Politicians: Take this drug if you’re sick. Can’t hurt.
Scientists: Stop! We need to do a double-blind, randomized trial first.
A debate rages over a malaria drug that might treat Covid patients. It hasn’t proved its value in scientific trials. But people who are sick don’t want to wait for the results of trials. They want access to the drug now.
Science confronts personal liberty.
For the scientist’s view of this debate, I interviewed an M.D. who used to be part of the FDA’s drug approval division. That view is presented in this Q&A as the responses to questions arising from the patient’s point of view.
Patient: Hydroxychloroquine could lessen the severity of a coronavirus infection. So if I get Covid, I want this drug. I don’t want my treatment to be decided by a coin flip.
Scientist: How do you know that the drug doesn’t make the disease worse?
There was that French study finding that patients on a combination of this drug and an antibiotic fared better than expected.
It was a lousy trial and you can’t tell much from it. There was no comparison group—randomly selected patients who didn’t get the drug.
There have been other small studies reported since then, and with mixed results. One had the drug speeding recovery. The next found no benefit.
But then there was the discovery that lupus patients, who take high doses of hydroxychloroquine for their disease, either don’t get Covid or get milder cases.
Discovery? This was anecdotal. It doesn’t mean anything when a doctor says, “I have three lupus patients and I’ve noticed that none of them got Covid.”
To draw any conclusion you need to have a large number of people who take the drug for lupus and who are also exposed to the virus. And you need to compare them to another group, such as people with lupus who didn’t take the drug, or people without lupus who took the drug.
What’s the scientific basis for expecting a benefit from hydroxychloroquine?
Two different things.
In the test tube this chemical, a variation on an ancient antimalarial called quinine, has antiviral properties. That doesn’t mean it will work against viruses in human cells, but it’s worth an investigation.
Separately, the chemical tamps down the body’s immune system. That’s why it’s useful against autoimmune diseases like lupus. Some grave conditions, including sepsis and SARS [severe acute respiratory syndrome], are a result of the immune system flooding the bloodstream with defensive cytokines. It might be a cytokine storm that dooms some Covid patients.
Okay, hydroxychloroquine might work, it might not. There’s nothing else to take. Why not use it?
This is not a benign drug. It can cause heart rhythm abnormalities, with fatal results. In high doses it can damage your retina.
What’s the dose?
When the drug is used to protect against malaria for travelers, the prescription is 400 milligrams of hydroxychloroquine sulfate once a week. That’s a fairly low dose, so the risk is low, while the benefit is clear for people venturing into areas where certain kinds of malaria are prevalent.
For lupus, 200mg to 400mg would be a daily dose, and so the risks are higher. The benefit is high, too.
We don’t know what the correct dose would be for Covid, or if it does any good at all. But the dose might be close to the lupus level.
You scientists insist on randomized tests. Why?
A disease may diminish spontaneously. If a drug has been given, you can’t tell if a good result is from the drug or from nature taking its course.
Why can’t you let patients and their doctors decide whether to try an experimental drug? Then compare the ones who decide to take it to the ones who don’t.
That doesn’t work. The set of people who decide to try the drug could be very different from the set who don’t—in age, severity of illness or other factors. That would muddy the results.
But with a miracle drug, it doesn’t matter whether your two groups are perfectly matched. It becomes obvious that the stuff works.
Yes, miracles can happen. Epinephrine to treat a patient in anaphylactic shock from an allergy is like that. Insulin for type 1 diabetics is, too.
Another example, going back to the 1940s, was penicillin for pneumococcal meningitis. Most of the early patients who got the antibiotic survived, whereas without treatment there would have been a high fatality rate. So doctors knew right away that the drug was valuable.
But those instances are rare. Usually the benefit from a drug is more nuanced. You need careful studies to find out whether a drug is effective, and when the gain from treatment is worth the risk from side effects.
What’s being tested in the trials of hydroxychloroquine?
There are scores of experiments underway around the globe, and they are looking at different things. The University of Pennsylvania medical school just started enrolling people in three separate trials. One will compare the drug to a placebo in patients who are sick but not sick enough to be in a hospital. Another will see if a prophylactic dose protects health care workers from being infected. The third will compare hospital patients on a high dose to hospital patients on a low dose.
All three tests will be randomized. The first two will also be blind, meaning that neither patients nor doctors will know who is getting the drug and who is getting a dummy pill.
Blind? Shouldn’t we have more transparency?
Not when you’re trying out a treatment. Patients are human. So are their doctors. If you believe in the treatment you are more likely to think that you’re getting better. If the doctors are believers they might be affected in how they take care of you or how they judge the results.
Why should any patient agree to be put into a coin-flip medical treatment?
One reason is that sometimes an experimental drug is scarce. You either agree to a 50-50 shot at the drug or you go away empty-handed.
Scarce? That’s not true of hydroxychloroquine, which has been on the market for years. The government has a stash of 30 million doses.
True. Maybe this particular drug will be widely available, even before the trials are concluded. But scarcity will definitely be an issue with the more exotic antivirals now in development, such as the ones based on synthetic antibodies.
Why else do people put up with random trials?
Often, participation gets you high-quality medical attention you wouldn’t get otherwise.
There’s a third reason: altruism. Trials help society. They reveal which drugs are effective. Future patients get treatments that work and not the ones that don’t work.
A few decades ago it was an open question whether pulmonary surfactants like Survanta or Exosurf would, by helping premature babies breathe, increase their survival rate. The Food & Drug Administration insisted on randomized trials. There were enough parents volunteering that the tests went forward and proved the value of the drugs. Surfactants became a standard of care, with the result that thousands of lives have been saved.