By Jamie S Sutherell
In recent years, there has been much attention given to the use of approved medical devices for an intervention outside of that device’s labelled indication, or what is commonly referred to as “off-label”. A common example is the use of biliary stents for the treatment of peripheral vascular disease, which for many patients has become the standard of care. In paediatric interventional cardiology, cardiovascular anomalies afflicting children are typically rare and diverse, meaning conducting adequately powered randomised clinical trials are difficult, if not impossible, to perform. When combined with a limited market potential for the manufacture of paediatric devices, the result is a select few number of cardiac devices that have been engineered and approved specifically for use in children. Devices are thus being used in children off-label by necessity.
In the US, physicians have the prerogative to legally use an FDA-approved device to treat any condition deemed to be medically appropriate, regardless of the package label indication2, 3. If more standard treatments are unavailable or unacceptable, off-label treatments may be very beneficial to some patients. However, this practice has important disadvantages. A cardiac device cannot be expected to exhibit excellent performance characteristics when utilised to treat a condition for which it was neither designed nor tested. The literature is replete with examples of biliary stents fracturing within vessel walls, or serving as a nidus for thrombus formation within the vessel4, 5. One would expect that a stent designed and tested for use in stenotic great vessels and conduits would display a better performance and safety profile. There are many other examples of suboptimal device performance when used in an off-label fashion.
Despite the recognition of a common off-label practice for cardiac device use in children, this process has not been documented (in contrast to an extensive literature documenting the practice and disadvantages of off-label prescription drug use in children). To address the lack of reports regarding this practice, our group evaluated the prevalence and nature of off-label device use in our active paediatric interventional programme. We examined all interventional catheterisation procedures performed in the three-year span from 1 July 2005, through 30 June 2008; non-interventional catheterisations, myocardial biopsies, electrophysiologic studies, and investigational devices were excluded from the study. The interventions performed were compared to the manufacturer’s indications for use, which were obtained from the “Instructions for Use” in the device package inserts.
During the three-year span, the majority of children (63%) had a procedure performed utilising an approved device in an off-label application (300 off-label procedures in 473 patients), and of all procedures performed, 50% were done so off-label (300 out of 595 total procedures). We then stratified the cardiac devices used during the three-year span into six general categories: dilation balloons, occlusion devices, embolization coils, stents, septostomy catheters, and “other” devices (devices that were very rarely used in our patient group, such as IVC filters and rotational coronary atherectomy catheters). Analysis of device use within each category was then carried out to identify specific therapeutic areas associated with higher frequency off-label use. Of the device types, stents were most frequently used for off-label indications (99% of all stents used, 66 of 67 interventions), followed by dilation balloons (78% used off-label, 189 of 243 interventions). Stents were commonly utilised off-label for co-arctation of the aorta, branch pulmonary artery stenosis and conduit stenosis, and to maintain patency of the ductus arteriosus in cyanotic newborns (coronary stents). Dilation balloons were commonly utilised off-label to dilate stenotic aortic valves, pulmonary artery stenosis, and co-arctation of the aorta. Embolization coils were more frequently used for a labelled indication (29% off-label, 23 of 80 interventions), as were occlusion devices (8% off-label, 13 of 169 interventions). Stainless steel coils were utilised most commonly off-label for the closure of the small patent ductus arteriosus. Although these results confirm what was long-suspected, they are the first to document the prevalence and nature of off-label use of approved medical devices in children with cardiac disease. Equally as important, our results stratify specific therapeutic areas within paediatric interventional cardiology associated with higher frequency off-label use.
The importance of enhancing device development for children has been recognised recently by governing bodies in the US. In 2007, the Pediatric Medical Device Improvement and Safety Act was passed, which among other things, created non-profit consortia to stimulate innovation in the development of medical devices for paediatric applications. It is hoped that this important legislation will help foster the badly needed development of medical devices designed explicitly for children.
The use of approved medical devices for off-label indications is an important and in many ways necessary practice within paediatric cardiology and interventional cardiology as a field. In many ways, it has become an integral part of the medical culture. However, with its obvious disadvantages, this practice is less than ideal. Our data define the scope of the issue by documenting the extent and nature of this practice, and underscore the need to enhance cardiac device review and approval processes to include paediatric applications.
References
1. Ansel GM, Jaff MR. The “art” of medicine and the “smokescreen” of the randomized trial off-label use of vascular devices. Catheter Cardiovasc Interv. 2008: 72; 998-1002.
2. Price MJ, Teirstein PS. The off- versus on-label use of medical devices in interventional cardiovascular medicine: clarifying the ambiguity between regulatory labeling and clinical decision-making, part I: PCI. Catheter Cardiovasc Interv. 2008: 72; 500-04.
3. McElhinney DB, Bergersen L, Marshall AC. In situ fracture of stents implanted for relief of pulmonary arterial stenosis in patients with congenitally malformed hearts. Cardiol Young 2008; 18:405-414.
4. Breinholt JP, Nugent AW, Law MA, Justino H, Mullins CE, Ing FF. Stent fractures in congenital heart disease. Catheter Cardiovasc Interv. 2008; 72:977-982.
5. http://www.fda.gov/oc/initiatives/fdaaa/PL110-85.pdf
