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Kylene Karnuth, a clinical lab scientist, works with coronavirus samples as researchers begin a trial to see whether malaria treatment hydroxychloroquine can prevent or reduce the severity of the coronavirus disease.
Reuters/ Craig Lassig
The race is on to ethically test coronavirus treatments
DO NO HARM

The race to develop coronavirus treatments pushes the ethics of clinical trials

Olivia Goldhill
By Olivia Goldhill

Science reporter

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The path to approving a clinical drug is a long, extremely expensive one. Trials typically begin with tests on animals, which take months or years. Then it takes several more years to prove a drug’s safety, transition to human testing, and finally to test efficacy in large groups.

But that timeline goes out the window in a pandemic.

There are no clinically approved drugs to treat the novel coronavirus that causes Covid-19; before December, there was no known virus to test a drug on, let alone spend years investigating. So doctors have two options: Turn to experimental treatments, or don’t treat patients at all. Both present gnarly ethical conundrums.

Rebecca Li, executive director of the Multi-regional Clinical Trial Center at Harvard University, says experimental drug use to treat Covid-19 should not be permitted. “Clinical trials are there for a reason,” she says. “Most drugs end up not working.” Clinical trials protect patients from possible harm from experimental treatments, and mean that clinicians don’t waste time on ineffective drugs. A pandemic is no a reason to skip these protective measures, she argues.

But others are more pragmatic. Arthur Caplan, director of NYU Langone’s Division of Medical Ethics says that when doctors are faced with suffering patients, it’s ethical for them to use drugs that have been approved for other health conditions as treatments. This happened with Ebola, swine flu, Zika, and now coronavirus, he says.

Some of the first coronavirus patients in China, for example, were experimentally given the HIV treatment lopinavir–ritonavir and the rheumatoid arthritis drug Actemra. Now, as the virus continues its rampage around the globe, doctors are eyeballing an increasing number of treatment possibilities—and dealing with the challenging ethics of testing their efficacy while making the safest choices for their patients.

Controlled trials—with caveats

When choosing to use an experimental treatment, doctors have to be as methodical as possible—taking careful note of how sick patients are when given treatment, the dose and timing of medication, and how they fared. “It’s not a study, not controlled, but you want observations to be systematic,” says Caplan.

If, after a couple of weeks and 10 or 20 patients the drug doesn’t seem to cause active harm, Caplan says scientists can quickly move to the first stage of clinical research.

Many of the current coronavirus clinical trials are based on those early experimental treatments. Early research on lopinavir–ritonavir suggests that the drug is not effective, though as the first study was small, researchers plan to investigate further. There are also ongoing trials into arthritis medication Actemra,  antimalarial chloroquine, and Japanese flu drug favipiravir

While clinical trials typically take months to years to get started, Li believes the current coronavirus trials will set records for speed: “I don’t think they could go any faster,” she says. It helps that there are a lot of coronavirus patients, so it’s easy to quickly enroll study participants.

But it’s not so easy to determine how those participants should—and shouldn’t—receive treatment. “Most people believe a placebo is necessary for a gold-standard trial,” says Li. In the strictest sense, a placebo would be nothing more than a sugar pill, as this allows scientists to determine whether the treatment under study is actively helping people.

The ethics of a true placebo don’t pan out in a pandemic situation: When patients are suffering from a serious medical condition, doctors use “standard care” as the placebo instead. “Since most new drugs don’t work or are harmful, you are not clearly worse off by being randomized to a placebo on top of usual care,” says Alex John London, director of the Center for Ethics and Policy at Carnegie Mellon University, who has written on the ethics of clinical research during public health emergencies.

For Covid-19, standard care is largely supportive. The lopinavir–ritonavir study tested the drug against giving patients oxygen, ventilation, antibiotics, and support for pumping blood, kidney function, and blood pressure as needed. Researchers can also run “adaptive trials,” meaning they test various drugs against each other, as well as as combining the drugs to see if that increases effectiveness. The format allows for certain drug treatments to be abandoned more quickly if it seems to be ineffective, and also allow more patients to have access to potentially effective treatments. But it can take longer to prove that a drug is effective when compared to another drug, as opposed to when it’s compared to placebo alone.

The best possible clinical trials should also be double-blind, meaning neither the doctor nor patient knows if they’re receiving the drug being tested. Doctors can’t selectively give the treatment to patients they think are sicker, and patients have less of a placebo effect from knowing they’ve had the experimental drug. But it can be difficult to achieve without advance planning. The World Health Organization (WHO)’s trials into coronavirus are not double-blind, as the organization said it had to balance rigor with speed.

Ethical issues are even thornier when testing vaccine candidates. Whereas drug treatments are given to people who are already sick, vaccines are typically created from scratch and given to people who are healthy. It requires huge numbers of study participants to determine both safety and effectiveness. Stanley Perlman, professor of microbiology and immunology at University of Iowa, points to a 1976 US swine flu vaccine that created roughly 10 cases of Guillain-Barré syndrome per million people vaccinated. Though most recovered, 25 people died from the vaccine.

Access vs. harm

As doctors and researchers struggle to balance rigor with speed, patients are waiting in the wings for treatments to appear.

In the United States, the most advanced coronavirus clinical trial is on the antiviral drug remdesivir. Unlike most drugs being studied, remdesivir isn’t approved to treat any health condition, meaning that patients can only access the drug if they’re accepted into the clinical trial. Although statistically, most drugs are not found to be effective—“it’s more likely it won’t work than it will,” Caplan says of remdesivir—family members of patients suffering from coronavirus are understandably desperate to try anything.

But rushing ahead doesn’t serve patients overall. “If you don’t do carefully controlled clinical studies, usually with a placebo, you go back years later and find out you’re wasting your time,” says Perlman. Caplan agrees, noting that failing to implement proper standards means that trials take longer, as it’s harder to ascertain whether the drug is truly having an impact.

“You have to keep in mind that randomized clinical trials are the rocks against which great expectations are routinely dashed,” says London. Around 90% of new drugs don’t get through testing, he notes, and half of these fall short in most advanced trials. “And these are all cases where researchers and sponsors can plan, long in advance, and do specific studies in animal models in preparation for human trials.”

Despite working at breakneck speed, it will likely take months, if not years, to find a treatment for Covid-19. Though ethical and rigorous studies are time consuming, that investment is necessary. Without clinical trials, London warns, patients can receive ineffective or harmful treatments, clinicians can waste time on pointless interventions, and money is wasted on invaluable resources.

Even in a pandemic, when treatments are so urgently needed, carefully designed trials are the best way to help patients.

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