Evelyn Pringle May 2007
There is a major controversy brewing over the off-label sale of biliary stents for unapproved uses. On March 12, 2007, the FDA held a meeting in Washington with the makers of the bile stents to remind them about the restrictions on their promotion of these devices for unapproved uses.
For the record, the FDA approved use for the majority of bile stents is for the temporary relief of bile-duct obstruction in cancer patients who are expected to live less than 6 months. For this reason alone, critics say, these devices should not be implanted in the arteries of patients with a normal life expectancy.
"Biliary stents are metal or plastic flexible tubes used to prop open the bile duct in patients with obstructions related to pancreatic cancer," according to the March 16, 2007 Pioneer Press. "The treatment helps drain the biliary tract and keep the bile duct open, thereby relieving pain."
On its web sit, the FDA stated that the March meeting was the result of an investigation "prompted by the promotion of metal biliary stents for vascular indications."
Representatives from between 10 and 20 stent makers attended the meeting, including officials from Medtronic, Ev3, and Boston Scientific, according to the Pioneer Press.
When a new device is approved, the FDA also approves the labeling which lists the indications for which the product may be used. Although doctors are allowed to implant a device in patients for indications not listed on the label, the maker of the device is banned by law from asking surgeons to use the product for uses not approved by the FDA.
At the March meeting, the FDA warned that some company web sites had crossed a "very fine line" in using language that could be considered to promote or encourage the use of biliary stents in vascular procedures.
FDA spokesperson, Karen Riley stated in the Pioneer Press, "FDA has become aware that metal biliary stents are being promoted and used to open arteries in the vascular system -- something they have not been tested to do, or approved for by the agency."
Ms Riley also added that the FDA "is concerned about the increasing reports of adverse events in patients who received biliary stents off-label for vascular therapy."
Specifically, the FDA has found the use of biliary stents for the treatment of femoral artery disease has led to an increase in adverse events.
According to Kenneth Cavanaugh, Jr PhD, a Regulatory Review Scientist with the FDA, in the September, 2006 Endovascular Today: "A recent search of the FDA's publicly available Manufacturer and User Facility Device Experience (MAUDE) database for medical device adverse event reporting suggests that virtually all of the renal stenting procedures currently conducted in the US are performed using stents not indicated for use in the renal vasculature, most commonly including biliary stents."
The off-label use of devices for RAS, he says, "can subject the patient to unknown risks because the safety and effectiveness of the devices, when used to treat renal artery stenosis, have not been adequately evaluated."
"Potential procedural adverse events that can result from such use," Dr Cavanaugh warns, "are vascular trauma, such as dissections and perforations, and embolization of air bubbles from the delivery system or particulates from the lesion."
Longer-term adverse effects, he notes, "may include stent fracture, additional particulate embolization, and restenosis."
According to experts, to gain approval for a class 3 implantable stent for use in arteries within the vascular system, a company is required to go through a Pre-Market Approval that requires extensive documentation of engineering and clinical testing and the process is costly and lengthy.
On the other hand, the approval process for non-vascular devices such as biliary stents is far less demanding. Documentation and required testing are much simpler and the device maker normally only needs to show that the stent is substantially equivalent to a similar device that is already on the market in the US.
However, true to form, the FDA has known about the rampant off-label sales of bile stents for years and this is another example of how the nation's regulatory watchdog has failed to protect consumers from the profit driven pharmaceutical industry.
According to Dorothy Abel, in the March 2003 Endovascular Today, in early 2003 the FDA sent a letter to bile stent makers "to remind them of their obligation to ensure that their devices are appropriately labeled for the way they are actually being used."
"In other words," she wrote, "they have been told to obtain the necessary approvals for the specific vascular indications."
"In addition," Ms Abel said, "the marketing clearance letter from the FDA for nonvascular stents now specifically states that these devices are not approved for use in the vascular system."
"The level of regulatory oversight for a device," she explains, "depends on several factors, including the potential risks associated with the device and how well the device, its testing, and its anticipated performance are defined."
Biliary stents she notes, "are intended to provide palliative treatment for patients with malignancies who have a life expectancy of approximately 6 months."
Given the terminal status of such patients, any long-term risks are not ordinarily a matter of concern, she says, "making the less-stringent regulatory oversight reasonable."
Agency enforcement records show that the FDA had knowledge of the continued off-label use 3 years ago as evidenced by the May 7, 2004, announcement by Cordis Endovascular, a J&J subsidiary, for a nationwide Class I recall of the firm's revised instructions for use of a biliary stent contained in its medical device notification dated March 29, 2004, because they were not approved by the FDA.
A Class I recall is the most serious recall, indicating that there is a reasonable probability that use of a product will cause serious adverse health consequences. The press release went on to list the serious adverse events that had occurred with the off-label use of the devices, stating the company is "aware of nine patient injuries due to air embolism, including seizure and coma, as well as seven incidents of device malfunction in connection with the use of this system outside of its approved indication."
Cordis also noted that it had sent a follow-up notification to customers on May 4, 2004, describing these severe adverse events and advising them to limit the use of the device to the FDA-cleared uses only.
And yet four years later in March 2007, the Wall Street Journal estimates that US bile duct stent makers sell about 90% of their devices to catheterization labs for use in arteries.
In addition to all the risks associated with the use of these devices for unapproved uses, their widespread off-label use is effecting the ability of bile stent makers who are seeking FDA approval to treat vascular indications to enroll patients in the required studies needed to gain approval because the off-label use is so common that many patients and doctors believe the devices are allowed to be used for other indications.
However, the profit-driven sales of devices for unapproved uses may be nearing the end because law enforcement agencies are warning that off-label marketing will continue to be a focus of anti-fraud enforcement efforts over the next two years, with more aggressive prosecution of device companies in particular, according to speakers at an American Bar Association health law conference February 22, 2007.
James Sheehan, of the US Attorney's Office for the Eastern District of Pennsylvania, told the audience that changing promotional practices of device makers will be more "problematic" because the industry has a different structure. Compared with very large pharmaceutical companies, he said, many device makers are typically much smaller, making it harder to communicate rules across the industry.
Also, he said, while there are perhaps a million doctors who can write prescriptions for drugs, only a relatively few number of people decide which particular devices will be used in a hospital, and often these doctors are involved in designing the device in the first place.
"From a marketing perspective, it's very hard to do unilateral disarmament," Mr Sheehan said of device companies. "If your competitors are closely involved with physicians, it's very hard to hold back and still have a business."
As with most cases of off-label uses, experts say that most patients are unaware when a surgeon decides to use a bile stent for an off-label use and thus, if an adverse event occurs patients are also unaware that the cause might be the bile stent.
And to be sure, the hospital and surgeons are not going to own up to the mistake after the fact, unless they find themselves blocked into a corner where they absolutely have no choice. They are also not going to warn other medical providers not to us the bile stents because it would require them to disclose their own culpability for what happened to the patient.
This in turn is a win-win situation for device makers because it allows them to avoid any liability for the injuries directly caused by the illegal marketing of the biliary stents for dangerous unapproved uses while the off-label profits continue to roll in.
With all the secrecy agreements in place as far as what goes on in the operating room, calculating an accurate estimate of exactly how many patients may have been injured or killed due to the off-label use of these devices is not possible.