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While COVID-19 has delayed and disrupted clinical trials across specialties, the trials aimed at disrupting the pandemic have struggled to keep up with the wild swings in epidemiology.

That was the experience in New York City.

"We went from a blank piece of paper to our first patient randomized who had COVID in a little over 2 weeks. Those timelines are almost impossible," said Alex Spyropoulos, MD, primary investigator on the comparing anticoagulation doses in a planned 308 severe COVID-19 patients at Northwell Health's Feinstein Institutes for Medical Research there.

"Northwell touched over 100,000 COVID-positive patients. And yet despite being in the epicenter of the epicenter, the pandemic passed us and we were only able to get few patients into our randomized trials."

"Investigators were quick to design trials, but the disease epidemiology curve got ahead of us," agreed Behnood Bikdeli, MD, of NewYork-Presbyterian Hospital/Columbia University Irving Medical Center in New York City.

His group's 100-patient comparing anticoagulant doses in the ICU fell short of 50% enrollment before the surge moved on to other cities.

Antithrombotic trials were especially on the back foot because the issue came as a surprise for a "respiratory infection," Bikdeli noted.

"Everyone went in the direction of thinking, 'Let's try to use antiviral agents' and some people, 'Let's try to use some of the anti-inflammatory agents.' People started to think of them a little earlier, and that's part of the reason we got more patients enrolled in those trials, and now we have some informative results," he said.

But at least two high-profile COVID-19 treatment trials out of Wuhan, China, suffered from the same phenomenon: A study of severe COVID-19 patients suggested no clinical benefit with remdesivir but was inconclusive due to lack of statistical power. Even though the trial began on February 6, patients meeting eligibility criteria became too difficult to find after March 12 and the trial was stopped after enrolling just 237 of the planned 453 patients.

A second study of convalescent plasma for hospitalized COVID-19 patients again showed no statistically significant benefit in time to clinical improvement, but was underpowered for many of the intended analyses with only 103 patients of the originally planned 200 treated before the outbreak petered out in Wuhan.

What's the Problem?

Academic centers, and the U.S. more broadly, are poorly set up to get trials running in a pandemic situation, noted Spyropoulos. "Every hospital has their legal oversight, regulatory oversight, informatics oversight, HIPAA [Health Insurance Portability and Accountability Act] oversight. By the time all those hurdles are passed, it's already gone."

A steep spike is also a research deterrent, said Chris Amos, MD, director of the Institute of Clinical and Translational Medicine at Baylor College of Medicine in Houston, which appears to be well underway with just such a spike.

"A benefit that we've had was that the impact was not felt immediately, so we've had some time to plan and prepare for increasing numbers of patients affected by COVID-19 and develop our approach to conducting clinical research," he told 乌鸦传媒.

"The biggest stress for us will be as the number of cases increase, the demands on the clinical faculty and staff also increases, and that in general makes it harder to find the staffing to engage in as many trials as we would like," he said. "We really like any patient that is willing and eligible to participate to be involved in clinical study, but if the surge is too intense you have trouble with that."

Another logistical problem for locally-run trials at a single health system or region: "There was not even time to get funding. All of us volunteered our own time," said Bikdeli about his group's IMPROVE COVID trial.

So far, the key successes in COVID-19 have come from national-level trials -- by the National Institute of Allergy and Infectious Diseases in the case of remdesivir and by the University of Oxford for dexamethasone's pragmatic U.K. trial.

"We need to tack away from single center studies, particularly trials, and embrace collaboration across the country so we can ensure that we are doing adequately powered studies with strong protocols, vetted broadly," argued Harlan Krumholz, MD, director of the Center for Outcomes Research and Evaluation at Yale-New Haven Hospital in Connecticut.

"My hope is that the pandemic will spark greater efforts to partner -- there is no reason to have large numbers of small trials," he told 乌鸦传媒. "We need to get into virtual rooms together and collaborate vigorously."

Small trials raise the risk of type 1 error that could misdirect the search for effective clinical treatments, noted Barbara Bierer, MD, faculty director of the Multi-Regional Clinical Trials Center of Brigham and Women's Hospital and Harvard in Boston, a research and policy center trying to improve clinical research practices.

She pointed to remdesivir's as a good example of fast-moving adaptive design and the proliferation of small hydroxychloroquine trials as a bad example. Hundreds of the latter are still listed as open on , "despite the evidence being available that they should be closed," Bierer said.

Having clinical trial networks in place beforehand to speed broad multisite collaborations is really ideal, she suggested.

What Can Be Done?

All isn't lost for trials stymied by quick cycles of spikes and lockdowns, though.

There is a possibility that a second wave of COVID-19 could buoy some of the foundering trials, Spyropoulos noted. "As a clinical trialist, I'm hoping to get that spike so we can get the answers, but as doctor and father I hope we don't."

Otherwise, the only solution to make any sense of such data is pooling patient-level meta-analytic data, he suggested.

For that reason, Bierer's center, along with collaborators at Johns Hopkins University in Baltimore, created the for sharing clinical trial protocols; adding like-minded clinical sites to turn a single-site trial into a multisite trial; and even sharing data that's already been collected from similar protocols.

"We will host deidentified data and, on the back end after the fact, see whether and how we can harmonize the data so we can draw inferences from the universe of data that's been collected at these different sites," she said. "It's much harder to do that on the back end...but it can be done."

They're currently reaching out to some of the hydroxychloroquine studies -- particularly those with controls -- to see if there's anything they should learn from that, she said. "Same for convalescent plasma, both pediatric and adult, because frankly no single site is likely to have enough that we can learn what we need to learn and be published."

For observational data, there's the for large-scale analytics, run out of Columbia University in New York City, Bikdeli noted.

Regulators have been responsive, flexible, and supportive of trials -- it's up to clinicians and centers now, Bierer said.

"There is nothing that is standing in our way of doing a better job than we're currently doing, other than we've never been in a situation like this in the last century," she added.

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