In March, a team of Chinese scientists studying whether the antiviral remdesivir was effective against Covid-19 ran into a problem. “Stringent public health measures used in Wuhan led to marked reductions in new patient presentations,” the researchers wrote. Without enough patients enrolled, the study ended early.

Last month, another Chinese team reported that a trial of the drug hydroxychloroquine had bumped into similar issues. “The recruitment of eligible patients was unexpectedly difficult,” the scientists wrote, explaining they had failed to reach their enrollment goal.

The snags reflect one of the paradoxes of infectious disease research — and one that could make it challenging to test experimental drugs and vaccines for Covid-19. When public health officials succeed in stamping out outbreaks, they also make it more difficult for researchers to find the volunteers they need for clinical trials. Earlier trials of drugs and vaccines for Zika and Ebola were stymied by such obstacles.

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“The challenge is really about capacity in a very hectic and demanding situation,” said John-Arne Røttingen, the chief executive of the Research Council of Norway, a government agency.

For scientists, conducting a clinical trial in an outbreak is akin to teams picking players in the NBA draft — if, instead of taking turns, all the teams were selecting players at the same time. It would be a free-for-all.

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In this case, as the Covid-19 crisis burgeoned in China and spread to other parts of the world, so many research groups set out to test different drugs that they were essentially competing for patients. The lack of coordination meant that some separate teams were investigating the same intervention.

Then, as case counts in some countries crashed, there weren’t enough patients to fill the studies.

The result, experts say, was a series of case reports and unexacting trials — some with small numbers of participants, some without control groups — that didn’t offer meaningful evidence as to whether treatments were effective or not. Further complicating matters: Some patients relied on these anecdotes to guide their decisions about their own treatment, taking them out of the pool of participants for more thorough clinical trials.

Experts stress that even during emergencies, gold-standard clinical trials remain critical. These trials — in which patients are randomized to receive an experimental therapy versus a placebo or standard of care — are the only way to demonstrate what works and what doesn’t, and what might actually be harmful.

“It is far more unethical to do a lousy trial that provides no information than it is to do a randomized, controlled trial that more quickly obtains efficacy and adverse response rates,” said Gerald Keusch, the associate director of Boston University’s National Emerging Infectious Diseases Laboratories, who co-chaired a committee that reviewed clinical trials during the West African Ebola crisis.

Four months into the crisis, well-run trials have started to generate more reliable answers. A remdesivir trial run by the U.S. government showed the drug hastened the recovery of people hospitalized with Covid-19 compared to placebo. Another trial showed that an arthritis drug did not help patients — a finding that, while negative, helps guide researchers to treatment options that still have potential.

Some groups are trying to bring order to the clinical trial disarray. A group of academic researchers has started the Covid-19 Collaboration Platform to help investigators at different institutions team up on trials. The National Institutes of Health has also partnered with more than a dozen drug companies to, among other aims, identify promising compounds from early studies and prioritize them for large confirmatory trials.

“You’re just trying to figure out how to take the existing clinical trial capacity and allocate it to the therapeutic candidates that are going to be most likely to succeed,” NIH Director Francis Collins told STAT.

Still, some experts say some of the trials just getting up and running now underscore the flaws of how companies approach these studies. Among them, Novartis’ placebo-controlled, randomized, double-blind trial of the malaria drug hydroxychloroquine, a drug for which there has been conflicting data on efficacy against Covid-19.

“We should not just be starting clinical trials now” for hydroxychloroquine, said Walid Gellad of the University of Pittsburgh’s Center for Pharmaceutical Policy and Prescribing.

He said the Novartis trial was duplicating other efforts and highlighted the need for drug companies and researchers to consider how to be ready to run clinical trials the next time a pathogen breaks loose. “It should be obvious that planning clinical trials is part of planning for pandemics, or at least that should be the lesson we’ve learned this time around,” Gellad said.

Part of the reason for the frenzy is that, while outbreaks can be expected in general, it’s unknown when exactly they will erupt. And the fact that this coronavirus, called SARS-CoV-2, had never been seen in people has resulted in a throw-the-kitchen-sink-at-it approach. More than 70 drug and vaccine trials have now been registered with the Food and Drug Administration alone and more than 200 programs are in planning stages.

There’s also a sense of urgency to run those trials — not only because there’s a need for treatment, but also because, as biostatistician Natalie Dean of the University of Florida put it, if outbreaks start suddenly, “they also stop.” That means researchers are hurrying to fully enroll their studies before local epidemics are brought under control.

With the Zika emergency, none of the experimental vaccines in development was proven to work and approved for sale before the crisis waned. Similarly, the West African Ebola outbreak ended while a trial for the therapy ZMapp was ongoing. It took another Ebola emergency, this time in the Democratic Republic of Congo, to show that ZMapp was not as effective as two other treatments.

Some trial sponsors have tried to get ahead of fluctuating case counts, as well as find ways of studying multiple drugs, without having to set up multiple trials. The World Health Organization’s Solidarity trial is comparing a number of drugs against the standard of care in more than 100 countries. With more sites participating, it means the trial can still proceed even if an outbreak ebbs in a certain location. And with each site enrolling patients, the hope is that the trial can be completed faster.

The trial run by the National Institute of Allergy and Infectious Diseases that found remdesivir sped recoveries was also designed so international sites could participate and so different drugs could be tried.

“This crisis underlies and points out the need to have a better clinical trial infrastructure in place,” Janet Woodcock, the director of the FDA’s Center for Drug Evaluation and Research, said during a recent presentation.

There are some universal challenges for clinical trials during emergencies, but one particular conundrum for Covid-19 is finding a therapy that can prevent cases of mild illness from turning more serious. Given that some 80% of people with Covid-19 recover without progressing to serious disease, investigators would need to enroll large numbers of patients so that there are enough people who do become severely ill to make a meaningful inference about whether a particular intervention worked.

One study investigating the anti-inflammatory drug colchicine is trying to do just that. It involves enrolling participants who not just have Covid-19, but who are also 40 or older and have one other risk factor that makes them more vulnerable to serious illness than a younger, healthy person.

The study, which is aiming to enroll 6,000 people, is also being conducted remotely, with participants receiving the drug in the mail and follow-up visits done via phone or video. That way, these patients, who are not sick enough to need hospital care, do not need to put a clinician at risk for all their evaluations.

“How do you study an intervention in this setting that’s not going to require a participant to come back and get intensive monitoring?” said Priscilla Hsue, a University of California, San Francisco, cardiologist and a trial investigator.

Testing a vaccine introduces even more complexity into clinical trials. Efficacy trials typically involve giving a large group of people the immunization and then seeing if they get sick less frequently than another group of people living in the same area who were not given the vaccine. The trials can be difficult to enroll because they don’t involve testing a therapy in patients who have already shown up to a hospital with an illness. And there needs to be a certain amount of virus circulating in that area so that enough people in the control group get infected and a comparison between the two groups can be drawn.

“With vaccines, they’re not immediately effective,” Dean said. “They’re given to healthy people out in the population, and you need huge numbers. You have to be smart with where you place things.”

Some experts have proposed testing vaccine candidates through challenge trials, in which volunteers are given the inoculation and then exposed to the virus. The aim is that these types of studies can be done faster than a standard trial, though they come with their own difficulties.

Unlike the Zika or past Ebola crises, the coronavirus pandemic is not expected to peter out without a vaccine. The aim now is to gain enough insights from this initial outbreak so that clinicians can have a better sense for what to use and what to investigate further in future waves.

“The first wave of infections in many countries seems to be under control,” Røttingen said. “That is a great development. But it’s really crucial we use this window of opportunity to learn as much as possible.”

Lev Facher contributed reporting from Washington.

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