Regulatory Focus™ > News Articles > Off-Label Use Case on Potential Path to Supreme Court, With Wide-Ranging Implications for FDA

Off-Label Use Case on Potential Path to Supreme Court, With Wide-Ranging Implications for FDA

Posted 04 September 2014 | By Alexander Gaffney, RAC

Off-Label Use Case on Potential Path to Supreme Court, With Wide-Ranging Implications for FDA

A debate in Arizona which in part focuses on the authority of the US Food and Drug Administration (FDA) to regulate the use of drug products may soon find its way before the Supreme Court, with major implications for a wide range of products.


The matter in question concerns a federal court case, Planned Parenthood v. Humble, challenging a 2012 Arizona law which makes it illegal to use the drug RU-486 (mifepristone) for uses not explicitly approved by FDA.

The drug is presently FDA-approved for the termination of pregnancy within 49 days of the start of a woman's last menstrual period. As FDA explains on its website, the approved regimen for use is as follows:

  • Day One: Mifeprex Administration: 3 tablets of 200 mg of Mifeprex orally at once
  • Day Three: Misoprostol Administration: 2 tablets of 200 mcg of misoprostol orally at once
  • Day 14: Post-Treatment: The patient must return to confirm that a complete termination has occurred.  If not, surgical termination is recommended to manage medical abortion treatment failures.

"The safety and effectiveness of other Mifeprex dosing regimens, including use of oral misoprostol tablets intravaginally, has not been established by the FDA," the agency wrote. The drug has been associated with dozens of serious adverse events, including deaths, though FDA has not determined a causal connection between the drug and the deaths.

The drug is often used in combination with misoprostol, a drug which causes the uterus to go into labor. However, misoprostol is not approved for any other purpose except for the treatment of stomach ulcers. Its labor-inducing properties are thus "off-label," meaning its use lacks the explicit approval of FDA.

Off-Label Uses

However, while marketing a drug for off-label uses is illegal in the US, the practice of prescribing drugs for off-label uses has long been legal (FDA does not regulate the practice of medicine), and is encouraged by FDA.

"Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment," FDA explains on its website. "If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product's use and effects."

In other words, while FDA might not have approved a product, it recognizes that evidence may exist to support its use in patients. In fact, off-label use often leads to the eventual approval of existing products for new indications.

Legislators to Ban Off-Label Use

But Arizona legislators, apparently hoping to limit access to abortion services, passed a law in 2012 (House Bill 2036) that would restrict access to RU-486 in cases where it would be used for an off-label indication.

The key passage of the law is as follows:

"The director [of the Arizona Department of Health Services] shall adopt rules relating to the abortion procedure. At a minimum these rules shall require . . . [t]hat any medication, drug or other substance used to induce an abortion is administered in compliance with the protocol that is authorized by the FDA and that is outlined in the final printing labeling instructions for that medication, drug or substance." (Emphasis Added)

Eventually, Planned Parenthood filed a lawsuit against the state, which resulted in a hearing before the California 9th Circuit Court of Appeals in the case.

Off Label: Allowed or Tolerated?

A central point of debate in the case is whether FDA permits the off-label prescribing of drugs, or simply tolerates it. The court found that the agency has actively permitted the practice since at least 1982, noting that the agency sees it as an essential part of the ecosystem of medical innovation.

"Such ‘unapproved’ or, more precisely, ‘unlabeled’ uses may be appropriate and rational in certain circumstances, and may, in fact, reflect approaches to drug therapy that have been extensively reported in medical literature," FDA wrote in a 1982 drug bulletin.

In June 2014, California's 9th Circuit Court of Appeals ruled in favor of Planned Parenthood's attempt to limit the implementation of the law, finding that Arizona lacked any compelling reasons to ban off-label use of the drug. The limits, the court found, would have unduly burdened patients without offering a legitimate benefit.

"Arizona argues that the law prohibits not just safe evidence-based regimens for medication abortion but also other, dangerous off-label regimens," the court explained in its ruling. "But the record contains no evidence that any such dangerous regimen exists or has ever been used by any abortion provider. Therefore, on the current record, the Arizona law appears wholly 'unnecessary as a matter of women's health.'"

On-label use of the drug, the court noted, actually involved a recommended dose three times higher than that given under an off-label "evidence-based" regimen.

Broader Off-Label Limits?

But the court notably avoided ruling on another central point of the case—one with major regulatory implications.

That question: Does federal law preempt Arizona's attempt to ban off-label prescriptions?

The issue has recently been at the forefront of other cases, such as the prescribing of painkillers. If Arizona is permitted to limit off-label prescribing of medicines, the thinking goes, might other states be permitted to limit off-label prescribing of other drugs as well?

For its part, FDA has called efforts to limit the prescribing of FDA-approved painkillers "extremely troubling," but has thus far declined to weigh in on off-label cases.

A Path to SCOTUS

But the off-label issue may soon become much harder to ignore.

On 28 August 2014, the California Circuit Court of Appeals ruled that Arizona could stay its earlier ruling while it files a writ of certiorari—essentially a petition for judicial review—with  the Supreme Court of the United States.

According to the Arizona Capitol Times, the ruling may have a good chance of being heard by the court based on a series of contradictory rulings by other appellate courts in similar cases. "That conflict increases the chances the justices will seek to set a single standard nationwide," the paper explained.

Whether four Supreme Court justices agree—the minimum number of justices requires to grant a writ of certiorari—remains to be seen, but this is certainly one case regulatory professionals should keep an eye on.

Categories: Regulatory News

Regulatory Focus newsletters

All the biggest regulatory news and happenings.