Off-Label Medical Device Use
Our FDA expert provides answers to questions about a serious, if common, situation.
The views and opinions in this article are those of the author and do not necessarily reflect those of the US FDA, the US Department of Health and Human Services, or the Public Health Service.
It seems the biliary and tracheobronchial stent industry is booming. Although only a couple of biliary stents were cleared for marketing in 1994, almost 30 new stents were made available in 2001, and almost equal numbers were cleared for marketing in 1999 and 2000. One may ask whether the incidence of biliary ducts obstructed due to malignant neoplasm has risen accordingly or if there was a great need to improve the devices available for treating this condition. Considering the medical community’s concurrent interest in and general acceptance of vascular stenting, and the absence of a significant number of new approvals for vascular stents, it is more likely that biliary and tracheobronchial stents are being used off-label. This column addresses some of the commonly asked questions regarding this phenomenon.
Q: Does the FDA care that practitioners use medical devices in a wide variety of circumstances that are outside of indications specified in the labeling for the device?
A: Yes and no. The FDA regulates interstate commerce of medical devices, not the practice of medicine. The Food, Drug, and Cosmetic Act (the Act) specifically states that “nothing in this Act shall be construed to limit or interfere with the authority of a health care practitioner to prescribe or administer any legally marketed device to a patient for any condition or disease within a legitimate health care practitioner-patient relationship.” As such, off-label use is a recognized phenomenon associated with patient care. A physician may not promote the off-label use; to do so is a violation of the Act.
There are also rules that apply to device manufacturers regarding off-label use. Manufacturers are not allowed to promote their devices for any indications other than those in the approved labeling. In addition, if they are aware that their devices are being used off-label, they are responsible for addressing the associated regulatory problem—that is, the manufacturer must then secure approval for the other indication or dissuade further off-label use. The FDA recently sent a letter to nonvascular stent manufacturers 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, they have been told to obtain the necessary approvals for the specific vascular indications. In addition, 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 FDA has made a clear statement that they do indeed care.
Q: Why do devices that will be used primarily for treating vascular disease receive marketing clearance for “tracheobronchial and biliary” indications?
A: The FDA does not have control over the submission of applications for marketing clearance by manufacturers. The manufacturer decides which indication they want for their device. One reason so many manufacturers have elected to avoid labeling their devices for vascular use is related to the regulatory pathway required for these devices. Nonvascular stents are shown to be “substantially equivalent” to legally marketed, similar devices indicated for the same use. Equivalence is demonstrated through submission of a premarket notification application [510(k)], which does not include clinical data or chronic bench tests such as pulsatile fatigue testing. Vascular stents, on the other hand, go through a more rigorous process to demonstrate that they are “reasonably safe and effective” for their specific intended use. Manufacturers must submit a PMA that includes clinical data and more extensive bench data. In addition to requiring different types of information, these two regulatory pathways have different review timeframes; the PMA approach is significantly longer.
Q: Why is there a difference in regulation of identical devices for different indications?
A: The level of regulatory oversight for a device 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. Tracheobronchial and biliary stents 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 associated with these devices are not a significant concern. In addition, the data needed to evaluate the performance of these devices in these anatomical sites are well defined, making the less-stringent regulatory oversight reasonable.
Although the practice of medicine has led to the general acceptance of the role of vascular stents, the required performance of these devices for various indications (eg, superficial femoral, carotid) has not been clearly defined. This definition is complicated by difficulties in identifying the appropriate alternative care (ie, an appropriate control) and the diversity of patients to be treated with the devices (eg, high-risk with no treatment alternative, low-risk with treatment options). As such, these devices are regulated through the more rigorous PMA process. The FDA believes that the risk/benefit profile for these devices should be clearly defined to allow for proper patient selection and use by physicians—that is, so the devices can be appropriately labeled for the specific intended use(s).
Q: Is there any sharing of liability when a device is used off-label?
A: If a physician uses a product for an indication not listed in the approved labeling, he or she is responsible for being well informed about the product, to base its use on firm scientific rationale and sound medical evidence, and to maintain records of the product’s use and effects. In an off-label situation, the physician essentially takes on the responsibility regarding the determination of the device’s suitability for the intended use, with the physician and/or the institution assuming liability.
Q: What are the limitations on reimbursement for off-label use?
A: Reimbursement is not an FDA concern, but understandably it is of concern to physicians. The FDA does, however, provide recommendations to the Centers for Medicare & Medicaid Services (CMS) with respect to whether an investigational device exemptions (IDE) application is for an experimental or a nonexperimental/investigational device. The CMS is more likely to reimburse for a nonexperimental device than for an experimental device, but only if the device is being used as part of an approved IDE study. The CMS should be consulted regarding the specific rules for reimbursement.
Q: Isn’t off-label use a “physician issue?”
A: Off-label use is a physician issue when it occurs at a relatively low frequency, on a case-by-case basis. Once it is clear that a device is being used on a regular basis for an indication outside of the labeling, the situation then becomes an FDA and manufacturer issue. Off-label device use cannot be equated with the use of a new surgical technique, as when carotid endarterectomy was developed, because the FDA does not evaluate surgical procedures. When a device is used in a new procedure, such as for transjugular intrahepatic stenting and carotid stenting, the device and, unavoidably, the procedure come under the scrutiny of the FDA.
The FDA will not determine whether the new device and the associated procedure should be the treatment of choice for a particular patient or patient population. That task remains with the physicians and others (eg, ethicists and health care administrators). The FDA makes a determination as to whether the new device should be available as a treatment option and also ensures that adequate information is made available to those responsible for making such decisions and to the patients who may be treated with the device.
Q: What is being done to address this problem?
A: The FDA acknowledges the difficulties in conducting studies for each vascular indication and is working with the manufacturers and users of these devices to develop the least burdensome studies needed to evaluate these devices. Two examples are the CARESS study (sponsored by ISES) that involves evaluating more than one manufacturer’s stent under a single study, and the FDA’s acceptance of historical control data for iliac studies rather than requiring concurrent or randomized controls.
Practicing interventionalists can help by working with the FDA and manufacturers to develop mutually acceptable studies and by participating in these studies, rather than continuing to use devices off-label.
Dorothy B. Abel is a Regulatory Review Scientist with the US FDA Center for Devices and Radiological Health in Rockville, Maryland; she is also a regular columnist for Endovascular Today. Ms. Abel may be reached at (301) 443-8262, ext. 165; firstname.lastname@example.org.