Editor’s note: The following column, primarily a report by Michele Cohen Marill covering a recent audio conference on off-label uses of devices, first appeared on the new weekly blog, MDD Perspectives, of BB&T’s sister publication, Medical Device Daily.

Using devices in an off-label manner is no longer the exception. It’s a mainstream practice producing billions in revenue. Yet the magnitude of off-label use raises serious questions about what it means to have an FDA-approved product — and how to market that product responsibly.

Some 60% of drug-eluting stents (DES) have been used off-label — and those off-label cases have a higher rate of blood clots. Biliary stents are commonly used in cardiac cases, despite an FDA warning that they are not approved for use in the vascular system. And a group of cardiovascular groups recently issued a long-overdue guidance on treating atrial fibrillation via interventional catheter devices — overdue since there may be up to 60,000 of these procedures every year but no FDA approvals of the devices for this extremely difficult application.

Can you see the red flags aflying? Widespread off-label uses signal some powerful marketing going on and that is why off-label use is now a subject of intense scrutiny. Blatant promotion of off-label use of devices is inviting the FDA, the courts and even the U.S. Congress to crack down on device manufacturers.

Stephen McConnell, a former assistant U.S. attorney and a partner with the mass tort and product liability group of Dechert LLP (Philadelphia), in a recent audio conference, said that off-label promotion “creates more [legal] cases that are likely to be filed against your company. It makes those cases more difficult to defend. And it increases the likelihood of a judgment against you.”

True, the FDA permits physicians to exercise their clinical judgment in off-label uses of devices and drugs. But the agency prohibits manufacturers from providing off-label information, except in narrow circumstances. Essentially, physicians have to ask for such material; it can’t be a sales rep’s pitch or a part of company-sponsored educational sessions.

What worries the FDA is that manufacturers will confound the approval process by testing a device only in the patients with the best possible profile —patients who don’t have serious underlying conditions, such as diabetes; patients neither too old nor too young; patients who can show the greatest benefit from the procedure. But then, gradually, the device use expands to a much broader market without rigorous clinical testing.

The most egregious cases of companies exploiting off-label use have resulted in civil suits, huge fines and even criminal charges. In 2003, EndoVascular Technologies (Menlo Park, California), a subsidiary of Guidant (Indianapolis), agreed to a $92.4 million fine and pled guilty to 10 felony charges for failing to report 2,623 incidents to the FDA concerning malfunctions related to stents used to treat abdominal aortic aneurysm.

When problems arose with the positioning of the stents, sales reps gave advice on how to remove them — without any clinical testing of the procedure. (Guidant, now a subsidiary of Boston Scientific [Natick, Massachusetts] shut down the subsidiary.)

Pharmaceutical companies also have faced strong penalties. Serono Labs (Geneva) in 2005 paid a $704 million fine for improper marketing of Serostim, an AIDS-wasting drug. When protease inhibitors greatly reduced the incidence of AIDS-wasting, Serono worked with the manufacturer of a device that measures body fat and mass to use the machines used to boost the market for Serostim. But the devices were not FDA-approved for that use. Serono also boosted Serostim sales by sending high-prescribing physicians on an all-expense-paid trip to Cannes, France, for an “educational” program.

Assistant U.S. Attorney General Peter Keisler called the settlement “an unequivocal message to the healthcare industry that American taxpayers should not pay for prescriptions induced by unproven medical tests and improper payments to doctors and pharmacies.”

As to DES devices, no one has accused the makers of misconduct. The stents have shown good results in preventing stenosis in approved uses for patients with previously untreated coronary lesions of less than 30 mm in length. And last December, an FDA panel concluded that the benefits of DES outweigh the risks for on-label use.

But researchers presented data showing a significantly higher level of thrombosis and an increased risk of death or myocardial infarction compared with bare-metal stents — with higher risks for off-label uses with more complex lesions or patients.

Citing concerns raised by that panel, Rep. Henry Waxman (D-California), chairman of the House Committee on Oversight and Government Reform, asked stent manufacturers Boston Scientific and Johnson & Johnson (New Brunswick, New Jersey) to provide information on stent studies — and company marketing. The committee has asked to see all the materials given to physicians by sales reps, as well as reports and communications related to their promotion, continuing medical education and off-label use.

Waxman’s office issued this statement on the request: “The Committee is looking into reports of improper marketing practices of companies such as Boston Scientific, especially when such practices may negatively impact public health. I want to learn why so many drug eluting stents were used in a manner that was never approved by the FDA and may result in more heart attacks.”

While cardiac experts debate the proper uses of DES devices, one thing is clear: the FDA and others are focusing in on marketing that looks and smells like off-label promotion. It is obvious that a manufacturer’s marketing plan can’t outline a strategy for off-label use as the predominant focus of the device.

Still another large red flag: a small market for on-label use of a product, but a big sales force for the product.

A manufacturer can’t look the other way as sales reps tout those off-label uses, either. Companies have an obligation to supervise sales reps and sanction those who “go over the line,” advised Linda Baumann, a specialist in healthcare regulatory compliance with the law firm of Arent Fox (Washington), during the audio conference. “They expect you to take corrective action if a problem is identified.”

Bottom line: Manufacturers that use off-label promotion as a way to avoid the FDA approval process are likely to feel the heat.

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