With the onset of COVID-19, the United Kingdom ran the largest randomized clinical trial worldwide in a demanding effort to rapidly identify potential treatments. Called the RECOVERY trial, in just three short but intense months, the study team enrolled 12,000 patients and 176 sites and even managed to contribute to a medical breakthrough: that dexamethasone could reduce the death rate in COVID-19 patients with severe respiratory conditions. How did the study sponsors accomplish this? What can other sponsors and public research funders learn from this endeavor?
Nicole Mather explains just how in a recent description published in the journal Nature. The IBM Services executive offers a view into the leadership and decisions, process changes and technologies that helped not only launch and conduct the largest COVID-19 study but the only one to date that has produced evidence of a therapy that can impact COVID-19 death rates in a patient cohort.
The RECOVERY trial NCT04381936 was a randomized Phase 2/3 clincial trial led by University of Oxford, the NHS and other collaborators. The study team investigated treatments in patients with COVID-19 of either Lopinavir-Ritonavir, Hydroxychloroquine, Corticosteroids, Azithromycin, Convalescent plasma or Tocilizumab to prevent death in patients with COVID-19. As TrialSite reported, this study, led by Peter Horby, actually led to breakthrough evidence that the corticosteroid dexamethasone actually reduces death by up to one third in severely ill COVID-19 patients.
Existing Public Infrastructure was Key
Ms. Mather explains that embarking on such a mass clinical trial in such a condensed time, while not compromising quality or “bypassing regulatory processes” was only possible to preexisting investments. Known NHS DigiTrials, the pandemic pushed the teams to work tirelessly—working “nights and weekends”—in an all out effort “to pivot NHS DigiTrials” to support this new endeavor.
But what was NHS DigiTrials?
NHS DigiTrials is a health data research hub for clinical trials. Readied by 2019, this public technology infrastructure was made possible by a dynamic partnership involving the University of Oxford Big Data Institute, IBM and Microsoft while commissioned by Health Data Research UK via the UK Research and Innovation Industrial Strategy Challenge Fund. The overall effort was led by Professor Marin Landray.
NHS DigiTrials was created to offer clinical trials teams data, expertise and infrastructure specific for clinical trials. Its supported by key participants on its governance board, including the Association of Medical Research Charities (AMRC), the National Institute of Health Research Clincial Research Network, and the Health Research Agency.
Why was RECOVERY Trial so different?
First and foremost was the combination of sheer size and acceleration of ramp up given the COVID-19 pandemic. Additionally, Ms. Mather offers key distinguishing features differentiating RECOVERY from standard approaches to clinical trials, including 1) short flexible protocol delineating the core requirements (resign, data, regulatory); 2) arms could be stopped or added; 3) Ethics Committee (EC) approval took 9 days as compared to the average for such a study of 1 to 2 months); 4) simple and straightforward recruitment procedures (two-page consent form, etc.); and 5) acceleration of data collection and processing via NHS DigiTrials and finally 6) expeditiously made results available to all via preprint server on medRxiv. Journal publication followed speedily in a month (The RECOVERY Collaborative Group. N. Engl. J. Med.; 2020).
What are Lessons Learned?
RECOVERY can teach all clinical trials professionals about how research can be not only sped up but also maintain quality and compliance while generating breakthrough evidence. Ms. Mather shared with the reader ways that sponsors, whether industry, government or academic or nonprofit can “revamp procedures and leverage technology to accelerate findings while adhering to core principles of transparency, patient-centricity and peer review. “They include the following:
1) Streamline bureaucracy. This author can attest to this fundamental principle. Whether it be industry, government or academic medical centers, in a bid to mitigate compliance risk and quality, organizations have piled on layers of oversight and administrative and functional checkpoints and stage gates that stifle the drive for improved healthcare research in today’s world. Mather suggests huge amounts of time and money are wasted and TrialSite concurs. Ironically, that such bureaucracy (and associated organizational culture) evolved to mitigate risk but actually does the opposite and magnifies risk!
Mather cuts right to the point: “There is no excuse—we must pare down to the key questions to accelerate the process.” She includes other real world examples with Ebola studies. The author also suggests, over the longer run, there are issues involving prioritization as well as elements such as the coordination of regulatory functions. Each core process or function will need careful consideration.
2) Leverage data systems. It was clear the NHS DigiTrials offered a clear advantage for The RECOVERY trial. This was due to timely and prescient public investment made by the UK’s NHS health-data systems. To a great extent, this public digital healthcare infrastructure investment helped close the loop between clinic and research. Electronic medical records were already integrated with and accessible to research systems hence, investigators and staff need only collect “minimal demographic and consent data.” Many of the patients’ data was already available as there is a national system.
3) Enable Trust. Ms. Mather touches on a subject many in America pay lip service to but don’t really understand, or perhaps they choose to just believe in a certain antiquated paradigm. To truly bridge the clinic and research requires closing the loop with the patient—involving and engaging the patient or by extension the community involved in any trial. Mather hits the nail on the head, declaring, “we must broaden efforts to involve patients and the public.” This of course is a primary driving force for TrialSite and research information delivered via an unbiased manner. Today, only a small percentage of patients actually participate in research and general trust levels in big pharma, big healthcare systems and government are at all time lows.
4) Maintain transparency. Related to trust above, only with consistent transparency can trust be nurtured and developed in communities and individuals. The sponsors were wide open with all material information during RECOVERY, sharing results immediately with all those concerned.
A Word About TrialSite
TrialSite News and its brand new social network, TrialSite Connect, were launched in dedication to more transparent and accessible research. TrialSite focuses on clinical research news, information exchange and social engagement in a bid to empower more individuals and health consumers, research and health care professionals and all others with an interest in clinical trials. Ms. Mather’s point of view hit home.
Dr. Nicole Mather Life-Sciences Lead, IBM Services (London), executive board member, NHS DigiTrials; and non-executive director UK Health Research Authority and Wellcome Genome Research Ltd.
Call to Action: Follow the link to Nature to read Ms. Mather’s article.