After President Trump was diagnosed with Covid-19, the nation watched intently as he received experimental treatments to combat the virus. Some of these therapies are the result of published clinical trials; others are under so-called compassionate use — as-yet unapproved treatments that are employed when nothing else is available.
The time has clearly come for a national coalition to coordinate hypothesis-driven clinical research trials to give the medical community the evidence it needs to safely and effectively treat and prevent Covid-19.
During the early days of the pandemic, research was fragmented and led by groups already positioned to start quickly. Gilead Sciences, for instance, already had in hand the antiviral remdesivir, which appeared to be a scientifically promising therapy against SARS-CoV2, the virus that causes Covid-19. The company was able to rapidly initiate multiple large clinical trials of the drug within weeks of the first outbreak.
Today, ClinicalTrials.gov lists more than 2,000 interventional clinical trials for Covid-19, including nearly 500 trials without random treatment protocols. While it’s laudable that so many pharmaceutical, biotechnology, and academic groups have mobilized to test potential treatments, it’s troubling that there are now multitudes of clinical trials studying similar agents, and therefore competing for participants, infrastructure capacity, and funding.
The drug colchicine, which may have benefit in treating Covid-19, has 22 different clinical trials worldwide registered to enroll patients. These trials differ by inclusion criteria, dosing, and comparator arms, and each trial competes with all of the others to enroll study subjects. Pragmatically, any one of these trials will struggle to enroll enough patients to meet the endpoints necessary to make meaningful conclusions, while health care providers will struggle to select which trial to offer their patients. The entire landscape is made even more complex by the frenetic pace of new knowledge and treatment approaches, rendering adequate trial designs obsolete by the time the trials can get started in earnest, let alone complete all participants.
Multicenter, properly designed, controlled clinical trials with explicit hypotheses are how to conquer disease and restore health in our communities. The U.S. is rich with clinical trial expertise. We urgently need a new and integrated approach for these trials.
To yield maximal returns and efficiency with Covid-19-related clinical research, we propose creating a national, not-for-profit, neutral, and no-fee coordinating coalition with expertise in virology, immunology, public health, ethics, health care disparities, trial design, and statistics.
Among other goals, a new coordinating coalition would be transparent, consensus-driven, and focused on patients and science. It would prioritize standards, efficiency, and ethics. The group also would establish a uniform definition of standard of care to enable easier comparison among treatments and implement guidance on acceptable and transparent outcome measures for every trial stage.
The coalition would offer incentives for early-stage trials to determine effective drug dosing in a limited number of centers to create a pipeline for promising medications to enter broader clinical testing. It would develop processes for testing therapeutic strategies and vaccines, select clinical trial sites that prioritize patient need and health disparities, and provide guidance on the ethics of using non-peer-reviewed preprint publications for reporting results of therapeutic interventions.
The Expanded Access to Convalescent Plasma for the Treatment of Patients with Covid-19 study — led by the Mayo Clinic and used by the Cleveland Clinic to treat Covid-19 patients — is a good example of why we need a neutral coalition for clinical trials. In the absence of a coordinated, widely available randomized trial and in the face of urgent need, physicians turned to the Expanded Access study in numbers well beyond its original intent, which was to demonstrate safety. The subsequent decision by the FDA to grant an emergency use authorization for convalescent plasma was based partly on this study, which was not originally intended to show efficacy in the absence of a large randomized controlled study.
Our organizations have successfully used the coordinating group approach to organize and oversee our own Covid-19 related research since the early days of the pandemic. The purview of these task forces spans the entirety of Covid-19 related activity, from basic science investigations to population health research, health disparities research, and specimen collection and allocation. This approach has allowed us to focus precious resources on high-value, scientifically grounded trials — selecting and executing studies with a high likelihood of helping patients infected with SARS-CoV-2. We believe this approach bears refining and expanding.
Forming a national, nonprofit clinical trials coalition will help ensure that Covid-19 research leads to rigorous, generalizable, and definitive results, and will also set the stage for future research priorities with the greatest impact. We invite public and private stakeholders to join together to make this proposal a reality.