Seeking a Coronavirus Cure—Not a Regulatory Stamp of Approval

March 24, 2020
By Mark Flatten

When is a cure a cure? Is it when it actually cures something? Or is it when the U.S. Food and Drug Administration (FDA) says it’s a cure?

To top FDA bureaucrats and many in the media, it’s the latter. But to those facing death from the COVID-19 virus, which has no FDA-approved treatment or vaccine, maybe not so much.

This question is over the use of two drugs that have shown remarkable signs of success in treating COVID-19 when used in combination. The first is the anti-malarial drug chloroquine and its newer version, hydroxychloroquine. The second is an antibiotic called azithromycin, commonly sold under the brand name Zithromax or Z-Pak.

Both chloroquine and azithromycin have been approved as safe and effective in treating other ailments by the FDA. Both are inexpensive and readily available. Both can already be prescribed to patients by doctors as an “off-label” treatment for COVID-19, meaning doctors are free to use it even though the FDA has not deemed it effective against the virus.

There are strong indications that the two medications taken in combination offer at least some hope for an effective treatment of COVID-19. One small study in France had a 100 percent cure rate. Other studies in China and South Korea have produced less definitive but still strong indications that some chloroquine-based cocktail is the most promising treatment available now.

President Trump quickly seized on these results and last week began touting chloroquine as a game-changing treatment for COVID-19. But FDA Commissioner Stephen Hahn was equally quick to squelch any idea that the drug’s effectiveness has been proven. The two drugs are not FDA-approved to treat the virus, either separately or in combination. At present, no treatment has been approved by the FDA to treat the pandemic, which to date has killed more than 16,300 people worldwide and more than 500 in the United States. However, it will be made available for “compassionate use” treatment by the FDA, so that its safety and effectiveness can be studied, Hahn said. FDA approval could be weeks, months or years away.

The media was quick to point out the rifts between the President and his top health advisors, reiterating that no drugs have been approved for the treatment of COVID-19.

It’s easy to look at all of this and conclude it’s all a big, tragic muddle between a medically illiterate president and an intractable bureaucracy more interested in red tape and academic studies than it is in saving lives. But most of it does make some sense, in a perverse government regulatory sort of way.

What Trump seems to be talking about is what’s happening in the real world. Doctors and researchers have been dosing patients with a chloroquine and azithromycin combination and have produced remarkable results—at least far better than doing nothing but slapping critical patients on respirators and hoping for the best.

Both drugs have long been approved by the FDA. That means the agency concluded they are safe to use in humans and are effective in treating the condition for which they were originally approved.

Both drugs have been in widespread use for decades, so their safe dosages and side effects are well known and pretty mild in the life-or-death context. Azithromycin was approved by the FDA in 2002. Chloroquine has been around since before World War II, long before the modern-day drug approval process at the FDA.

So the bottom line is that in the midst of a global pandemic in which hundreds of people are dying daily, there is a lot of potential upside to be weighed against the minimal risks of the unknown. As Trump put it at a news conference: “We ought to give it a try.”

The other side of the equation is what it means to have a treatment approved by the FDA. In normal circumstances, drug developers spend an average of 12-15 years and in excess of $1.4 billion to get a new treatment approved by the FDA. Generally, it is a three-stage process in which the drug must be proven safe in humans and effective in treating the targeted condition. This is done through intensive studies on human patients called clinical trials. Throughout the process, extensive data is compiled to not only prove safety and effectiveness, but also to refine dosing levels and look for subgroups of the population who might have adverse side effects.

Ultimately, the bottom line question the FDA is required to answer is whether the medicinal benefits of the product outweigh its risks. If they do, it’s supposed to be approved.

In this context, the caution of Hahn and other top advisors to the President seems to be that the chloroquine and azithromycin combination is not “FDA-approved” because it has not been statistically proven to be effective through the collection of data that is normally obtained in clinical trials. As a result, they have taken to calling the results being seen worldwide as anecdotal. In the FDA’s world, a million people saved by a drug would amount to “anecdotal” evidence as to its effectiveness. It is not “proven” to be effective until it has undergone clinical trials and the FDA has deemed it to be effective based on statistical analysis.

It’s not as crazy as it sounds, if approached from the perspective of a bureaucrat, especially one at an agency that has long been criticized for being overly cautious to the detriment of patients, including terminally ill ones for whom there is no other treatment available.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, has done a better job than most explaining why the apparent rift between the President and the medical community is overblown, or at least misunderstood, in the media. “There’s an issue here of where we’re coming from,” he said Sunday on “Meet the Press.” “The President has heard, as we all have heard, are what I call ‘anecdotal reports’ that certain drugs work. So what he was trying to do, and express, was the hope that it might work, let’s try and push their usage. I, on the other hand, am not disagreeing with the fact that, anecdotally, they might work. But my view is to prove, definitively, from a scientific standpoint, that they do work. So I was taking a purely medical, scientific standpoint. And the President was trying to bring hope to the people.

“I think there’s this issue of trying to separate the two of us. There isn’t fundamentally a difference there.”

The one puzzling comment from Hahn is his reference to “compassionate use.” Also called expanded access, this is a program at the FDA that allows people to access medications that have passed early clinical trials but have not yet received final approval by the FDA. That would not seem to apply to the two drugs at issue here. Since they have both been approved for other things, doctors are free to prescribe them for any condition as they see fit for what is called “off-label” treatment. When a new drug is approved by the FDA, it is usually for a single condition. This is driven largely by the complexity and cost of getting any drug approved by the agency.

But once it has been approved for one condition, the drugs can usually be prescribed by doctors to treat any ailment as they deem fit. So doctors are free to start using hydroxychloroquine and azithromycin today. What is needed, as others have rightly pointed out, is more information on appropriate dosing and potential side effects that might result from combining the two medications.

The concept of studying drugs in the general population rather than controlled clinical trials is not unique, even within the FDA. Aside from the normal three testing phases in the standard protocols, the FDA sometimes requires what are called “Phase 4” studies, in which drugmakers are required to continue collecting data on patients in the general population after approval. Even with the rigorous testing, side effects sometimes do not emerge in the tightly-controlled clinical trials. In fact, about a third of all new drugs approved by the FDA later have some kind of safety issue after reaching the market, according to a study of 10 years of data published in 2017. Not all are withdrawn. Most often, additional warnings are added to the product’s label.

Some even advocate largely eliminating traditional late-stage testing and allowing a drug to be dispensed and closely monitored in the general public, a concept generally referred to as real-world evidence trials. The basic idea is that after a drug’s safety in humans has been proven in Phase 1 clinical trials, and there are strong indications as to its effectiveness in what are called Phase 2 trials, it would be authorized for sale to the public. That way, rather than basing the drug’s effectiveness on studies of a few hundred carefully screened patients in clinical trials, data would be collected from thousands of patients using the product in the real world.

COVID-19 would seem to lend itself to this approach, and it seems consistent with what both Trump and his medical advisors are saying. This is a global pandemic that has killed thousands, crippled the world’s economy, and led to shutdowns of states and nations. There just is not time to wait for tightly controlled statistical studies on a small number of patients, particularly for drugs that have been on the market for decades.

What dying patients need now is a cure. Not a regulatory stamp of approval from the FDA.

Mark Flatten is the National Investigative Journalist at the Goldwater Institute.