Off-label Drug Use Increases Risk of Adverse Events in Adults: Study

The findings of a new study appear to confirm worries that federal regulators have held for decades, indicating that use of prescription drugs for unapproved indications increases the risk of harmful side effects. 

A group of Canadian researchers say that doctors who prescribe drugs to patients for uses that are not approved by the health regulators as safe and effective may place individuals at a 44% increased risk of suffering an adverse drug event. The findings were published in the medical journal JAMA Internal Medicine on November 2.

The results appear to back up long-held policies by the FDA in the U.S., which has banned drug companies from promoting their products for unapproved uses, known as “off-label” marketing. While it is legal for doctors to prescribe drugs for any purpose they see fit, drug companies are prohibited from promoting such unapproved uses until they provide sufficient evidence to establish that it is safe and effective.

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When drug makers engage in “off-label” drug marketing they have faced large fines and penalties, but the industry has recently been pushing back against the ban, arguing that it violates their First Amendment freedom of speech rights.

The study’s findings may provide strong support for the continued enforcement of the ban, highlighting the serious risks consumers may face if drug makers are able to promote off-label drug use without conducting sufficient studies and research.

Consumers May Face Risks from Untested Off-Label Uses

Researchers looked at data on 46,021 patients who received 151,305 drug prescriptions in Quebec, Canada. They then determined which prescriptions were given for off-label uses, and which off-label uses were, or were not, backed up by scientific evidence.

The study then followed up on those patients until the end of treatment, until the drug was discontinued, or until the end of follow up, which went from January 1, 2005 through December 30, 2010.

According to the findings, the rate of adverse drug events for off-label use was overall 19.7 per 10,000 person-months. That compares to a rate of 12.5 for on-label use, meaning off-label use resulted in a 44% higher risk of harmful side effects.

When researchers looked at those off-label uses backed by science, but not yet approved by Health Canada, that country’s medical and health regulatory agency, there was little difference in the rate of adverse events. However, off-label uses that were not backed up by science were 54% more likely to result in adverse drug events. Strong scientific evidence for off-label use was present only 20% of the time.

Off-Label Drug Marketing

In August, a federal judge issued a preliminary injunction which prevents the FDA from enforcing its off-label promotion restrictions on Amarin Pharma, which wants to promote its fish oil products for uses that the FDA has not deemed safe or effective.

The FDA warned the judge that blocking its ability to regulate advertising by drug manufacturers will pose a serious public health risk. However, the judge said the FDA’s off-label marketing rule may be unconstitutional, referencing recent decisions that give corporations increased speech rights. The ruling only currently applies to Amarin.

An accompanying editorial by Drs. Chester B. Good and Walid F. Gellad, with the U.S. Department of Veterans Affairs and the University of Pittsburgh, notes that the study’s findings, the most comprehensive yet to date, appears to back up the FDA’s premise that promoting unproven drugs for unapproved uses is dangerous for patients.

“Critics of off-label drug promotion point to dietary supplements as an example of the kinds of claims that are commonplace when regulation is lax and worry about an erosion of the authority of the FDA to ensure safety and efficacy of drugs,” they wrote. “Are these concerns about safety warranted? Does evidence show that off-label prescribing might be less safe than on-label prescribing? In light of these concerns, the study of off-label drug use and adverse drug events…is particularly timely.”

In recent years, the FDA has cracked down on a number of major drug companies for off-label promotion violations.

In November 2013, Johnson & Johnson agreed to pay $2.2 billion to the federal government to settle its Risperdal illegal marketing claims. Investigators say that the illegal marketing led to the unnecessary and risky use of drugs like Risperdal, which is sometimes used in nursing homes as a form of chemical restraint, potentially putting dementia patients’ lives at risk.

The DOJ began investigating Johnson & Johnson’s marketing of Risperdal in 2004, looking into an alleged kickback scheme between the drug maker and Omnicare, the nation’s largest provider of drugs to nursing homes.

Although federal drug regualtors and other safety officials have been working to reduce the use of antipsychotics in nursing home patients, indicating that the drugs carry little benefit for dementia patients and may increase the risk of death, widespread overuse of the medications continues to be a problem following years of illegal marketing.

Off-label use of the anti-nausea drug Zofran has also been a concern in recent years, after GlaxoSmithKline was charged with off-label drug promotion several years ago. Promoting Zofran for pregnancy-related morning sickness was among the claims that led to a $3 billion settlement with the federal government, as the drug maker never conducted any studies to establish that Zofran use while pregnant was safe for unborn children.

The company now faces a growing number of Zofran lawsuits from women who gave birth to children who suffered congenital heart problems, cleft palate, cleft lip and other birth defects. Critics point out that, for those children, the penalties against GlaxoSmithKline came too late and many doctors are still unaware of Zofran pregnancy risks.


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