Pediatric Medical Devices: Provisions Support Development, but Better Data Needed for Required Reporting
Released: 2011-12-20T00:00:00

Letter

Background

Medical devices include items used for the diagnosis, cure, mitigation, treatment, or prevention of a disease. These devices range from simple tools like bandages and surgical clamps to complicated devices like pacemakers; unless exempt by FDA regulations, devices are generally subject to FDA premarket review. Pediatric patients may be among those a device is intended to treat and generally are defined as those age 21 years or younger. FDAAA included provisions to support and track pediatric device development.

Medical Device Premarket Review Process

Unless exempt by regulation, medical devices are generally subject to FDA premarket review before they may be legally marketed in the United States. The extent of the premarket review is generally correlated with the level of risk the device poses. Applications to market medical devices are primarily submitted to and reviewed by FDA’s Center for Devices and Radiological Health (CDRH).

Under the PMA premarket review process, FDA reviews and makes approval decisions on applications for class III devices. Among other things, PMA applications must include the indication for use—including the disease and population the medical device is intended to treat—and evidence (typically clinical data) providing reasonable assurance that the device is safe and effective. After an initial screening of an application and determination that the review should proceed, FDA’s reviewers conduct a scientific review of the application and may refer applications to an external advisory committee composed of individuals with expertise in a particular medical specialty, such as cardiovascular or neurology— known as a medical specialty panel. FDA charges manufacturers a fee to review PMA applications, but PMA applications for devices intended solely for pediatric use are exempt from any fees.

For devices that have been approved through the PMA process, a manufacturer that wants to add a pediatric population (or otherwise significantly change the approved indication for use) must submit and receive FDA approval for a PMA panel-track supplement. manufacturers a fee to review PMA panel-track supplements, but those intended solely for pediatric use are exempt.

In 1990, Congress authorized FDA to exempt from the premarket review requirement to demonstrate effectiveness certain medical devices in order to provide an incentive for the development of devices that treat or diagnose rare diseases or conditions, including those in children. Manufacturers of such devices still must show that the probable benefit outweighs the risk of using the device and that the device will not expose patients to unreasonable or significant risk of illness or injury. These devices, called HUDs, are intended to treat or diagnose a disease or condition that affects fewer than 4,000 individuals in the United States. In order to market an HUD in the United States, an HDE application must be submitted to and approved by FDA.

Although FDA reviews and approves other types of PMA supplements, a panel-track supplement is required if the manufacturer wants to change the indication for use of an approved PMA device to add a pediatric population, according to FDA officials. must also provide a description of the device and scientific rationale for the use of the device for the rare disease or condition.

Once the HUD designation is granted, the manufacturer can then seek device approval by submitting an HDE application. In addition to including the indication for use, the HDE application must include a detailed description of the device, along with evidence demonstrating device safety, and data and a rationale supporting the probable benefit of the device. Device labeling is also reviewed and must include a statement indicating that the device is a humanitarian device. According to FDA guidance, criteria for HDE approval are focused on safety, probable benefit, and lack of a comparable device. FDA does not charge manufacturers a fee to review HDE applications.

Manufacturers of HDE devices are allowed to recover certain development and production costs but are generally prohibited from making a profit on their device. Unless exempt, HDE applications must include a cost assessment to demonstrate that the amount charged for the HDE device does not exceed the cost of research and development, fabrication, and distribution. After FDA approval, in order for an HDE device to be used in patient care, it must be reviewed and approved by an institutional review board (IRB) to assess the safety of the device.

If FDA review results in premarket approval, FDA issues an approval order to the manufacturer, which includes the approved indication for use statement. FDA also approves all printed material accompanying the device—known as the device labeling. The approval order, labeling, and a summary of safety and effectiveness data are available on FDA’s website; all three documents contain the approved indication for use statement.

Pediatric Populations for Medical Devices

Although the upper age limit experts use to define the pediatric population varies, for purposes of certain statutory provisions for PMA and HDE device applications, FDA considers pediatric patients as those who are age 21 years or younger at the time of diagnosis or treatment. FDA issued guidance in 2004 that specifies age ranges for four main pediatric subpopulations: neonate, infant, child, and adolescent (see table 1). According to FDA officials, the agency defined an additional subpopulation, transitional adolescents, for its internal application review purposes. These officials noted that in some cases patients in this age range may not require special considerations compared to adults. A pediatric medical device may be indicated for use in more than one pediatric subpopulation.

According to FDA officials, some pediatric devices are indicated for use in both pediatric and adult patients, such as devices with an indication for all patients with a given condition above a certain age. Additionally, a device’s indication for use statement might not specify the age of the intended population, but based on additional clinical information that may be included in the approval documents, FDA might consider a device labeled for pediatric use. For example, the indication for use statement for an influenza diagnostic test might not specify a pediatric population, but FDA could consider the device labeled for patients of all ages. In addition, a device’s indication for use statement might specify a minimum blood vessel size or body weight rather than a certain patient age, and if pediatric patients meet the criteria, the device could be considered labeled for pediatric use.

FDAAA Provisions on Pediatric Medical Device Development

To stimulate pediatric medical device development, FDAAA exempted HDE devices labeled for use in pediatric patients (including those for both pediatric and adult patients) from the HDE profit prohibition for applications approved on or after September 27, 2007, when FDAAA was signed into law.prohibition, HDE applications must include data to prove that the device In order to receive the exemption from the profit can safely be used in a pediatric population and to support the number of individuals likely to use the device each year. Based on this information, FDA determines an upper limit on the number of devices that can be distributed or sold each year—to treat both pediatric and adult patients— known as the annual distribution number (ADN). Manufacturers may only receive profits from the sale of HDE devices exempt from the profit prohibition and indicated for pediatric or pediatric and adult use up to the ADN. In addition, FDAAA requires that FDA’s Pediatric Advisory Committee annually review all HDE devices granted exemption from the profit prohibition to ensure that the exemption remains appropriate for the pediatric populations for which it is granted.

FDAAA also required PMA and HDE applications to include, if readily available, a description of any pediatric population or subpopulation(s) that suffer from the disease or condition that the device is intended to treat, diagnose, or cure and the number of affected pediatric patients. FDAAA further required FDA to annually report to congressional committees on the number of PMA and HDE devices approved in the preceding year (1) for which there is a pediatric subpopulation that suffers from the disease or condition that the device is intended to treat, diagnose, or cure; (2) labeled for use in pediatric patients; and (3) exempt from user fees because the device was intended solely for pediatric use.

To help connect individuals with ideas for pediatric medical devices with experienced professionals to assist them through the medical device development process, FDAAA also authorized demonstration grants for pediatric device consortia to promote pediatric device development. Pediatric device consortia receive 2-year grants, administered by FDA, to conduct certain activities for device projects, such as mentoring and managing the development process, assessing the scientific merit of a proposed device, and providing assistance and advice as needed on business development and navigating the regulatory process. In their demonstration grant applications, consortia were not only required to demonstrate their capability to develop pediatric devices—by having members with medical and scientific expertise in device development and relationships with manufacturers—but they were also required to identify two to five device projects that the consortia would directly support under the demonstration grant. Grantees must submit quarterly and annual reports to FDA describing how they have used grant funds to support innovation and the phase of development for the devices for which they provided assistance. Phases of development include, for example, concept, prototype (during which a model is developed), clinical (during which the device is tested), and marketing (during which the device goes through the regulatory process).

Characteristics of the Population and Limited Economic Incentives Cited as Barriers to Pediatric Device Development

Certain characteristics unique to pediatric populations—including physiological differences in pediatric patients and challenges with recruiting pediatric participants for clinical trials—are barriers to developing pediatric medical devices that were cited by stakeholders.

Pediatric patients are composed of different subpopulations with differences in size, growth rate, metabolism, heart rate, activity level, and other differences. For example, younger pediatric patients— neonates, infants, and children—have higher heart rates or respiratory rates than adults. This difference, as cited by some stakeholders, makes some devices used for adults, such as certain heart valves, not appropriate for use in young children; thus a device that has already been developed for an adult may have to be redesigned for a pediatric population. Another unique characteristic cited is the range of pediatric subpopulations and the difficulty in developing potentially different devices for each of these subpopulations. For example, a device that is developed for a toddler may not be appropriate for use in an adolescent, even if they have the same disease or condition. As a result, manufacturers may have to develop and test a different device for each subpopulation although the disease or condition may be the same.

Recruiting pediatric patients to participate in clinical trials has also been cited as a challenge for manufacturers. Performing experimental procedures on children naturally raises concern for their safety, and it may be difficult to obtain parental consent on behalf of the child to conduct experimental procedures. This issue is compounded because the pediatric population is not just one population but rather many subpopulations. Therefore, manufacturers find it difficult to recruit enough children for each pediatric subpopulation over a reasonable time frame and within a manageable number of investigational sites to ensure enough test subjects to meet clinical trial requirements.

Given these unique characteristics of the pediatric population, as well as the fact that the market for pediatric devices is generally smaller than the market for adult devices, there are limited economic incentives for manufacturers to develop pediatric medical devices. Stakeholders indicated that the cost of developing pediatric medical devices relative to the potential revenue generated by sales in a small market is a significant barrier to the development of new pediatric medical devices. Stakeholders also noted that the cost of research and development for pediatric medical devices can be the same as for adult devices while the market size is often smaller. Given these factors, stakeholders report that the return on the investment to develop and test pediatric medical devices usually falls below the profit goals of most medical device manufacturers.

Stakeholders noted that the FDAAA provision allowing pediatric HDE devices to earn a profit is one helpful step to encourage pediatric medical device development; however, they indicated that this provision is not enough to address the small market for pediatric devices and the resources necessary to study a device in a pediatric population. An official from one device manufacturer that had a pediatric HDE device approved since FDAAA was enacted told us that the ability to earn a profit for the HDE device, while helpful, was not part of this manufacturer’s decision to develop and market it. Stakeholders noted that the maximum number of 4,000 individuals for HDEs limited the effectiveness of this incentive for development of devices for larger pediatric populations. Stakeholders also noted that incentives used for pediatric drug development would not necessarily work for pediatric medical device development. For example, patent protection for medical devices is not as meaningful an incentive as it is for the development of pediatric drugs because the typical life cycle for medical devices (about 18 months) is significantly shorter than the typical life cycle for a drug.

Other barriers identified by stakeholders included an incomplete understanding of unmet pediatric device needs and issues related to the medical device regulatory process.

Several stakeholders commented that there is no consistent inventory of the devices that need to be developed for pediatric populations. Although it is unclear who should maintain this inventory, FDAAA did require FDA to annually report on the number of devices approved in the preceding year that were labeled for use in pediatric patients or for which there is a pediatric subpopulation that suffers from the disease or condition that the device is intended to treat, diagnose, or cure. FDA has reported to Congress that the pediatric device data contained in these reports may help identify areas of pediatric device research and development that need to be addressed. However, FDA has issued only one of these reports to date. Furthermore, some of the information from which FDA would develop these reports may not be as useful as possible in determining unmet need. Specifically, manufacturers are to include the information on pediatric subpopulations in their premarket approval applications if readily available; however, one manufacturer organization stated that it was unclear about the specific information requirements, and thus manufacturers may not be submitting useful information for tracking unmet pediatric device needs.

Stakeholders also cited as barriers to pediatric device development certain issues related to the medical device regulatory process in general. For instance, it was reported that the amount of time that it will take to get through the regulatory process cannot always be predicted, which limits the ability to appropriately budget for development. One manufacturer organization also noted that FDAAA authorized FDA to consider published data from adult studies and studies in different age groups when determining effectiveness for pediatric device approvals; this manufacturer organization commented that where appropriate, FDA should also use scientific evidence other than randomized controlled studies, such as well-documented case histories, to show probable benefit or demonstrate effectiveness. Recognizing the need to discuss the ways scientific research data can be used for pediatric medical device applications, FDA announced in November 2011 that it would hold a public workshop to discuss the use of scientific research data, including published scientific literature, to support and establish pediatric indications for medical devices.

Stakeholders also noted barriers that were unique to HDE devices, including pediatric HDE devices. One manufacturer organization stated that FDA has provided no general guidance to manufacturers regarding the type or level of evidence that must be developed to demonstrate that an HDE device meets the probable benefit standard. According to the organization, this lack of guidance ultimately hinders the use of the HDE program as a pathway to market devices that treat or diagnose diseases and conditions that affect fewer than 4,000 patients, including pediatric patients. According to stakeholders, difficulties in obtaining insurance coverage for HDE devices are also a barrier to development because HDE devices are approved by demonstrating safety but not effectiveness.

Although the two manufacturers’ representatives we spoke with reported experiencing frustration with the HDE approval process, they noted that overall, their interaction with FDA reviewers was positive in that FDA responded to their questions in a timely manner and provided specific guidance where necessary.

Finally, stakeholders stated that individuals with innovative ideas for new pediatric medical devices do not necessarily know what steps to take to bring their ideas for pediatric medical devices to the market, and it would be helpful to connect these individuals with manufacturers and to help them navigate the device development and regulatory process. Individuals with ideas for medical devices range from engineers to clinicians, who often need to work together to develop and manufacture a pediatric medical device. In addition, it is necessary to have funds to sustain development and an understanding of how to navigate the regulatory process. A commonly cited example of the challenges faced by pediatric device innovators is the experience developing the titanium rib, which took about 14 years to develop before it was approved for the market in part because its inventor, a physician who saw the need for such a device, did not have the information or resources to navigate the development and regulatory process. FDA officials and other stakeholders reported that the pediatric device consortia have helped to address this barrier. In addition, FDA officials reported that other efforts by FDA to organize early meetings before device manufacturers submit applications to clarify required clinical information and meetings with groups such as the pediatric orthopedic surgeons have also helped device innovators navigate the device development and regulatory process.

Pediatric Device Consortia Have Assisted over 100 Device Projects; Many Were in Early Development

The pediatric device consortia reported assisting 107 pediatric device projects—that is, projects to develop new pediatric devices—in the first 2 years of the demonstration grant program. In order to facilitate the development and approval of pediatric medical devices, FDA awarded grants totaling about $5 million to four pediatric device consortia in fiscal years 2009 and 2010 (see table 2). The consortia receiving these grants provided assistance that included review of projects by clinical experts to evaluate the devices’ usefulness in a clinical environment and help connecting innovators with manufacturers as well as potential sources of additional federal grant funding. The consortia also conducted other activities to support pediatric medical device development and connect individuals who have ideas for medical devices with information and resources, such as lectures, forums, and relevant conferences.

For the device projects assisted by the consortia, the phase of development varied. Although the consortia assisted a total of 107 device projects, 34 were inactive or were device projects that the consortia were no longer assisting at the time of our review. Of the 73 active device projects, about half (36) were in the prototype phase (see table 3).

In order to monitor the progress of the device projects the pediatric consortia assisted, FDA requires each consortium to report on the development phase of each device project—including the directly supported device projects included in the grantees’ applications as well as other device projects that received consortia assistance—on a quarterly and annual basis. Throughout the grant period, device projects were presented to the consortia and consortia members determined the kind of assistance to provide for development of these devices. The assistance provided depended on the device’s phase of development. For example, for a device in the concept phase a consortium could assess its scientific merit to see if there is a need for the device or if it makes sense to develop it; for devices that were further along, a consortium could help produce prototypes. For devices in the marketing phase, the consortia could consult on next steps, including working with FDA, a step which the developer needs to take to market a device. As of the most recent grantee reports available in September 2011, 3 of the 107 devices that were assisted by the consortia were commercially available and 1 had received HUD designation.

Of the 107 device projects assisted by the consortia, 13 were directly supported—that is, they were identified in the grant awards to receive a portion of the grantee’s demonstration grant funding. Table 4 lists these directly supported device projects, which were identified by the grantees in their applications and selected by FDA to receive support through the consortia grants. FDA’s evaluation criteria included (1) the significance of the device to address pediatric needs, (2) how well the project was designed, (3) the likelihood for marketing success, (4) the expertise and training of project leaders, and (5) evidence that the institution where the consortium was located supported the project.

FDA Lacks Reliable Information to Readily Identify All Pediatric PMA and HDE Devices

FDA Has Not Consistently Collected Reliable and Timely Information Needed to Report on Pediatric Devices

Although FDAAA required FDA to annually report to congressional committees on the number of PMA and HDE devices approved in the preceding year that were labeled for use in pediatric patients, the agency lacks reliable information to readily identify all such pediatric devices. Under standards for internal control in the federal government, relevant, reliable, and timely information should be available for external reporting purposes; however, FDA has not consistently collected reliable and timely information needed to report on pediatric devices. In response to FDAAA, FDA developed an electronic flag within its Center Tracking System (CTS) in 2008, to help CDRH internally identify PMA and HDE devices that were labeled for use in pediatric patients.officials, the agency’s medical device reviewers should check the pediatric flags during the PMA and HDE process based on all of the information available in the application. However, FDA officials reported that these electronic flags are not consistently applied, and that the agency does not provide formal training or guidance to its device reviewers regarding proper implementation of the pediatric flags. Therefore, information from FDA’s tracking system is not sufficiently reliable to identify PMA and HDE devices labeled for use in pediatric patients.

According to FDA In the absence of reliable information from its internal tracking system that could be retrieved in a timely manner to identify approved PMA and HDE devices labeled for use in pediatric patients, FDA reported that staff completed labor-intensive file reviews—which included examining voluminous application files as well as discussion with FDA reviewers—to complete its first annual report. This report, which covered devices approved in fiscal year 2008, did not specify the criteria FDA used to identify devices labeled for use in pediatric patients in its manual data collection process. An FDA official involved in the preparation of the fiscal year 2008 report told us that FDA staff considered devices to be labeled for pediatric patients if FDA officials determined that the devices were for patients younger than 18 years of age; however, this criterion was not explicit in the report. Instead, FDA’s report noted that a committee report described pediatric medical devices as those used to treat or diagnose Further, in diseases or conditions in patients from birth through age 21.the absence of documented criteria used to prepare the fiscal year 2008 report, FDA officials involved in preparing the combined fiscal years 2009- 2010 report at the time of our review were not aware of the specific criteria used for the fiscal year 2008 report and, as a result, created their own criteria and labor-intensive file review for identifying and reporting on approved PMA and HDE devices labeled for use in pediatric patients. As of October 2011, the combined fiscal years 2009-2010 report had not been issued; FDA officials reported that it was in the agency’s internal review and clearance process.

In addition, FDA does not have readily available, reliable information to identify other pediatric information that FDAAA required the agency to report annually. Specifically, FDA officials said that the agency does not have reliable information to readily identify and report on the number of PMA and HDE devices approved each year for which there is a pediatric subpopulation that suffers from the disease or condition that the device is intended to treat, diagnose, or cure.to annually report the number of PMA devices exempt from a user fee because they were solely intended for pediatric use. Although the agency reported that none of the devices approved in fiscal year 2008 were exempt from a user fee for this reason, FDA officials stated that as a result of our inquiry they reevaluated some of the PMA applications for which user fees were paid and identified certain PMA applications from other years that may not have properly received the user fee exemption. FDA officials said they were in the process of providing refunds to applicants that should have been exempt from the user fee.

Furthermore, FDAAA required FDA Without readily available information on the approved PMA and HDE devices labeled for use in pediatric patients or the number of approved devices for which a pediatric subpopulation might be indicated, FDA cannot easily identify and aggregate data to complete statutorily required reporting in a consistent and timely manner. The inconsistent information presented in these reports makes it more difficult for policymakers, industry stakeholders, and innovators to identify what opportunities and needs exist for devices to diagnose and treat pediatric patients.

Fifteen PMA and 3 HDE Devices Have Been Explicitly Indicated for Use in Pediatric Patients since FDAAA Was Enacted

While the indication for use statement for most approved PMA and HDE devices did not identify the age of the intended population, our review identified 18 devices approved since FDAAA was enacted that were explicitly indicated for use in pediatric patients.found that 15 PMA and 3 HDE devices approved since FDAAA was enacted have indication for use statements explicitly stating that the devices are for patients that include patients age 21 or younger, pediatric patients, or skeletally immature patients. However, the approved indication for use statements for most of the 118 PMA and HDE devices approved since FDAAA was enacted do not specify the age of the intended patient population. Specifically, the indication for use statement Specifically, our review was silent on the age of the intended patient population for 75 percent of PMA devices and 38 percent of HDE devices approved during that time (see fig. 1). Given that a device’s indication for use statement may not explicitly state the age of the intended patient population or specify if it is for pediatric patients, additional pediatric devices could exist because other labeling and clinical information can be used to determine if the device can be used in pediatric patients.

Of the 18 PMA and HDE devices explicitly indicated for use in pediatric patients since FDAAA was enacted, most were explicitly indicated for adolescents. The majority of those indicated for adolescents were indicated for patients age 18 and older. Nine devices (50 percent) were indicated solely for patients age 18 or older—the age group FDA considers to be transitional adolescents for internal application review purposes—and 2 of those were indicated solely for patients age 21 or older. Two devices were explicitly indicated for children and none were explicitly indicated for neonates or infants (see table 5). In addition, the most common medical specialties of devices explicitly indicated for use in pediatric patients were microbiology (39 percent); cardiovascular (22 percent); anesthesiology and ear, nose, and throat (11 percent each); and clinical chemistry, ophthalmology, and gastroenterology (6 percent each).

Although three HDE devices approved since FDAAA was enacted were explicitly indicated for use in pediatric patients, the number per year may increase in the future, as the number of HUD requests and designations per year for devices intended to treat diseases that occur in pediatric patients increased after FDAAA was enacted. Because HUD designation is the first step to obtaining HDE approval, increasing HUD designations indicate potential for future pediatric HDE devices.According to FDA, the agency received about one HUD request per year on average for devices intended to treat a disease that occurs in pediatric patients before FDAAA was enacted and about five requests per year on average in the years after the law was enacted. Likewise, FDA granted about one HUD designation for devices intended to treat a disease that occurs in pediatric patients per year prior to FDAAA and almost five such HUD designations per year in the years after (see fig. 2).

Since FDAAA was enacted, two of the three HDE devices explicitly indicated for use in pediatric patients (patients age 21 years or younger) were granted the exemption from the HDE profit prohibition. One of these two exempted devices, the Medtronic Melody® Transcatheter Pulmonary Valve and Ensemble® Transcatheter Valve Delivery System (Melody® TPV) was approved in January 2010 for use in treating pediatric and adult patients with a blocked or leaky pulmonary heart valve that has previously been replaced to correct congenital (birth) heart defects and with a vessel size above a certain threshold. In September 2011, FDA’s Pediatric Advisory Committee reviewed the Melody TPV and determined that the HDE profit prohibition exemption remained appropriate.Anastamosis) Surgical KitHUD was approved in March 2011 for use in neurosurgery during intracranial vascular bypass procedures in patients 13 years of age or older who meet certain criteria. (See app. I for more information on the two devices.)

Conclusions

It is too early to determine if the FDAAA provisions authorizing demonstration grants for pediatric device consortia or allowing manufacturers to earn a profit on pediatric HDE devices have had a substantial impact on the number of approved pediatric devices; however, the provisions show potential for more pediatric devices in future years. Although stakeholders identified barriers to developing and receiving FDA approval to market pediatric medical devices, programs such as the pediatric device consortia can foster an environment for device innovators to share ideas and advance the development of pediatric medical devices. The number of devices that the pediatric device consortia have supported through the early phases of development and the positive feedback from stakeholders indicate that pediatric devices are being developed. Further, the increase in the number of HUD requests and designations for devices that treat pediatric populations since FDAAA was enacted indicate potential for development of additional pediatric HDE devices in the near future. Over the past 10 years, it has taken a few years for a manufacturer to submit an HDE application and receive FDA market approval after receiving HUD designation; therefore the profit eligibility incentive for pediatric HDE devices may have induced an increase in the number of pediatric HUD requests.

Although the future for pediatric device development may be promising, FDA lacks reliable and timely information on pediatric devices approved for the U.S. market. To meet statutory reporting requirements, FDA must have data systems in place to produce timely, reliable information to readily identify and track devices the agency has approved for use in pediatric patients. Without a systematic database to identify medical devices approved for use in pediatric patients, FDA cannot provide data so that policymakers, innovators, and physicians may understand the extent of medical device availability and needs for further development.

Recommendation for Executive Action

We recommend that the Commissioner of FDA collect reliable information to report data related to pediatric medical devices. Specifically, FDA should take steps to consistently collect information using its existing pediatric electronic flag or otherwise develop internal controls to readily and reliably collect and report information on devices for pediatric use.

Agency Comments

We received comments on a draft of this report from HHS, which are reproduced in appendix IV. The department agreed with our recommendation that FDA collect reliable information related to pediatric medical devices and commented that FDA is in the process of modifying and updating its current tracking system, related data quality controls, and training program requirements for pediatric medical device premarket submissions. The department further stated that when this process is complete, FDA’s pediatric information collection efforts will satisfy the department’s pediatric device operations and oversight needs, including the development of the annual pediatric report.

We are sending copies of this report to the Secretary of Health and Human Services, the Commissioner of FDA, and other interested parties. In addition, the report will be available at no charge on the GAO website at http://www.gao.gov.

If you or your staff have any questions about this report, please contact me at (202) 512-7114 or crossem@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs may be found on the last page of this report. GAO staff who made major contributions to this report are listed in appendix V.

Appendix I: Summary of HDE Devices Granted Exemption from the HDE Profit Prohibition

The Food and Drug Administration Amendments Act of 2007 (FDAAA) also required that we describe the key characteristics of devices approved through the humanitarian device exemption (HDE) process that were granted exemptions from the HDE profit prohibition because they were labeled for use in pediatric patients. This appendix describes the conditions and the indicated patient populations of the two pediatric medical devices that were granted exemption from the HDE profit prohibition—Medtronic Melody® Transcatheter Pulmonary Valve and Ensemble® Transcatheter Valve Delivery System (Melody® TPV) and ELANA (Excimer Laser Assisted Non-Occlusive Anastamosis) Surgical KitHUD. We also describe when each device was approved for the U.S. market and what is known about profits made by the manufacturers of each device. In addition, we describe what is known about the costs and insurance coverage and off-label use of the Melody TPV device—the one HDE device exempt from the HDE profit prohibition that was sold and in use in the United States at the time of our review.

Summary of Pediatric HDE Devices Exempt from the HDE Profit Prohibition

To describe the key characteristics of each device, we interviewed officials from Medtronic, Inc., and Elana, Inc.—manufacturers of the Melody TPV and ELANA devices, respectively—and examined manufacturer-provided documentation, such as billing code information, related to the Melody TPV device. We also interviewed officials from the Food and Drug Administration (FDA) who manage the HDE process and examined FDA documents for each device, including approval documents and an annual report for the Melody TPV—which manufacturers granted exemption from the HDE profit prohibition are required to submit annually to FDA. (Table 6 provides key characteristics of the two pediatric HDE devices granted exemption from the HDE profit prohibition.)

Survey of Physicians and Hospitals That Have Used the Melody TPV

To obtain information regarding costs of the Melody TPV device as well as insurance coverage for and off-label use of the device, we surveyed 36 physicians at the 25 children’s hospitals and pediatric units of medical centers (which we collectively refer to as children’s hospitals) that according to the device’s manufacturer, had used the Melody TPV at least 10 times. We received complete responses from 27 physicians at 20 children’s hospitals for an overall response rate of 75 percent of physicians and 80 percent of hospitals in our sample.

Almost all (93 percent) of the 27 respondents reported that their hospital purchased the Melody TPV at the manufacturer’s list price of $30,500. All but 2 physicians reported that their hospital purchased the two components—the valve and the delivery system—of the Melody TPV device separately. A physician that we spoke with said his hospital kept several valves and several of each size delivery system in stock and purchased more as needed. Twenty-four of the 25 physicians at children’s hospitals that purchased the components separately reported paying the list price for each component—$24,000 for each Melody Transcatheter Pulmonary Valve and $6,500 for each Ensemble Transcatheter Valve Delivery System.

Many physicians we surveyed reported that they experienced at least some difficulty obtaining health insurance coverage for the Melody TPV device regardless of the type of insurance held by the patient (see table 7). Twenty-five of the 27 responding physicians reported experiencing difficulty obtaining coverage for patients with private health insurance at least some of the time, with 3 of those physicians reporting that it was always difficult. For Medicaid and Children’s Health Insurance Program (CHIP) coverage, 4 physicians reported that the device was not covered at all by this type of insurance. Additionally, 18 of the 22 responding physicians who reported receiving reimbursement for the device through Medicaid or CHIP also reported difficulty obtaining that coverage at least some of the time, with 4 of those reporting that it was always difficult. Most responding physicians (19 of 27) reported not treating any patients covered by Medicare, but 4 of those who did treat patients with Medicare coverage said that obtaining Medicare coverage Further, 7 of the 27 responding for the device was always difficult.physicians reported that health insurance coverage influenced their clinical decision to use the device. For example, 3 physicians reported that delay or denial of insurance coverage for the Melody TPV device has led them to conduct open heart surgery in patients for whom use of the device would otherwise have allowed them to delay this more invasive surgery.

Consistent with what stakeholders reported about challenges to obtaining insurance coverage for HDE devices in general, physicians we surveyed reported challenges obtaining health insurance coverage for the Melody TPV device. These included comments about the time required to discuss coverage with the insurers to obtain reimbursement, insurers’ lack of familiarity with the medical device, challenges because insurers consider the medical device experimental, and problems because the Melody TPV procedure did not have a current procedural terminology (CPT) code at the time of our survey.

About half (52 percent) of physician respondents reported that they have implanted the Melody TPV device in a pediatric or adult patient for an indication other than the indication on the label of the device—an off-label indication—since it was approved for the U.S. market in February 2010. However, all but 1 of those physicians said they used it off-label 20 percent of the time or less across instances when they implanted the device in pediatric patients. Further, 29 percent of responding physicians stated that they never used the device for an off-label indication in pediatric patients. In addition, each instance of off-label use should have been for an indication approved by the hospital’s institutional review board (IRB). For example, 1 physician reported that he routinely implanted the Melody TPV for one of three IRB-approved protocols, two of which were for an off-label indication but all were for pediatric patients.

Appendix II: PMA and HDE Devices Explicitly Indicated for Use in Pediatric Patients since Fiscal Year 2006

Of the 118 devices approved through FDA’s premarket approval (PMA) and HDE processes in the 4 years since FDAAA was enacted, 18 (15 percent) were explicitly indicated for use in only pediatric patients— those age 21 or younger—or both pediatric and adult patients. Of the 86 PMA and HDE devices approved in the 2 years before FDAAA was enacted, 21 were explicitly indicated for use in only pediatric patients or both pediatric and adult patients (see table 8). Of these, few devices were explicitly indicated for use in patients under age 18—that is, in each fiscal year, most devices that explicitly indicated a pediatric population were indicated for use in patients age 18 years and older.

Appendix III: PMA and HDE Devices Explicitly Indicated for Use in Pediatric Patients, Fiscal Years 2008 through 2011

Device name, number Devices approved through the Food and Drug Administration’s (FDA) premarket approval (PMA) process Propel sinus implant, P100044

Pediatric subpopulation (if available)

Indicated for use in patients 18 years of age or older following ethmoid sinus surgery to reduce the need for postoperative intervention.

Indicated for the in vitro qualitative detection of antibodies to hepatitis B e antigen (anti- HBe) in human adult and pediatric (2 to 21 years old) serum from individuals who have symptoms of chronic hepatitis and those who have recovered from hepatitis B infection.

Indicated for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (e.g., diet, fiber therapy, and antimotility medications).

Indicated for the in vitro qualitative detection of hepatitis B e antigen (HBeAg) in human adult and pediatric (2 to 21 years old) serum from individuals who have symptoms of hepatitis or who may be at risk for hepatitis B virus infection.

Indicated to screen patients 21 years and older with ASC-US (atypical squamous cells of undetermined significance) cervical cytology test results to determine the need for referral to colposcopy or to assess the presence or absence of high-risk Human Papillomavirus genotypes 16 and 18, and for other uses in women 30 years and older.

Indicated for the qualitative detection of antibodies to hepatitis C virus in venipuncture whole blood specimens from individuals 15 years or older.

Date approved 4/27/2010

Summary of indication for use Indicated for the treatment of severe persistent asthma in patient 18 years and older whose asthma is not well controlled with inhaled corticosteroids and long-acting beta agonists.

Indicated for patients with hearing loss who meet the following criteria: (1) 18 years of age or older, (2) stable bilateral sensorineural hearing loss, (3) moderate to severe sensorineural hearing loss defined by Pure Tone Average, (4) unaided speech discrimination test score greater than or equal to 40 percent, (5) normally functioning eustachian tube, (6) normal middle ear anatomy, (7) normal tympanic membrane, (8) adequate space for Esteem implant determined via a high resolution computerized tomography (CT) scan, and (9) minimum 30 days of experience with appropriately fit hearing aids.

Indicated for the qualitative detection of antibodies to hepatitis B core antigen in human adult and pediatric serum and plasma and neonatal serum. It is intended as an aid in the diagnosis of acute, chronic, or resolved hepatitis B virus infection in conjunction with other laboratory results and clinical information. (No age provided, indicated for pediatric and adult patients)

Indicated for reducing the severity of postoperative cardiac adhesions in pediatric patients who are likely to require reoperation via sternotomy. (No age provided, indicated for pediatric patients)

Indicated for continually recording interstitial fluid glucose levels in people ages 18 and older with diabetes mellitus for the purpose of improving diabetes management.

Indicated for the qualitative detection of IgM antibodies to hepatitis B core antigen in human adult and pediatric serum and plasma and neonatal serum. It is intended as an aid in the diagnosis of acute, chronic, or resolved hepatitis B virus infection in conjunction with other laboratory results and clinical information. (No age provided, indicated for pediatric and adult patients)

Device name, number PMA panel-track supplement devices Meditec MEL 80 Excimer Laser, P060004-S001

Pediatric subpopulation (if available)

Indicated for primary lasik treatments for (1) the reduction or elimination of naturally occurring hyperopia, (2) in patients who are 21 years of age or older, and (3) with documentation of stable manifest refraction over the past year.

A single-use immunoassay for the qualitative detection of antibodies to hepatitis C virus in fingerstick whole blood specimens and venipuncture whole blood specimens from individuals 15 years or older.

Indicated for catheter-based cardiac electrophysiological mapping (stimulating and recording), for the treatment of (1) type I atrial flutter in patients age 18 or older, (2) recurrent drug/device refractory sustained monomorphic ventricular tachycardia due to prior myocardial infarction in adults, and (3) drug refractory recurrent symptomatic paroxysmal atrial fibrillation.

Devices approved through FDA’s humanitarian device exemption process (HDE) ELANA Surgical KitHUD, H080005

Indicated for creating arteriotomies during an intracranial vascular bypass procedure in patients 13 years of age or older with an aneurysm or a skull base tumor affecting a large (> 2.5 mm), intracranial artery that failed balloon test occlusion, cannot be sacrificed, or cannot be treated with conventional means due to local anatomy or complexity.

Indicated for use as an adjunct to surgery in the management of pediatric and adult patients with the following clinical conditions: Existence of a full (circumferential) Right Ventricular Outflow Tract (RVOT) conduit that was equal to or greater than 16 mm in diameter when originally implanted and Dysfunctional RVOT conduits with a clinical indication for intervention, and either Regurgitation: ≥ moderate regurgitation, or Stenosis: mean RVOT gradient ≥ 35 mmHg. (No age provided, indicated for pediatric and adult patients)

Date Device name, number approved NeuRx RA/4, H070003 6/17/2008

Summary of indication for use Indicated for use in patients with stable, high spinal cord injuries with stimulatable diaphragms, but who lack control of their diaphragms. The device is indicated to allow the patients to breathe without the assistance of a mechanical ventilator for at least 4 continuous hours a day. For use only in patients 18 years of age or older.

We identified each device’s medical specialty based on data from FDA’s product code classification database—which contains device names and product codes assigned based upon the medical device product classification designated under 21 C.F.R. Parts 862-892. Although the database indicated a medical specialty of cardiovascular for the ELANA Surgical KitHUD, FDA officials reported that upon further review they determined that the product code assigned for the device is technically inaccurate. To correct this technical inconsistency, FDA will issue a corrected product code for this product in the near future. The corrected medical specialty for the device should be neurology, according to FDA officials.

Appendix IV: Comments from the Department of Health and Human Services

Appendix V: GAO Contact and Staff Acknowledgments

GAO Contact

Staff Acknowledgments

In addition to the contact named above, Kim Yamane, Assistant Director; Rebecca Abela; Carolyn Fitzgerald; Cathleen Hamann; Shirin Hormozi; Lisa Motley; and Dan Ries made key contributions to this report.

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