Tag Archives: Off-Label Use

Rise, fall of two St. Louis pharma companies

Midwest Health Journalism Program fellow Jim Doyle, a reporter at the St. Louis Post-Dispatch, tells the story of Forest Pharmaceuticals (a subsidiary of Forest Laboratories), which has been accused by federal regulators of sketchy marketing practices, primarily involving its antidepressants Celexa and Lexapro and unapproved pediatric use. The company has pleaded guilty to federal criminal charges and agreed to pay $300 million in criminal and civil penalties, Doyle reports.

Armed with the breaking news, Dolye then goes deeper, finds the company’s local roots, charts its rise and tries to pinpoint where it went wrong. It’s the same formula he used for his story on another imploding local drug-maker, KV Pharmaceuticals, earlier this year.

Conflicts of interest + off-label use = Blockbuster

Medtronic is back at the FDA, asking for approval of another spine fusion product. Not coincidentally, the Journal Sentinel‘s John Fauber is also hard at work, this time exposing the conflicts of interest and off-label applications which helped make Medtronic’s first spine fuser, Infuse, into a dubious blockbuster.

First approved for a relatively narrow application, Infuse now succeeds thanks to widespread off-label use. It’s key component is BMP-2, a protein which “essentially turned whatever it touched into bone,” Fauber writes.

One recent study found a fourfold increase in the use of all BMP products in five years, from 24,000 procedures in 2003 to 103,000 in 2007. About 85% of that was off-label use, according to the study, which was presented in March at an orthopedic surgery meeting.

If you’re wondering what problems could result from all of these applications, Fauber’s got a story for that too.

According to Fauber, the 2002 Infuse introduction was straight out of the classic drug industry playbook:

First, a buzz is created about a potential new therapy. Then, research – often by doctors with financial ties to the product – is presented to the FDA for a specific use in a narrow group of people. Once the product is on the market, other uses for it are promoted in articles and presentations, often by doctors with financial ties to the company.

And it’s those financial ties, of course, that Fauber is determined to ferret out. He starts with a man whose name (and photo) will already be familiar to Fauber fans: Thomas Zdeblick.

Conflicts of interest involving Thomas Zdeblick, a prominent surgeon at the University of Wisconsin-Madison, are at the heart of the BMP-2 story. He and a small group of doctors from around the country with financial ties to Medtronic have paved the way toward the product’s approval and widespread use.

Zdeblick holds patent rights to a key component of the product and has received more than $22 million dollars in royalties and other payments from Medtronic since 2002. He also is co-author of research reports about the pivotal FDA clinical trial that led to the approval of Infuse.

When Infuse was first approved, it was noted that physicians with financial ties to Medtronic produced results twice as good as those of their independent counterparts. At the time, the panel dismissed it with a joke about how every physician should have a stake in Medtronic, as it sure seemed to improve outcomes. When Fauber tried to find out more about these early concerns and disclosures, however, he ran up against a wall of FDA obfuscation, intentional or otherwise.

The FDA redacted sections of its 2001 file listing the financial disclosures of the Infuse investigators, and it repeatedly told the Journal Sentinel that information no longer was available.

An FDA spokesman first e-mailed this reply: “The information you are asking for was part of the sponsor’s presentation and FDA did not require submission nor did the agency maintain copies.”

Then Friday, a different FDA official said the agency erred and the records were available, but they would be difficult to find.

With a similar BMP-2 based Medtronic product, Amplify, now under consideration, the story of Infuse is more relevant than ever.


14 meds used off label need further study

Researchers have assembled a list of 14 widely prescribed drugs they believe urgently need additional study to determine safety and effectiveness for off-label use. Their list, which specifically targets meds that are widely used off-label without proper scientific backing, include a number of popular antidepressants and antipsychotics. And the most common off-label use for six of the drugs was for bipolar disorder.

“Off-label prescribing means that we’re venturing into uncharted territory where we lack the usual level of evidence presented to the FDA that tells us these drugs are safe and effective,” Randall Stafford, associate professor of medicine at the Stanford Prevention Research Center, who is the senior author of the study, says in a statement. “This list of priority drugs might be a start for confronting the problem of off-label use with limited evidence.”

At the top of the list was AstraZeneca’s Seroquel antipsychotic, which was approved by the FDA to treat schizophrenia. Not only did this drug lead all others in its high rate of off-label uses with limited evidence (76 percent of all uses of the drug), the researchers say it raised additional concerns because of its high cost at $207 per prescription, heavy marketing and the presence of a “black-box” warning from the FDA.

The study, which appears in Pharmacotherapy, appears only days after an FDA advisory committee criticized the growing off-label use of antipsychotics in children and amid an investigation by a group of state Medicaid directors. The consortium is evaluating the use of the drugs in children on state Medicaid rolls to ensure they are properly prescribed. The growing use of the medicines has been driven partly by the sudden popularity of the diagnosis of pediatric bipolar disorder.