Up to a third of all prescriptions are written off-label. Coronavirus has no approved treatment.

One of the most alarming things about COVID-19 is that there are no FDA-approved drugs to fight it.

Instead, doctors have turned to medications such as azithromycin, chloroquine, hydroxychloroquine, interferon, or ribavirin, which are officially approved to treat other conditions such as malaria, rheumatoid arthritis, and hepatitis C.   

While researchers are racing to understand whether those drugs work against COVID-19, there is still no clear proof that they help.  

Giving a patient a drug not approved by the Food and Drug Administration for a particular condition is called off-label prescribing. While that practice is legal—even common—it’s also sometimes controversial.

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That’s because there typically isn't much evidence that they're safe and effective for those off-label purposes, as with the drugs now being used to treat COVID-19, says Joshua Sharfstein, M.D., vice dean for public health practice and community engagement at the Johns Hopkins Bloomberg School of Public Health, and a former FDA principal deputy commissioner.  

And in some cases, drug companies, physicians, and others have been known to prematurely and inappropriately promote the use of drugs for unapproved uses.

Off-label prescribing may also be confusing to consumers, according to a nationally representative Consumer Reports survey conducted a few years ago. Seventy-eight percent of Americans said it was extremely or very important that the FDA fully vet the safety and efficacy of a medication for a particular use, something that doesn't happen when a drug is used off-label.

Here’s what you need to know about off-label prescribing, including when it can be a good idea and how to make sure your doctor is doing it safely.

Off-Label Prescribing Is Common

To get FDA approval for a drug, a pharmaceutical company must submit data from clinical trials showing that the medication is safe and effective to treat a specific condition, says Robert McLean, M.D., president of the American College of Physicians and a practicing physician at the Northeast Medical Group of Yale New Haven Health in Connecticut.

That can take years and usually costs about $20 million per trial, with some larger trials of more than 1,000 patients costing upward of $77 million, according to a 2018 analysis by researchers at the Johns Hopkins School of Medicine.

But sometimes a drug is known or thought to be useful in treating other conditions as well, says Steven Woloshin, M.D., a professor of medicine at the Dartmouth Institute for Health Policy and Clinical Practice and a visiting professor of medicine at Harvard, who has researched the effects of drug marketing on physician prescribing.  

While companies may not always seek additional FDA approvals for a drug to treat those other conditions, doctors often prescribe them for those purposes. In fact, between 12 and 38 percent of all prescriptions written in doctor's offices are for off-label uses, according to a July 2019 Congressional Research Service report.

Companies can't advertise their drugs for off-label use, but doctors often learn about them, legally, through medical literature provided by drug company sales reps or from continuing medical education, says Adriane Fugh-Berman M.D., a professor of pharmacology and physiology at the Georgetown University Medical Center who has studied off-label marketing.

And drug companies have been known to skirt the law by, for example, soliciting case studies from doctors highlighting their successful use of drugs for off-label purposes, and hiring “thought leaders” to write about and promote the results in industry-funded speeches or classes, Fugh-Berman wrote in a research paper

In a 2019 JAMA paper, Woloshin found that in the past 20 years companies have paid more than $11 billion in settlements and penalties for their unlawful, mostly off-label, drug promotion. 

Some companies have sued the FDA on First Amendment grounds, arguing that they should be allowed to promote off-label use, says Woloshin. Amarin, a company that makes a prescription fish oil pill, recently won such a suit, potentially opening the door for more to follow.  

That’s concerning, Woloshin says, because decades of research shows that off-label drug promotion to doctors influences their prescribing habits, sometimes to the detriment of patients.  

One example: In the early 2000s, a company promoted using antipsychotics, approved to treat schizophrenia and bipolar disorder, to sedate patients with dementia in nursing homes, even as the FDA warned against it. “The labeling now includes a black-box warning, the most severe kind of warning the FDA issues, that doing so increases the risk of death,” Woloshin says.

When Off-Label Prescribing Can Make Sense

Only about a quarter of off-label prescribing is supported by strong scientific support, according to the Congressional Research Services report. But that doesn’t mean it’s all useless or dangerous. “Just because something is an off-label use doesn’t mean it doesn’t work,” says McLean. “And it doesn’t mean it’s inappropriate.”

Here’s when off-label prescribing can be worth trying. 

No other treatments are available. In dire situations, when no other options are available or a patient doesn't respond to any approved options, it can make sense to try an unapproved drug. For someone critically ill with COVID-19 and on a ventilator, for example, “it’s hard to imagine that some families wouldn’t want to try a drug even if was a long shot that it might work and the chance of side effects high,” says Woloshin. 

“The problem is extending that logic to people who aren’t so sick or who aren’t sick at all,” he says. That’s because when a person is less ill, he or she stands to benefit less, but the risk of a drug still remains high.

For example, hydroxychloroquine increases the risk of severe irregular heartbeats and even death. That might be an acceptable risk if a patient is on the verge of dying, Woloshin says. But for someone who has only mild symptoms, the heart risk might not be worth it because it's unclear whether the drug will help.

An unapproved drug might work as well or better than standard care. McLean says that sometimes a drug may become such an accepted medical treatment that doctors may not even realize it’s not officially approved for that use. He cites certain muscle relaxers like tizanidine and cyclopentadiene often used to help a person sleep. “They’re officially approved as muscle relaxers," he says, "but I use them as sleep aids, either alone for sleep or if a person has muscle issues, too.” 

Another example is a treatment for macular degeneration, a degenerative eye disease that can lead to blindness, Fugh-Berman says. While doctors sometimes treat it with an approved drug called Lucentis, many have switched to a related, nearly identical drug made by the same company, called Avastin, that costs far less but isn't approved to treat the condition.

You’re in a group that wasn’t studied. In many cases, drugs are officially approved for only very narrow cases, such as people with specific stages of certain cancers, says Peter Lurie, M.D., president of the Center for Science in the Public Interest, a nonprofit consumer advocacy group, and a former associate commissioner for public health strategy and analysis at the FDA.  

“Let’s say your study is in certain patients with stage 4 cancer, then you have a patient with stage 3. Do you discard the drug as a possibility or would you consider it?,” he says. “Within limits, in this case, people could consider using a drug off-label a reasonable thing to do.”

In other cases, drugs are studied (and approved) only in certain groups of people. Most drugs aren’t studied in children, in older people, or in pregnant women, for example, Woloshin says. “So if the FDA approval doesn’t extend to them, you wouldn’t be able to use the drugs in those populations without off-label use.”

What You Can Do

Here are some steps you can take to understand whether a drug your doctor prescribed is off-label and if it's appropriate for you.

When your doctor prescribes a drug, ask if it’s an approved use. If he or she doesn’t know, ask your pharmacist, Fugh-Berman says.

Look it up. Go to DailyMed (dailymed.nlm.nih.gov/), a government-funded database of all approved medications and their FDA-approved drug labels, and search for your medication. Click on “Indications & Usage” to see if your condition is listed.

Ask about the evidence. If it’s an off-label use, ask your doctor if it’s supported by well-designed trials that show improvement in people with your condition, Woloshin says. Also ask your doctor if he or she thinks the drug will work better than approved drugs for your illness.

Check with your insurer.  Some insurers may require that you first try a conventional treatment before agreeing to cover an unapproved one, especially if the drug is expensive, says Lurie. Even then, the insurer may still deny coverage if it doesn’t find scientific support or medical justification for the off-label use, says Barbara Young, Pharm.D., editor for AHFS Patient Medication Information, who has researched off-label prescribing.