The man-in-the-street view of the controversy around chloroquine and its alternative form, hydroxychloroquine, goes something like this: tests performed somewhere (France and China?) indicated its efficacy, but a slow-to-act FDA hasn’t authorized its use even when it could save thousands of lives. But now, with pressure from President Trump, FDA has relented and the drug is becoming available. Great story of presidential leadership, right?
Like so many issues today where science intersects with politics, unpacking this mythmaking requires onerous attention to details. Of most concern, though, is that even after the new trials might show a beneficial result, enabling patients to receive the drug will be problematic.
No matter how the clinical trials going on at this time work out, it’s a great time to be in the business of supplying hydroxychloroquine, as well as azithromycin (branded by Pfizer as Zithromax), an antibiotic also believed to have a beneficial impact on infected patients.
The first problem with the chloroquine story is that the drug has been approved literally for decades, and since off-label use of drugs is generally legal and accepted, there was never a time when FDA prohibited its use. (“Non-prohibition” is not the same as “recommended use,” of course—there is a reason that drug labels list approved uses.) Most medical professionals, aware that the drug has potential side effects (more so for chloroquine than for hydroxychloroquine), have been hesitant in its use—although there have been reports of doctors writing prescriptions for themselves and others, and the drug quickly went into short supply after the President’s comments.
Pharmacy boards and medical authorities across the country have issued policy statements to minimize hoarding or self-prescribing the drug; multiple state authorities issued prohibitions on prescribing the drug without sound medical reasons, which usually was interpreted to mean that the drug should be reserved for existing approved indications, such as malaria, lupus and rheumatoid arthritis.
That was more or less the situation until March 28, when FDA issued an “emergency use authorization” (EUA) to the HHS Office of Assistant Secretary for Preparedness and Response (ASPR) to allow use of chloroquine and hydroxychloroquine in the Stockpile for Covid-19 treatment. ASPR is the HHS function that runs the National Stockpile. The week before, several major drug companies (Novartis/Sandoz, with 30 million doses of hydrochloroquine, and Bayer Pharma, with 1 million doses of chloroquine) announced donations to the US Strategic National Stockpile.
EUAs have a history: most often they have been invoked to rush a diagnostic test into the healthcare frontlines when an epidemic looms; they were invoked with the zika virus and Ebola virus outbreaks of recent years. The authorization goes back at least to the Project Bioshield Act of 2004, and has been amended multiple times. An EUA for doxycycline and ciprofloxacin was invoked in 2016 for an anthrax scare. EUAs require the prior invocation of a domestic emergency by the Dept. of Homeland Security (which exists nationally for Covid-19 since President Trump’s declaration on March 13).
Mylan Pharma has announced on March 19 that it will restart production of hydroxychloroquine, with ability to provide “50 million tablets to potentially treat a total of more than 1.5 million patients.” (It’s not clear whether that’s a monthly or annual figure.)
There are 18 companies with the ability to provide hydroxychloroquine to the US market (meaning, they have prior FDA authorization to do so, with approved labels at the DailyMed site maintained by NIH), as well as numerous repackagers. Many of them are in India, and India had instituted a policy (since revised) of limiting the export of drugs relevant to the Covid-19 pandemic. (4/6 update: according to a Bloomberg News report, India reinstituted an across-the-board ban of exporting hydroxychloroquine; the country has several thousand Covid-19 cases. Over the weekend, President Trump spoke with India Prime Minister Modi to “give consideration” to a US request; Trump also doubled down on his recommendation for using the drug, saying he might use it himself. In researching approved manufacturers, Pharmaceutical Commerce found producers in Hungary, Taiwan and the US, in addition to the many Indian producers.)
The FDA EUA specifies drug distribution from the National Stockpile only, and it appears that most of that distribution will ultimately go to hospitals. And since FDA has declared a shortage in chloroquine/hydroxychloroquine supply, its availability for lupus and rheumatoid arthritis patients is in question—which was the main reason many medical professionals were pushing back on President Trump’s hints about the drugs’ efficacy for Covid-19.
The case of the Arizona couple who took chloroquine obtained from a fish-tank sanitization treatment, with the husband dying and the wife hospitalized, further charged the debate around the drug; that news broke on March 23.
Novartis/Sandoz’ contribution to the National Stockpile (part of a global contribution of 130 million doses) will inevitably be seen as farsighted, having been made as medical professionals around the world began focusing on the drug. The company also announced that it was committing to “to keeping prices stable for a basket of essential medicines that may help in the treatment of COVID-19.”
The other problem, which will play out now and until new supplies ramp up, is which Covid-19 patients will get the drug. If Mylan’s 50-million-for-1.5-million-patients ratio holds, it implies roughly a 30-day regimen of a pill a day, so, one could speculate, there is sufficient supply for the next few months in the US, when all the existing stocks are added up. (As of April 2, there were about 220,000 active Covid-19 cases in the US.) However, at least one of the clinical trials is looking into the drugs’ effectiveness as a Covid-19 preventive. Regardless of how that trial plays out, it won’t be long before people will be pounding on pharmacy doors looking for a drug to prevent the infection, or the 80% or so of patients who have only mild symptoms and thus do not become an active case.
In retrospect, there never was a prohibition on using hydroxychloroquine for Covid-19 patients, but what did exist was an inability to plan for the inevitable rush to the drug as the pandemic took hold. The Trump administration could have pushed for the EUA simultaneously with the declaration of the national emergency–but who knows what stocks would have been available at that time? It’s also possible that the politicized debate around the Defense Production Act (now invoked to accelerate supply of ventilators for Covid-19 patients) could also have applied to supplying the hydroxychloroquine sooner; the companies that have gone forward with production increases did so on their own (in fact, there’s a case to be made for invoking it now). Instead, what we’re left with is a few tweets and angry finger-pointing, while healthcare providers scramble to save lives.