Pediatric Interventional Cardiology in the United States is Dependent on the Off-label Use of Medical Devices
Robert Beekman, III, MD, Division of Cardiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave. Cincinnati, OH, USA. Tel: 513-636-7072; Fax: 513-636-2410; E-mail: RBeekman@cchmc.org
Objective. A substantial unmet medical device need exists in pediatric care. As a result, the off-label use of approved devices is routine in pediatric interventional cardiology, but the extent and nature of this practice has not been previously described. The purpose of this study, therefore, is to evaluate the prevalence and nature of off-label cardiac device use in an active pediatric interventional program in the United States.
Study Design. This study is a retrospective review of all interventional cardiac procedures performed at our institution from July 1, 2005 to June 30, 2008. Diagnostic (noninterventional) catheterizations, myocardial biopsies, invasive electrophysiology studies, and studies involving investigational devices were excluded. Interventions performed were compared with the manufacturer's labeled indications for each device.
Results. During this 3-year period, 473 patients (median age 4.1 years) underwent 595 transcatheter interventions. An approved device was utilized for an off-label application in 63% of patients, and in 50% of all interventions performed. The most frequent off-label procedures were stent implantations (99% off-label), balloon dilations (78% off-label), and coil embolizations (29% off-label). In contrast, the off-label use of septal and ductal occluders was relatively uncommon.
Conclusions. In our routine (noninvestigational) practice of pediatric interventional cardiology, 63% of patients underwent procedures utilizing medical devices for off-label indications. These data underscore the need to enhance cardiac device review and approval processes in the United States to include pediatric applications.
The off-label use of prescription medications and medical devices is common in pediatrics. Justification for this widespread practice is easily understood. Pediatric disease processes are more commonly acute than chronic, and when chronic conditions do occur they are often rare.1 Thus, a relatively small patient population (compared with adults) is available to enroll in randomized clinical trials designed to evaluate the safety and effectiveness of drugs and devices in children. Furthermore, the return on investment is modest at best for industry to design and evaluate therapies intended for relatively rare pediatric conditions. Congenital heart disease is a prime example of a relatively uncommon disorder for which targeted, condition-specific therapies have been developed only infrequently.
Paralleling the growth of interventional transcatheter therapies for patients with congenital heart disease, there has been a growing practice of utilizing approved devices off-label, in ways unrelated to their intended applications. However, the prevalence and nature of this practice has not been previously studied. We thus sought to identify the prevalence of off-label device use in interventional pediatric cardiology, and to define those specific therapies associated with a higher frequency of off-label use. These data will inform future efforts to develop device approval and labeling for specific pediatric cardiac applications.
All interventional cardiac catheterizations performed at our institution in the 3-year period from July 1, 2005 until June 30, 2008 were included in this study. Diagnostic (noninterventional) catheterizations, myocardial biopsies, invasive electrophysiology studies, and studies involving investigational devices were excluded. Medical devices evaluated in this analysis included any device used to alter anatomy or physiology during a catheter-based intervention, and thus diagnostic catheters, sheaths, and guidewires were excluded. The devices were then classified as belonging to one of six therapeutic categories: dilation balloons, occlusion devices, embolization coils, stents, septostomy catheters, and “other” devices. Interventions performed were compared with the labeled indications for use of each device, obtained from the package inserts approved by the Food and Drug Administration (FDA). Procedural data for the interventions were obtained through analysis of the Cincinnati Children's Hospital cardiac catheterization database (Centricity, GE Medical Systems, Waukesha, WI, USA). This study was approved by the Cincinnati Children's Hospital Institutional Review Board.
The term “off-label” is defined as use of an approved medical device for an intervention outside of that device's FDA-approved labeled indications. In this study, therefore, each device use was considered either to be congruent (on-label), or incongruent (off-label) with the labeled indications for that specific device. Approved indications for medical devices in the United States specify procedures, but not patient ages; the majority of device labels do not mention use in children at all. Therefore, in this study, the absence of pediatric age-specific labeling was not sufficient to define a device use as being off-label. This point differentiates the off-label use of medical devices, as defined in this study, from the characterization of off-label medication use in children which is almost always age-based.
Data analysis included standard descriptive statistics. Off-label uses of approved devices were analyzed by device category, and the data are presented in tabular form. To avoid skewing of the data (double- or triple-counting devices or procedures), subjects who had more than one of the same device utilized during the same procedure were counted as having undergone a single intervention. Examples of this would include multiple embolization coils placed into different collateral vessels during the same procedure, multiple septal occluders placed onto an atrial septum, or multiple stents implanted into the same vessel. On the other hand, subjects who had interventions performed using different devices during the same procedure (e.g., pulmonary valve dilation and atrial septal defect occlusion) were counted as having undergone multiple interventions. Stent placement into different vessels during the same catheterization (e.g., stenting of right and left branch pulmonary arteries) were also counted as multiple interventions.
During the 3-year study period, 473 patients underwent 595 transcatheter therapeutic cardiac interventions. The median patient age was 4.1 years (range 1 day to 45 years). An approved device was utilized for an off-label application in 63% of all patients, and in 50% of all interventions performed. Summary data concerning these interventional procedures are presented in Table 1.
Table 1. Summary of Interventional Procedures (July 1, 2005 through June 30, 2008)
|Percent of procedures off-label||50|
|Percent of patients receiving off-label Device||63|
The frequency of on-label and off-label use within the six device categories are shown in Table 2. The most common interventions performed during the review period utilized dilation balloons (valvuloplasty and angioplasty) and occlusion devices (septal and ductal occluders), with these two categories accounting for more than 69% of all interventions. Virtually all stent procedures (99%) were performed for off-label indications, while dilation balloons accounted for the second highest rate of off-label use (78%). Septostomy balloons, occlusion devices, and embolization coils were most frequently used on-label (100%, 92% and 71%, respectively).
Table 2. Number and Type of Intervention by Device Category
|Dilation balloons (angioplasty, valvuloplasty)||243||54 (22)||189 (78)|
|Occlusion devices (septal, ductal)||169||156 (92)||13 (8)|
|Embolization coils||80||57 (71)||23 (29)|
|Stents (biliary, coronary, bronchial)||67||1 (1)||66 (99)|
|Septostomy catheters||18||18 (100)||0 (0)|
|Other devices (e.g., IVC filter, RF wire, blade, cutting balloon)||18||9 (50)||9 (50)|
Table 3 lists the six therapeutic device categories with the device labeled indications, and the type and frequency of off-label use in our center during the review period. Dilation balloons, approved for pulmonary valvuloplasty and peripheral vascular stenosis, were most commonly used off-label for pulmonary artery and aortic valve stenosis. Stent implantation was virtually never on-label. The most common off-label stent applications were for branch pulmonary artery stenosis, conduit stenosis, and aortic coarctation. Coronary artery stents were utilized off-label for pulmonary venous stenosis, and to maintain patency of the ductus arteriosus in cyanotic newborns. The single on-label use of a coronary artery stent (age aside) was to treat severe right coronary artery stenosis in a 9-year-old child with Kawasaki disease. Embolization coils, approved for occlusion of arteriovenous malformations and fistulae, were commonly used on-label to close aortopulmonary collateral vessels. However, coils were also utilized off-label for closure of the small patent ductus arteriosus. Cutting balloons, used uncommonly in our practice during this study period, were only utilized off-label for pulmonary artery stenosis, creation of an atrial septal defect and a Fontan fenestration. Similarly, radiofrequency perforation catheters were only employed off-label to perforate the pulmonary valve plate in newborns with pulmonary atresia and intact ventricular septum.
Table 3. Labeled Indications and Off-label Applications by Device Category
|Dilation balloons (angioplasty, valvuloplasty)|
n = 243
|— Valvar pulmonary stenosis (57)|
— Iliac, femoral, iliofemoral, popliteal, renal artery stenosis
— Arteriovenous dialysis fistula stenosis
|— Pulmonary artery stenosis (76)|
— Valvar aortic stenosis (38)
— Conduit stenosis (20)
— Coarctation of the aorta (20)
— Superior vena cava stenosis (12)
— Atrial septal defect enlargement (10)
— Pulmonary vein stenosis (4)
— Fontan fenestration enlargement (3)
— Other (3)
|Occlusion devices (septal, ductal) n = 169||— Secundum atrial septal defect closure (92)|
— Patent ductus arteriosus closure (52)
— Fontan fenestration closure (10)
— Muscular ventricular septal defect closure (2)
|— Patent foramen ovale closure (10)|
— Venovenous collateral occlusion (1)
— Pott's shunt occlusion (1)
— Blalock–Taussig shunt occlusion (1)
n = 80
|— Arterial and venous embolization (56)|
— Arteriovenous fistula embolization
|— Patent ductus arteriosus occlusion (24)|
|Stents (biliary, coronary, bronchial) n = 67||— Malignant neoplasms of the biliary tree|
— Abrupt/threatened closure of coronary lumen (1)
— Tracheobronchial strictures or fistulas
|— Branch pulmonary artery stenosis (31)|
— Conduit stenosis (11)
— Coarctation of the aorta (9)
— Superior vena cava stenosis (4)
— Stenting of patent ductus arteriosus (4)
— Pulmonary vein stenosis (3)
— Stenting of atrial septal defect or fenestration (2)
— Occlusion of arteriovenous fistula with covered stent (2)
n = 5
|— Obstructive lesions of synthetic or native arteriovenous dialysis fistula||— Pulmonary artery stenosis (3)|
— Creation of atrial septal defect (1)
— Creation of Fontan fenestration (1)
|Radiofrequency perforation catheter n = 4||— Creation of atrial septal defect||— Perforation of atretic pulmonary valve (4)|
Occlusion devices (septal or ductal) are the rare example of a medical device developed and approved specifically to treat pediatric congenital heart disease. As a result, their predominant use was on-label for closure of secundum atrial septal defects, patent ductus arteriosus, and muscular ventricular septal defects. Nevertheless, some occlusion devices were utilized off-label to occlude patent foramen ovale, venovenous collaterals, or systemic-pulmonary shunts (a Blalock–Taussig, and a Pott's shunt).
An extensive literature documents the practice and disadvantages of off-label prescription drug use in children.2–7 Approximately 75% of all FDA-approved medications licensed since the early 1970s have limited or no labeling for children; therefore, by necessity many medications are utilized off-label in children.8,9 This practice is not unique to pediatrics. A 2006 study found that approximately 21% of all medications in ambulatory internal medicine settings were prescribed for off-label purposes.10 The majority of cancer and AIDS patients are prescribed at least one approved drug off-label during their course of treatment.11 A similar literature documenting the off-label use of medical devices in pediatrics, and specifically in pediatric interventional cardiology, does not exist. The present study is intended to contribute to the nascent literature addressing this important topic, and we hope that these data will inform ongoing efforts to improve cardiac device availability for children.
The data presented in this article are the first to define the scope and nature of off-label medical device use in pediatric interventional cardiology, and confirms that this is an extremely common practice. In this recent 3-year period, 63% of patients undergoing a therapeutic cardiac catheterization received an intervention utilizing a medical device in an off-label fashion. The devices utilized most commonly off-label were stents and dilation balloons, as 99% of stent procedures and 78% of balloon dilations were performed for off-label indications. Occlusion devices and embolization coils were most often used for FDA-approved indications.
The disadvantages of this common off-label practice are clear. A cardiac device cannot be expected to exhibit excellent performance characteristics when utilized to treat a condition for which it was neither designed nor tested. Examples of suboptimal device performance in pediatric interventional cardiology are provided by two devices regularly utilized off-label: embolization coils and biliary stents. Stainless steel coils are utilized worldwide to occlude the small patent ductus arteriosus, an application for which they were not designed. While coil performance is acceptable for this purpose, it is less than ideal. The literature is replete with examples of the embolization of coils to pulmonary and systemic arteries, intravascular hemolysis and residual shunts in a substantial number of cases.12–14 Devices designed specifically for closure of the ductus, although more costly than coils, perform significantly better.15 Similarly, stents designed to treat biliary tree malignancies are commonly utilized off-label to treat pulmonary artery and conduit stenosis, and may perform suboptimally. When these stents are deployed in stenotic pulmonary arteries and conduits, they may result in vessel wall injury, be the nidus for thrombus formation, or may fracture circumferentially. The last is an unfortunate example of mechanical failure that can lead to stent embolization and/or vessel restenosis.16,17 One would expect that a stent actually designed and tested for use in stenotic great arteries and conduits would display a better performance and safety profile.
Currently, there are only limited examples of cardiac devices designed, tested, and approved in the United States specifically for treatment of cardiovascular disease in children. These include occluders for closure of the secundum atrial septal defect, muscular ventricular septal defect, and patent ductus arteriosus. Other pediatric cardiac device needs are currently unmet—an unfortunate situation that leads to the widespread practice of off-label device use documented in the present study. The dearth of approved cardiac devices for children relates fundamentally to the nature of this patient population and to the structural defects that affect it.18 The population of children with congenital heart disease is small compared with the large number of adults with acquired cardiovascular disease available for device study. Furthermore, the cardiovascular anomalies that affect children are rare and diverse. These factors make the conduct of adequately powered randomized clinical trials difficult if not impossible in pediatric cardiology. Absence of data obtained from such trials is a challenge to current FDA review and approval processes for medical devices. As an additional obstacle, the small pediatric population limits the market potential for industry, and thus inhibits entrepreneurial development of novel cardiac devices for children. The net result of these multiple factors is that few cardiac devices are developed and approved specifically for pediatric indications. When a device does not exist, the clinician in the United States is faced with the choice of not treating the condition, resorting to surgical alternatives, or utilizing an approved device in an off-label fashion for which it was neither designed nor tested.19
In the United States., off-label use of an approved medical device by a physician falls within the bounds of acceptable standard of care. The FDA is responsible for approving the use and sale of medical devices, and licenses an “indication for use” for each. Physicians have the prerogative to legally use a device to treat any condition deemed to be medically appropriate, regardless of the device's labeled indication.20,21 FDA guidelines state that “good medical practice and the interests of the patient require that the physicians use legally available drugs, biologics, and devices according to their best knowledge and judgment.”22,23 If standard treatments are unavailable or unsuccessful, then off-label treatments may be beneficial to patients, and in some cases may be the only available option for treatment. However, once a device has been approved for a specific indication, the FDA often has only a limited role in overseeing its ongoing use.24 Devices will not be subject to FDA scrutiny to assure their safety and efficacy for any off-label applications that may occur. Furthermore, industry is unable to apply its research and development capabilities toward refining an approved device for an off-label pediatric application. (According to FDA policy, manufacturers are not permitted to promote or advertise their devices for off-label use.)
The need for design and testing of medical devices explicitly intended for children and their medical conditions has been recognized by the US Department of Health and Human Services and the FDA. In a 2004 report to Congress, Health and Human Services and FDA stated that “it is clear that further study is warranted to evaluate the scope of the unmet needs” in reference to pediatric medical devices.18 They recommended that a comprehensive needs assessment for the development of pediatric-specific devices be performed. The US Congress responded in 2007 with the passage of the Pediatric Medical Device Improvement and Safety Act (PL-110-85). This legislation, among other things, recognized the need for improving postmarket safety monitoring of devices utilized in children, and encouraged creation of nonprofit consortia to stimulate innovation in the development of medical devices for children.25 It is hoped that this important legislation will help foster the development of cardiac devices designed specifically for children and the cardiovascular disorders that affect them.
In summary, the present study is the first to formally document the prevalence and nature of off-label cardiac device use in pediatric interventional cardiology. However, this study is limited by its retrospective nature. Furthermore, because it was performed in a single pediatric interventional cardiology program, the study may not precisely reflect patterns of device use in other pediatric catheterization laboratories. Nevertheless, there is a critical need to enhance cardiac device review and approval processes in the United States to include pediatric applications, and we hope that the data reported herein will inform these important future efforts.
Conflict of interest: Drs. Hirsch and Beekman serve as consultants for AGA Medical LLC.