gov.uk/government/consultations/consultation-on-proposals-for-legislative-changes-for-clinical-trials For Landray's paper on the magic of randomisation see N Engl J Med 2020; 382: 674-78 For the FDA analysis report see Nat Rev Drug Discov 2021; 20: 254-55 For more on on legislative changes see https://www.gov.uk/government/consultations/consultation-on-proposals-for-legislative-changes-for-clinical-trials