Off-Label Prescribing With Limited Evidence: What We Have To Lose

President Trump told reporters on Monday that despite warnings from the Food and Drug Administration, he had been taking the prescription drug hydroxychloroquine “as a preventative” against COVID-19. As of this writing, there are no FDA-approved drugs that have been shown to treat or prevent COVID-19. But if the FDA hasn’t approved hydroxychloroquine as a preventative treatment for COVID-19, how could Mr. Trump have been prescribed the drug?

The answer, which I addressed in an article in March, is that doctors are permitted to prescribe hydroxychloroquine or any FDA-approved drug off-label, meaning to treat a different condition or indication than the condition the FDA approved it to treat, which applies to patients with COVID-19.” Off-label drug usage and prescribing are commonplace in the United States today: about one in five prescriptions is for off-label use.

Though the reasons that a physician might prescribe a drug for an off-label purpose are diverse, these uses should have a grounding in evidence that exceeds the “lot of positive calls” that Mr. Trump cited for hydroxychloroquine’s effectiveness on Monday. (Contradicting Mr. Trump’s anecdotes, a recent study published in JAMA found no association between hydroxychloroquine use and lower in-hospital mortality for a cohort of COVID-19 patients in New York City.)

When patients fill on-label prescriptions, they can be sure that the FDA has “conducted a careful evaluation of [the drug’s] benefits and risks for that use,” “the decision to use the drug is supported by strong scientific data,” and “there is approved drug labeling for healthcare providers on how to use the drug safely and effectively for that use.” The same, however, cannot be said about off-label drug use. By definition, off-label medications medication use (or use in a different patient demographic or dosage) has not been thoroughly vetted with clinical trials evaluated by the FDA.

The process of conducting clinical trials to receive FDA approval for new uses or dosages of a drug is expensive and can take years. So, some evidence-based uses of a drug may not be on-label. Partially due to the expensive nature of clinical trials, physicians are free to prescribe any FDA-approved drug for any purpose they see fit, regardless of what the drug was initially approved to treat. But simultaneously balancing a professional oath to do no harm, upholding an ethical obligation to act in the best interests of patients, and respecting the autonomy of patients is often complicated.

In the case of patients that do not have severe cases of COVID-19, however, infectious disease specialist Dr. Rachel Bystritsky warns that prescribing drugs like hydroxychloroquine that do not have an established clinical benefit is unethical and potentially dangerous. The authors of a recent research letter published in JAMA Internal Medicine agree, stating that physicians have a responsibility to prevent “unsupervised use of the products with dangerous consequences to the people who take them.”

Off-label prescribing that lacks the support of sound clinical evidence runs serious risks. As Dr. Benjamin Rome and Dr. Jerry Avorn outlined in an article in the New England Journal of Medicine in April,

benefits to patients are unknown and may be negligible… medications such as hydroxychloroquine have well-documented risks; subjecting patients to these risks would be unjustifiable in the absence of meaningful clinical benefit… widespread off-label use can limit access for patients who need them for their established use.

Though Dr. Rome and Dr. Avorn were referring to the FDA’s decision to grant emergency use authorization to hydroxychloroquine, the same reasoning holds for off-label prescribing.

When reporters have reminded President Trump that no experimental data exists to back up his claims about the effectiveness of hydroxychloroquine as a treatment or prophylactic for COVID-19, Mr. Trump has responded by asking “what do we have to lose?” The FDA recently published guidance documenting what we have to lose: “Hydroxychloroquine and chloroquine can cause abnormal heart rhythms such as QT interval prolongation and a dangerously rapid heart rate called ventricular tachycardia.”

Randomized clinical trials are the core of how government regulators prevent dangerous prescription drugs from reaching patients. That’s for good reason. Though some prescriptions can be made ethically without the backing of randomized control trials, these situations are and should remain the exception, not the rule.

It is worth noting that drugmakers often have little incentive to generate high-quality new clinical evidence for off-label uses of their FDA-approved drugs, especially in the case of generics. Incentivizing the production of better data on off-label uses of existing FDA-approved drugs is an important policy challenge that remains largely unaddressed. But doing just that is crucial because patients deserve to know that the prescription drugs they take have been tested and researched by experts. With a few notable exceptions, prescriptions should be made for indications when there is evidence that shows that the benefits of adherence clearly outweigh harms.

Throwing caution to the wind with off-label prescribing, without sound clinical evidence, means that patients will no longer be able to trust that their medicines are safe and effective. That’s something we can’t afford to risk, now or ever.

Research for this piece was supported by the Laura and John Arnold Foundation.

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