To the Editor — According to a recent publication by the US Food and Drug Administration, only 5% of the more than 2,000 registered COVID-19 clinical trials were randomized and adequately powered to yield actionable results for identifying effective treatments1. Of these trials, many failed to enroll sufficient numbers of participants, as studies have been dominated by various independent groups running small investigational studies competing for the same patient population, sometimes with overlapping study objectives1. In spite of efforts to coordinate large-scale clinical trials in the United States2, big trials (those comprising more than 10,000 patients) for COVID-19 have struggled to achieve completion. This approach needs to change.
In the United States, most hospitals lack the infrastructure to conduct clinical trials. Trials are therefore centered around major academic research hospitals, limiting access to promising treatments and participation by diverse populations. This undercuts the ethical imperative of health researchers to identify the most effective therapeutic agents as expeditiously as possible, demonstrating safety and efficacy across different populations.
We propose the creation of a standing Federal Pandemic Management Agency (FPMA), tasked with accelerating the development of effective therapeutics, while proactively identifying facilities and partnerships for accelerated preclinical development. The agency would oversee the establishment of a greatly expanded national clinical trial infrastructure, readied to implement simplified, adaptive master clinical platform studies that can be conducted seamlessly in a pandemic surge. Enabling a cohesive and streamlined clinical trials strategy promises to reduce suffering and save lives and to enhance the efficiency of therapeutic trials between pandemics.
Lessons can be learned from outside the United States. In March 2020, with COVID-19 rates surging and hospitals and medical staff overwhelmed, the UK established, in record time, a nation-wide platform for clinical trials to evaluate repurposed drugs for COVID-19. The RECOVERY trial initiated a randomized, multi-arm master protocol designed to quickly evaluate six treatments in a head-to-head comparison with standard of care as the control arm. RECOVERY enrolled 7,586 patients across 172 sites within 1 month of ethics committee approval of the protocol3, and within 3 months, the study had generated sufficient data to draw two important conclusions: dexamethasone was effective in reducing mortality, whereas hydroxychloroquine was not4,5. Dexamethasone was rapidly adopted as standard of care for treating hospitalized patients with COVID-19, with a recent study estimating that 22,000 lives were thereby saved in the UK and up to 1 million worldwide6.
Given the urgency and severity of COVID-19, the RECOVERY trial initially focused on identifying treatments that reduce mortality for the sickest patients. Designing the trial for a pandemic context meant that the master protocol needed to be simple. To facilitate participation, the protocol was designed to enable providers to focus on patient care, with few deviations from standard practice — any additional work for participating in the trial was limited to data entry and training of staff that could be accomplished in minutes, use of simplified patient consent forms and randomized assignment of treatment3. Although blinded clinical trials are the gold standard, under pandemic circumstances an open-label trial was readily integrated into standard care, allowing providers and patients to understand the risks and benefits of the treatment and providing a level of transparency that facilitated trial participation. The large enrollment numbers and hard clinical endpoints, such as mortality, in RECOVERY compensated for the potential confounders of an open-label trial.
Leveraging a nationalized healthcare system allowed the UK RECOVERY trial to quickly enroll patients using their electronic health records and analyze data at scale. Although the United States does not have a centralized healthcare system like that in the UK, we believe that the UK RECOVERY trial nonetheless serves as an appropriate model for the United States, by placing focus on a nation-wide adaptive platform trial designed for simplicity of enrollment and data collection.
Reporting directly to the White House, the FPMA could prioritize, coordinate and oversee efforts to contain a pandemic, while evaluating therapeutics and vaccines. There exist more than 6,000 US acute-care hospitals, and over half have more than 100 beds. Over the past 2 years, most hospitals did not enroll patients in COVID-19 trials due to lack of infrastructure, whereas many academic and high-volume sites were overwhelmed by multiple competing trials. Moreover, most studies were too complex to seamlessly integrate into the workflow of an already stressed health system. A coordinated national clinical trial network would increase efficiency, cost effectiveness and enrollment of diverse populations, while avoiding duplication of efforts. The solutions below build on existing efforts, while others will require longer-term planning and investment.
First, clinical trials should be simplified so that they can be conducted during a pandemic. This would include the use of off-the-shelf adaptable and simplified multi-arm master protocols, similar to that of the UK RECOVERY trial, with a focus on safety and significant clinical endpoints, and with multiple master protocols run in parallel. The simplified protocols should be randomized but unblinded and designed to allow ease of enrollment and minimal disruption of patient care. A centralized Institutional Review Board (IRB) and contracting process will facilitate study start-up.
Document templates, including protocol, investigator brochure, informed consent and case report forms, can be prepared in advance and then tailored to each specific study. A minimal dataset regarding patient outcomes should be entered into a centralized study data-management system to answer safety and efficacy questions as expeditiously as possible. Such real-world master protocol studies will lower costs, reduce duplicative efforts, increase the rate of patient enrollment, improve quality of evidence and provide results in a compressed timeframe.
Second, the US clinical trial infrastructure should be increased. All acute-care hospitals with over 100 beds and accountable healthcare organizations that receive Centers for Medicare & Medicaid Services (CMS) funding should be required to have a clinical trials office prepared to conduct inpatient and outpatient studies, with funding and training for staff provided by the federal government. This will provide added benefit to the national clinical research enterprise, when not in pandemic mode, to support real-world studies of new therapies and comparative effectiveness studies.
Third, multiple clinical trials should not compete for the same patients and resources. All CMS-supported healthcare facilities and plans should prioritize enrollment of patients into master protocols. Study drugs can then be assigned to the master protocols by an FPMA expert panel based upon scientific merit, expected clinical impact and ability to scale up manufacturing of the drug quickly.
Lessons from the COVID-19 pandemic must inform national efforts in the United States to develop effective therapies when the next pandemic occurs. The current US approach with fragmented, overly complex, expensive and often underpowered clinical trials competing for a limited number of patients has largely failed to yield actionable results despite substantial investments. A coordinated national response is therefore required to safeguard health and security.
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Wise, J. et al. BMJ 370, m2800 (2020).
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RECOVERY Collaborative Group. N. Engl. J. Med. 384, 693–704 (2021).
National Health Service. https://www.england.nhs.uk/2021/03/covid-treatment-developed-in-the-nhs-saves-a-million-lives/ (23 March 2021).
The authors declare no competing interests.
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Yajima, R., More, A.F., Garvan, C. et al. A US clinical trial network is needed for the next pandemic. Nat Med 28, 1330–1331 (2022). https://doi.org/10.1038/s41591-022-01831-1