Pediatric mechanical circulatory support is a critical unmet need in the United States. Each year, up to a hundred US children die waiting for a heart transplant, in part because of a lack of suitable pediatric mechanical circulatory support devices.1,2 Extracorporeal membrane oxygenation (ECMO), the standard of care for pediatric mechanical circulatory support, is widely recognized as being inadequate for chronic circulatory support, which is often necessary for children waiting for a heart transplantation. Even in the current era, just one out of every two listed children is successfully bridged to transplant with ECMO.3–6
To address this need, a variety of miniaturized ventricular assist devices (VADs) are currently being developed both in the United States and abroad.7–10 The US effort has been facilitated by the National Heart, Lung, and Blood Institute (NHLBI), which is sponsoring the development of five novel pediatric mechanical circulatory support devices.7 Meanwhile, several devices developed in Europe including the Berlin Heart EXCOR Pediatric VAD,8,9 and the MEDOS VAD10,11 have been imported to the United States with permission of the US Food and Drug Administration (FDA) on single-use emergency exemption basis. Nevertheless, none of these devices is currently approved for use in the smallest children (body surface area 0.7 m2 or less) where the need for mechanical circulatory support is the most pressing.12
In order for medical devices to obtain FDA approval in the United States, manufacturers of pediatric devices will need to navigate the regulatory process. The purpose of this report is to review the basic regulatory process for high-risk medical devices, and to identify the important challenges likely to face manufacturers of pediatric mechanical circulatory support devices during the FDA regulatory approval process. It is hoped that early recognition of the challenges will help avoid delays in securing access to life-saving medical devices for children.
In January 2006, leaders from the FDA, NHLBI, academic pediatric community, and industry convened in Rockville, Maryland, for the first FDA Workshop on the Regulatory Process for Pediatric Mechanical Circulatory Support Devices.13 The purpose of the workshop, hosted by FDA, was to provide the pediatric community with an overview of the federal regulatory process for high-risk medical devices and to review the challenges for pediatric mechanical circulatory support devices.
Table 1 lists some of the pediatric mechanical circulatory support devices currently under development in the United States or in clinical use in Europe. Most of the US devices are being developed through federal contracts through the NHLBI Pediatric Circulatory Support Program established in 2004.7,14 All devices are intended for cardiac support except for the Pediatric Cardiopulmonary Assist System (Ension, Inc., Pittsburgh, PA), which is intended for both cardiac and respiratory support. All but the Berlin Heart EXCOR Pediatric VAD8,9 and MEDOS VAD10,11 are in preclinical stages of development.7
Key Elements of Regulatory Pathways
As with all high-risk medical devices, pediatric VADs must undergo FDA approval for marketing through one of two regulatory pathways: the Humanitarian Device Exemption (HDE) pathway, or Pre-Market Approval Application (PMA) pathway.15Table 2 summarizes the key elements of these two regulatory pathways. Pediatric mechanical circulatory support devices for children (i.e., under age 18 years) may be eligible for consideration as humanitarian use devices (HUD) because (1) pediatric heart failure is a rare condition (fewer than 4,000 cases in the United States per year), and (2) the only alternative device currently available in the United States (under an HDE) is restricted to patients aged five to 16 years with a body surface area of 0.7 m2 or greater and less than 1.5 m2, and is limited to providing left-sided support only.
Under the HDE regulatory pathway, the requirement to demonstrate reasonable assurance of effectiveness (required for PMA approval) is waived. Instead, HDE applicants must demonstrate that their device will not expose patients to an unreasonable or significant risk of illness or injury, and that the probable benefit outweighs the risk of using the device. In making this determination, the FDA must consider the probable risks and benefits of currently available devices and alternative forms of treatment.
This difference in approval threshold (Table 2) means that under the HDE pathway, medical devices may receive FDA approval without a large-scale controlled clinical trial (which is usually required to demonstrate reasonable assurance of safety and effectiveness for a PMA) provided that the clinical experience combined with the results of appropriate bench testing, can demonstrate the favorable risk-benefit profile16,17 described above. Regardless of the regulatory pathway chosen, manufacturers are required to provide the FDA with a detailed device description, appropriate preclinical testing protocols and results, manufacturing information, and appropriate labeling for the device. Manufacturers are required to maintain the names and facilities to which HDE-approved devices are shipped, in addition to correspondence with the reviewing Investigational Review Board for the institution where the device is used. The use of the device requires initial and continuing Investigational Review Board approval.16 In addition, devices approved for humanitarian use may not generate a profit. However, manufacturers are permitted to recover the costs of research and development, manufacturing, and distribution of a device approved under an HDE.
To be eligible for the HDE regulatory pathway, a manufacturer must demonstrate that the device meets eligibility criteria for an Humanitarian Use Device (HUD).17 That is the device is intended for 4,000 or fewer patients in the United States per year and no comparable device is available, other than under an Investigational Device Exemptions application or an existing HDE. HUD status is reviewed and granted by the FDA's Office of Orphan Products Development. Once HUD designation is granted, the manufacturer is eligible to apply for device approval through an HDE application to the FDA's Center for Devices and Radiological Health. Figure 1 summarizes the typical steps for HDE approval.
Challenges of the Regulatory Approval Process
Table 3 summarizes some of the challenges specific to the regulatory approval process for pediatric mechanical circulatory support devices. While a clinical trial is not generally required for HDE approval, a small study may help manufacturers to (1) acquire specific adverse event data (e.g., bleeding, infection, neurological dysfunction), (2) refine the appropriate patient population for the device, and (3) establish suitable labeling for the device. Nonetheless, clinical trial design will likely present challenges because of the complexity of the patient population and the lack of extensive high-risk medical device regulatory experience among pediatric specialists. In addition to clinical trial design, manufacturers should be aware that postmarket studies will also likely be needed once a device has been approved.
In this report, we highlight some of the challenges manufacturers of pediatric mechanical circulatory support devices may face during the FDA regulatory approval process. Early recognition of these challenges may help shorten the regulatory approval process, making potentially life-saving medical devices available to children more efficiently. Nevertheless, we must be cautious about rushing medical devices to market that could place children at serious risk. Therefore, manufacturers electing to perform a clinical trial should devote careful attention to clinical trial design to maximize the likelihood of generating meaningful data to allow for adequate interpretation of the risks and benefits of a device.
Sample Size and Population Heterogeneity
Small sample size and substantial population heterogeneity are the two factors most likely to affect the interpretability of pediatric studies. These problems, which are common limitations in pediatric research, may limit the strength of evidence supporting the inference of safety and probable benefit as needed for approval of an HDE application. Indeed, rare and heterogeneous conditions present a difficult challenge for patient selection: including too much variability in subjects could render the data uninterpretable; however, excluding too many patients could render a study difficult to complete. To achieve an appropriate balance, study planners will need to consider carefully the influence of a wide variety of covariates that contribute to patient heterogeneity and may be associated with patient outcome, such as patient age, cardiac anatomy, body size, blood pump size, blood pump mechanism, device/cannula configuration, and illness severity.
Another challenge facing an HDE applicant is determining how the statutory language for HDE approval applies to pediatric VADs. Indeed, demonstrating that a pediatric VAD does not expose patients to an unreasonable risk of illness or injury and that the probable benefit of using the device outweighs its risk, taking into account other available treatments will require careful consideration, and may be especially challenging with relatively limited clinical experience with a device. Discussion over this language occurred during the June 2005 FDA Expert Advisory Committee Panel meeting of the Abiomed Abiocor Implantable Replacement Heart for example.18 It is conceivable that similar discussion could arise during review of pediatric VADs. Manufacturers performing a clinical trial should use clear study endpoints with prespecified, clinically relevant hypotheses. This strategy will help the FDA optimally review the data in a prospective clinical trial such that an appropriate risk-benefit decision can be determined more effectively.
Methodological challenges may also arise in comparing the safety performance of pediatric VADs to ECMO, the current standard of care for pediatric mechanical support.2 Comparisons to the retrospective ECMO experience may problematic because serious adverse data may not have been collected using definitions that can be considered comparable to those recently adopted by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS).3–6,19,20 This may be especially challenging for neurologic adverse events, where detailed prospectively-collected neurologic data for a comparable population of ECMO patients is limited. Alternative strategies to compare the safety profile of first-generation devices may be necessary. Ultimately, efforts to align adverse event definitions across pediatric registries would increase the likelihood of making meaningful safety comparisons among various circulatory support devices.
Pediatric mechanical circulatory support studies could also face logistical challenges stemming from the rarity of pediatric heart failure. The sparse distribution of US cases could create two potential problems for study planners. First, it may be difficult to determine a priori which institutions should be included in an Investigational Device Exemption (allows an investigational device to be used in a clinical study) because of the difficulty in predicting where new cases are likely to arise during any given enrollment period. Second, because of the large number of centers required to enroll patients, it may be difficult to control unwanted variability in the study protocol for crucial factors such as anticoagulation protocols, for which center-specific differences may be common. The INTERMACS registry may alleviate this problem, in part, by providing regulators with a mechanism for capturing relevant data irrespective of patient location. However, achieving consensus on a standardized uniform anticoagulation protocol may be problematic, but should be a prerequisite for acquiring meaningful data on thromboembolic risk, a recognized complication associated with these devices.
Amid these challenges, pediatric specialists may have less medical device regulatory experience compared with their adult counterparts, who have become more adept at navigating the regulatory approval process over time. Drawing from the adult regulatory experience—and the growing successful pediatric experience21,22—could be an effective way for pediatric investigators to rapidly acquire the knowledge and skills necessary to perform high-quality clinical trials in children.
Pediatric mechanical circulatory support is an important pediatric health concern and will offer significant challenges to device developers, federal regulators, and the pediatric clinical community. Small population size and substantial population heterogeneity are the two factors most likely to substantially affect the interpretability of pediatric studies designed for regulatory approval. Acquiring the skills and knowledge to perform high-quality trials in pediatrics despite the challenges will require dedicated effort from both the pediatric and regulatory communities. Early and continued communication with the FDA and careful clinical trial planning will be important to avoid delays in securing access to potentially life-saving devices for children.
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