The Food and Drug Administration’s rush to greenlight unproven malaria medicines to fight the coronavirus may derail clinical trials of other potential cures for the deadly virus.
Right now, dozens of potential therapies — from antivirals to antibodies taken from the blood of coronavirus survivors — are being tested in people. The first results from these studies could come within months if drugmakers enroll the thousands of patients needed to complete the research.
But with the malaria drugs chloroquine and hydroxychloroquine available by prescription from any doctor, and the president touting them as coronavirus treatments at his daily briefings, enlisting volunteers to enroll in clinical trials of other potential therapies may be a tough sell.
Researchers are concerned that clear answers on the efficacy of dozens of other medicines, which will only come from clinical trials, could be delayed by the fervor. Online hype of the malaria drugs, along with the president's endorsement, is already fueling drug shortages. The FDA added both chloroquine and hydroxychloroquine to its shortage list this week, after prescriptions spiked as much 7,000 percent in March.
The Trump administration is also considering authorizing another unproven coronavirus treatment for emergency use. The drug, a Japanese flu medicine called Avigan, has been publicly endorsed by Japanese Prime Minister Shinzo Abe. But it is not approved by the FDA, and the agency has rejected it in the past over concerns about side effects.
An emergency authorization from the FDA could clear the way for off-label use before U.S. clinical trials even begin — raising the question of how research could catch up.
“We have to use science to save ourselves, not hunches,” said Mildred Solomon, president of the bioethics thinktank Hastings Center. “If we lead people into a frenzy of stockpiling something they’ve got their hopes in, how are we ever going to get the knowledge we need to get ourselves out of this problem?”
Only by running randomized clinical trials of experimental treatments will scientists and doctors find a cure for the coronavirus, says Holly Fernandez Lynch, a bioethicist at the University of Pennsylvania. Such trials are the gold standard for getting answers, because doctors cannot cherry-pick who gets a dose of the drug being studied or which results to share.
Drugmakers are also struggling to balance ongoing clinical trials of experimental coronavirus treatments with the flood of requests for emergency access to those potential therapies. Gilead, which developed the experimental antiviral drug remdesivir, said late last month that it would temporarily stop granting requests for compassionate use, a pathway to access experimental medicines outside of clinical trials.
“In recent weeks, there has been an exponential increase in compassionate use requests,” the company said, adding that the system was not designed for use in a pandemic. “Enrollment in clinical trials is the primary way to access remdesivir to generate critical data that inform the appropriate use of this investigational medicine.”
The FDA is working quickly with a range of pharmaceutical companies through its recently established coronavirus treatment acceleration program, Commissioner Stephen Hahn said in a statement provided to POLITICO. “We are also looking at pragmatic and expedited ways to make these products available to patients, while still ensuring the FDA’s standards are met,” Hahn said.
It is not clear whether remdesivir or other potential therapies are effective against the coronavirus. The data for chloroquine and hydroxychloroquine is limited and mixed. Small early studies out of France have been questioned because of how scientists analyzed their results — and the lead researcher’s history of manipulating data. One subsequent Chinese study found no benefit at all, while another, posted online this week but not peer-reviewed, suggests that hydroxychloroquine speeds recovery in patients with mild symptoms.
Regulators in other nations are treading cautiously when it comes to potential coronavirus drugs. Chloroquine and hydroxychloroquine should only be used to treat the virus in clinical trials and in severe cases, the European Medicines Agency said in a statement this week. The European counterpart to the FDA noted that both compounds can have serious side effects, particularly when combined with other drugs.
The Trump administration’s push to make experimental therapies widely available for use outside of clinical trials have earned swift criticism from patient groups accusing the FDA of folding to political pressure. In one case, the group Patients Over Pharma has publicly urged FDA Commissioner Stephen Hahn to act based on the best science rather than political calculus.
Reports of chloroquine and hydroxychloroquine shortages across the country also raises the question of who should be prioritized to receive a medicine that has been around for years. Some have likened the potential quandary to how health care providers are using ventilators and who should be prioritized in those situations. But the comparison doesn’t quite match up, said one senior HHS official who points to early data and big questions about the drugs’ effectiveness.
“If it’s about ventilators, there is no question in my mind what the positive benefit is,” the official said. “Here, I do agree that there is an issue of triage and who gets access and who doesn’t — but I’m still not convinced it matters.”
Representatives for HHS Assistant Secretary for Preparedness and Response Robert Kadlec, who manages the national stockpile that will dole out the now millions of chloroquine pills in the supply, did not respond to questions about how the agency would prioritize certain groups or balance between trials and off-label use.
Even with the infusion of donated pills into the government’s stockpile, the federal attention on chloroquine has fueled shortages already happening around the country, said David Karp, a Texas doctor and president-elect of the American College of Rheumatology, a group of providers that treats people with lupus and arthritis — who have used the drugs for years to manage their symptoms.
Interest in the drugs soared once they were discussed on the White House briefing stage. “Very quickly the supply in local pharmacies went down to zero,” Karp said, adding that pharmacies and hospitals all over the country have struggled to secure supplies. “I haven’t talked to any rheumatologist who hasn’t had a patient call their office and say ‘I can’t find any of my medication.”
“With it being in the news, suddenly people say ‘I should get this so in case I need it, I have it,’” said American College of Physicians president Robert McLean, a rheumatologist who has prescribed the drug for years to treat lupus and arthritis. The doctors’ group sent a letter to Trump late Monday warning of low supplies fueled by the coronavirus frenzy.
“There is clearly a looming shortage,” said McLean.
Sen. Elizabeth Warren (D-Mass.) wrote to Hahn on Thursday demanding answers on how the agency will stem shortages.
There is also concern among doctors and researchers about how quickly potential risks, unknown side effects or just ineffectiveness could be sorted out with off-label use that does not feed central databases or published trials.
Drugmakers are shielded from liability if their products end up not working or causing harm through a measure activated when the president declared a public health emergency, known as the PREP Act. One of the ways to get that shield is an emergency use nod from the FDA. Discussions about the PREP Act and potential emergency authorizations had been going on for at least a week before the Sunday announcement, one official said.
Health experts warn that even if chloroquine and hydroxychloroquine work against Covid-19 — and many have questioned the data so far — no one medicine will be the answer to an outbreak that has already killed more than 30,000 worldwide and infected at least 174,000 in the U.S. alone.
“We still are going to have to do physical distancing. That is the proven method here, not a magic pill,” said Solomon.
But even as health officials around the president — like top infectious disease doctor Anthony Fauci — have warned that social distancing guidelines may need to stay in place much longer, the president has been optimistic about reopening the economy. By Sunday, Trump scaled back from a hope that distancing would be over by Easter, saying instead that tactics should stay in place through April. Some states, like Virginia, have put rules in place until June.
“Quite frankly if you look across infectious disease history, its extremely rare that we ‘defeat’ a virus,” said longtime rheumatologist McLean. “You learn how to manage it.”