Doctor writing something on a sheet of paper
13 May 2015

Going Off-Label: When Doctors Prescribe Drugs For Unapproved Uses

Every drug sold on the American market comes with a stamp of approval; if it can be sold in the US lawfully, data provided by the drug’s manufacturer has been reviewed by the US Food & Drug Administration. But having the data come from the manufacturer is a little like putting the fox in charge of the hen house, isn’t it?

Government scientists review the results of clinical trials to determine whether or not drugs are safe enough for people to take. They also decide if clinical trials have demonstrated that the drug is effective in treating specific conditions.

But the FDA’s approval ends there, at specific conditions in specific patients.

Off-Label Prescription Is Surprisingly Common. But Is It Safe For Patients?  Doctor writing something on a sheet of paper

When we’re prescribed drugs, most Americans assume that our medications are FDA approved for the specific conditions that we have. But as it turns out, that assumption isn’t always correct.

Drug companies are not required to study their products in wide segments of the population, and so the medical community often lacks the information necessary to understand whether or not a drug is safe or effective in patients with other conditions. But doctors aren’t prohibited from prescribing drugs for unapproved uses, and the FDA doesn’t exert any oversight over how drugs are prescribed after being released onto the American market. Simply put, the FDA does not regulate the practice of medicine.

Prescribing drugs for unapproved uses, a practice you might see referred to as “off-label” prescription, is probably more common than you think.

Researchers Have Found That More Than One Out Of Five Prescriptions Is Off-Label.

In 2006, researchers at Dartmouth Medical School filtered through nationally-representative data to determine the extent of off-label use for 160 of the most commonly-prescribed drugs in the US. Using records compiled by IMS Health, the nation’s largest database of prescribing information, they found every time any one of those 160 drugs had been prescribed and then determined what condition it was prescribed to treat.

They split the results into two large groups: drugs that were prescribed “on label,” for FDA approved uses, and ones prescribed “off-label.” They found that 21% of all drugs, more than one out of every five prescriptions written, were for unapproved uses.

Then they took a look at which off-label uses were supported by strong scientific evidence. The vast majority of all off-label prescriptions, anywhere from 61% to 84%, “had little or no scientific support.”

Is Off-Label Use Good Or Bad For Patients?

Researchers can point to instances in which off-label use has come to reveal surprising new benefits, and some drugs have even been reapproved for new indications after clinical experience demonstrated their advantages over a traditional therapy.

But results like those found in the Dartmouth study have led some critics to say that off-label prescription treats real people like experimental test subjects.

Writing in The Journal of Law, Medicine & Ethics, medical ethics professor Rebecca Dresser and practicing physician Joel Frader said:

“In the absence of [strong scientific] evidence[,] off-label prescribing can expose patients to risky and ineffective treatments […] To exercise responsible self-regulation, members of the medical community must determine whether available evidence justifies specific off-label uses and must promote information-gathering when the evidence is inadequate.”

If the Dartmouth study’s results are any indication, sound advice like that isn’t being heeded. Again, the researchers found that up to 84% of the prescriptions for off-label use were being written in the absence of strong scientific evidence.

Are Some Patients More Likely To Be Prescribed Drugs Off-Label?

Off-label prescription use is generally thought to be higher in certain populations than others.

Pediatric patients are more likely to be prescribed a drug off-label than adults. In southwestern France, a team of researchers reviewed every drug prescribed to patients under the age of 16 in 46 different doctors’ offices. Almost 38% of the pediatric patients who received any prescription were given a drug for an unapproved use.

A group of Italian researchers reviewed 30 separate studies of off-label prescribing in pediatric patients. Many of these studies focused on hospitals and general practitioners in the US. On the high end, children were being prescribed drugs off-label 80% of the time.

Off-Label Prescription Use During Pregnancy

Pregnant women may be another area of concern. As in children, widespread ethical considerations prevent most drugs from being studied in pregnant patients prior to approval. For that reason, few pharmaceutical products are explicitly approved for use during pregnancy, and the effects of most drugs on fetal development are poorly understood.

But according to the US Centers for Disease Control & Prevention, around 90% of pregnant women “take at least one medication during pregnancy and 70% take at least one prescription medication.” Researchers at the National Birth Defects Prevention Study found that between 2006 and 2008, 50% of pregnant women reported taking 4 or more medications during pregnancy, and just under 30% said they had taken 4 or more during the first trimester.

Timing is extremely crucial in this case: during the first trimester, unborn children are most likely to be affected adversely by a harmful drug. And since so few medications have been adequately studied during pregnancy, it’s unclear which ones have the potential to cause birth defects. The CDC reports that “less than 10% of medications approved by the [FDA] since 1980 have enough information to determine their risk for birth defects.”

Does The FDA’s Pregnancy Category System Stop Doctors From Prescribing Drugs That Are Known To Be Harmful?

While the agency plans to phase this system out, the FDA currently ranks drugs in one of five Pregnancy Categories based on the amount, type and results of studies that have investigated their effects on fetal development.

  • Category A marks drugs that have “failed to demonstrate a risk to the fetus” during all trimesters of pregnancy in “adequate and well-controlled human studies.” These drugs are widely regarded to be safe for women to take during pregnancy.
  • Drugs are assigned to Category B when studies in animals have failed to demonstrate such risks, or when animal studies have demonstrated risks but adequate, well-controlled studies in human subjects haven’t.
  • Category C is less certain, and headed by the words “Risk not ruled out.” For these drugs, studies in pregnant animals have shown risks, but there aren’t any adequate studies that have investigated its effects in humans.
  • Category D includes drugs for which adverse event reports or post-marketing research has demonstrated “positive evidence of human fetal risk.” While these drugs have been found to increase the risk of birth defects, the FDA notes that “potential benefits may warrant use of the drug in pregnant women despite potential risks.”
  • X is even more stark: “studies in animals or humans have demonstrated fetal abnormalities and / or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.”

But do these simple recommendations actually guide the prescribing decisions of doctors as the FDA intends?  Do they prevent physicians from prescribing harmful drugs to pregnant patients?

Studies Find That Many Women Are Prescribed Drugs With The Potential To Cause Fetal Harm

Here are the results of three studies that have found an alarming number of pregnant women are being exposed to drugs in Category X:

In 2004, researchers at the University of Massachusetts reviewed the prescribing records for 152,531 pregnancies between 1996 and 2000. 6,976 of the pregnant women included had been prescribed drugs from Category X, and 7,333 had received drugs from D. Almost 38% of the women had been given drugs in Category C. All told, nearly half of the pregnancies studied had been exposed to a drug for which scientific evidence does not explicitly support, or actively discourages, use during pregnancy.

The following year, researchers at Harvard University’s Medical School studied the pregnancies of 1,626 women, using prescription records logged between 2001 and 2003. The majority of these women (56%) were prescribed a prescription drug. But 4% had been prescribed drugs listed in the FDA’s Pregnancy Categories D or X.

In Saskatchewan, Canada, researchers performed a similar study, and found even higher amounts of pregnant women being prescribed drugs that have been demonstrated to adversely affect unborn children. Out of 18,575 women, 5.2% had been prescribed Category D drugs, and 3.9% had received Category X drugs.

Off-Label Treatments For Morning Sickness Common, Often Untested In Pregnant Women

Estimates place the number of pregnant women who experience nausea and vomiting, or “morning sickness,” during the first trimester at anywhere from 70% to 90%. Some of these women will be able to control their symptoms adequately through non-pharmaceutical lifestyle changes, but severe morning sickness is a serious medical condition that can threaten both a mother’s life and that of her unborn child.

Until 2013, there hadn’t been an FDA-approved medication for the nausea and vomiting of pregnancy for 30 years. In the interim, many doctors turned to off-label treatments in an attempt to alleviate their patients’ symptoms. In fact, according to a 2014 editorial in the American Journal of Obstetrics & Gynecology:

“97.7% of prescriptions for the treatment of nausea and vomiting in pregnancy in the United States are with medications not labeled for use in pregnancy, not indicated for nausea and vomiting in pregnancy, and not classified as safe in pregnancy by the Food and Drug Administration.”

One of the most commonly-prescribed off-label treatments is Zofran, a drug with the active ingredient ondansetron. It is only approved to treat severe nausea and vomiting in patients undergoing chemotherapy, radiotherapy and surgical anesthesia. But like most pharmaceuticals, Zofran’s manufacturer has never studied the drugs effects in pregnant patients.

The author noted that US prescriptions of ondansetron for nausea and vomiting in pregnancy rose from 50,000 per month in 2008 to 110,000 per month in 2013. Assuming that the author’s estimate of ondansetron prescriptions held steady through 2014, doctors could have written as many as 1.32 million prescriptions for ondansetron that year. There are approximately 4 million US pregnancies every year. At most, we can estimate that one-third of pregnant women in the US were prescribed ondansetron off-label as a morning sickness treatment.

Ondansetron prescriptions rose gradually throughout 2013, despite the FDA having approved a new drug as safe and effective in treating morning sickness in April of that year. Unlike Zofran, Diclegis has been studied extensively during pregnancy. According to the drug’s labeling information, at least 27 epidemiological studies of Diclegis’ active ingredients have found “no increased risk for malformations from first trimester exposures.”

Epidemiological research on Zofran, on the other hand, had associated the drug with an increased risk of birth defects as early as 2012.

When Does Off-Label Become Unlawful?

All this information makes one thing glaringly obvious: when physicians prescribe drugs off-label, especially during pregnancy, they should take great care in reviewing all the medical evidence that supports, or discourages, that use. Even advocates for off-label use are adamant on this point: physicians should only prescribe drugs for unapproved purposes with the backing of strong scientific support.

But what if doctors don’t have all the information? Or what if they’re given misinformation?

In 2012, the US Department of Justice posed a theory that might explain Zofran’s meteoric rise in off-label prescription. According to the federal government, Zofran’s manufacturer had been promoting the drug to doctors as a morning sickness treatment, in many cases misrepresenting its safety and efficacy during pregnancy. Under federal law, promoting drugs for unapproved use is prohibited.

In the wake of the government’s allegations, which Zofran’s manufacturer continues to deny, at least seven US families have filed lawsuits. These parents claim that Zofran has the potential to cause birth defects, but say that the drug’s manufacturer withheld adverse event reports from the FDA and failed to warn the medical community of vital evidence that suggested it could alter fetal development.

If these allegations are true, doctors weren’t just prescribing Zofran off-label in the absence of scientific evidence. They were doing so on the basis of misinformation, inaccurate claims supplied by Zofran’s manufacturer.