Mechanical circulatory support of the heart for adults is becoming more widely used, particularly as a bridge to cardiac transplantation and also, more recently, as so-called destination therapy for patients not eligible for cardiac transplantation. Currently, however, limited mechanical circulatory support options are commercially available for smaller children and infants, and only outside of the United States.1–4 The Food and Drug Administration (FDA) recognizes the need for, and interest in, the development of these devices for the vulnerable pediatric population.
On April 1, 2004, the Medical Devices Technical Corrections Act of 2004, Public Law 108-214, was enacted. Section 3 of the law required the Secretary of Health and Human Services (HHS) to submit a report to Congress on any barriers to the availability of devices intended for use in the pediatric population. The congressional report was published in October of 2004.5 The report recommended that, at the current time, it was premature to change any existing statutory authority, regulation, or agency policy or practice to encourage the invention and development of pediatric devices. Based on the complexity of the issues and wide-ranging perspectives regarding device needs in the pediatric population, HHS will undertake a systematic needs assessment to further evaluate barriers and solutions to addressing the unmet device needs in the pediatric population.5 A comprehensive discussion of these barriers and aids to fostering the development of new pediatric devices in the systematic needs assessment can be found in the congressional report. As of this writing, no timetable has been established for the completion of the systematic needs assessment.
In addition, the FDA participated with representatives from the National Institutes of Health (NIH) in a briefing of congressional staffers on July 14, 2004.5 Part of NIH's overview, on fostering pediatric device development, included the National Heart, Lung and Blood Institute's recent funding of several contracts for the development of devices specifically for pediatric mechanical circulatory support. Mechanical circulatory support for the pediatric population has gained interest as adult mechanical circulatory support has moved from experimental to accepted treatment for bridge to cardiac transplantation and destination therapy. There remains a great need for purpose-designed pediatric circulatory support device systems, optimized for the needs of the pediatric patient population.
Definition of Pediatric Devices
The FDA recently addressed the premarket review of pediatric devices by issuing a guidance.6 The objectives of the guidance were to define the pediatric population, to identify types of information required to provide reasonable assurance of safety and effectiveness of devices intended for use in the pediatric population, and to define guiding principles and protections sponsors should consider for pediatric subjects in clinical trials. Although the guidance was not specifically written to address pediatric mechanical circulatory support, much of the information presented in the guidance document may be considered applicable.
The guidance defines the pediatric population as being from birth to 21 years of age. In addition, the guidance defines ranges of pediatric subpopulations: newborn (neonate) from birth to 1 month of age, infant from greater than 1 month to 2 years of age, child from greater than 2 to 12 years of age, and adolescent from greater than 12 to 21 years of age. The FDA does recognize that these divisions are somewhat arbitrary and that the patient's weight, body size, physiologic development, neurologic development, and neuromuscular coordination may be more appropriate factors for consideration than chronological age alone. Additional pediatric subpopulations may need to be considered as well. For example, premature and very-low or low-birth-weight infants, or preadolescents may also be suitable subpopulations.
FDA Premarket Requirements
There are three main pathways by which devices go to market: Premarket Notification (commonly referred to as a 510(k), the section of the Food, Drug and Cosmetics Act that describes this program), Premarket Approval (PMA), and Humanitarian Device Exemption (HDE). The 510(k) approach, in effect, compares a new device to a similar, marketed device. For pediatric mechanical circulatory support devices, there are no currently marketed devices, thus the Premarket Notification pathway is not a viable option. Therefore, the most likely pathways to market are the PMA and HDE.
A PMA is the most stringent type of device marketing application. PMA approval is based on a determination by the FDA that the PMA contains sufficient valid scientific evidence to provide a reasonable assurance that the device is both safe and effective for its indicated use(s) in the intended patient population(s).7 A reasonable assurance of safety is defined as showing that the probable benefit(s) to health outweigh the probable risk(s) associated with the use of the device, and that there is not an unreasonable risk of injury or illness from the device. A reasonable assurance of effectiveness is defined as a demonstration that a significant portion of the patient population using the device as intended will experience clinically significant results.
For an HDE, the effectiveness requirement of the PMA is waived. Therefore, HDE approval is based on a determination by the FDA that the HDE contains sufficient valid scientific evidence to provide a reasonable assurance that the device is safe (as for a PMA) and provides a probable benefit for the intended patient population(s). Scientifically valid clinical investigations, demonstrating that there will be a probable benefit for the intended patient population, are not required. However, the sponsor must provide information describing the known clinical experience, if any, with the device as used in the intended patient population.
A PMA allows the device to be marketed for as broad a patient population as the scientific evidence for the reasonable assurance of safety and effectiveness supports. In addition, market approval of a device under a PMA allows the manufacturer to sell the device for profit. In contrast, a device marketed under an HDE is intended to treat or diagnose a disease or condition that manifests itself in fewer than 4,000 individuals per year. Further, for an HDE, the device must not otherwise be available, and no comparable device (other than another device with an approved HDE or a device under an approved investigational device exemption) may be available to treat or diagnose the condition.7 Under an HDE, a manufacturer is only allowed to recoup costs associated with the research, development, fabrication, and distribution of the device.7
Determination of Safety and Either Effectiveness or Probable Benefit
As with any complex medical device, the design of a device system intended to provide mechanical circulatory support for a pediatric patient population begins by determining, based in part on clinical input, the device system (i.e., overall) specifications. From the system specifications, the specifications for the individual subsystems are derived; finally, individual component specifications are established. During this initial design phase, a risk analysis (e.g., a Failure Mode Effects and Criticality Analysis) can be performed and the device design modified as necessary to mitigate anticipated safety concerns. At this stage in the design process, test protocols can be developed, traceable to specific elements of the device specifications, to verify that the device performance as tested demonstrates that the device meets all of the design specifications. It should be noted that test protocols should be designed to test device performance over its full design range(s), and in all possible device configurations, rather than only testing over the “expected” range(s) anticipated to be encountered in “typical” clinical use.
Even with an extensive preclinical testing program, use in the clinic will produce inevitable surprises. Data gathered on adverse events and user concerns will ultimately lead to design modifications. Obsolescence and/or specification changes of components by vendors will almost certainly occur throughout the life cycle of the device forcing minor design changes. As well, manufacturers will undoubtedly want to make evolutionary changes in their device designs. All such changes, if they impact on device safety and either effectiveness or probable benefit, should be shown to have the effect intended, and to introduce no new concerns, before being implemented in clinical practice.
In the FDA's experience, mechanical circulatory support devices have many elements in common but are different enough to necessitate evaluation for a reasonable assurance of safety and effectiveness (for a PMA) or safety and probable benefit (for an HDE) on a case-by-case basis. Because of the inherent differences between devices, it is impossible to provide a list of valid scientific evidence requirements that will guarantee approval of a marketing application. Further, the FDA is not permitted to provide detailed consultation assistance to individual sponsors because of conflict of interest and ethics regulations to which employees are bound. Because the FDA is not as intimately familiar with all of the complex design details or background research and development information for the device as is the sponsor, a detailed test strategy is best proposed by the manufacturer; the appropriate FDA staff will comment on the adequacy of the proposed testing strategy if requested to do so.
The FDA recognizes that, although mechanical circulatory support devices purpose-designed for a pediatric patient population will address a critical unmet need, the size of the intended patient population is limited, making the conduct of a meaningful clinical trial difficult. Accordingly, sponsors are urged to take full advantage of preclinical testing to provide strong evidence of device safety and, possibly, effectiveness or probable benefit prior to initiating limited clinical trials. In particular, the recent implementation of the HHS-wide Critical Path Initiative is intended to reduce the burden of bringing innovative medical therapies (drug and device) to market. One element of the Critical Path Initiative proposes the use of computer simulation, among other possibilities, to explore critical aspects of device behavior prior to initiation of clinical trials. The surge in interest in using computational techniques (e.g., computational fluid dynamics) to assess the performance of mechanical circulatory support devices is evidenced by the many interesting presentations using computational fluid dynamics at the June 2005 meeting of the American Society for Artificial Internal Organs in Washington, DC. Accordingly, the FDA supports this approach, perhaps combined with flow visualization or other experimental techniques, as appropriate, as part of the dataset used to demonstrate the suitability of a proposed device for clinical use.
The FDA invites pediatric circulatory support device manufacturers to contact the agency early in the development process to ensure that appropriate preclinical testing is performed, thus potentiating progression to a clinical feasibility trial. Sponsors of pediatric mechanical circulatory support devices are encouraged to take advantage of both formal and informal meetings with the agency to discuss investigational protocols and the least burdensome approach to obtaining marketing approval for their devices.
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2. Duncan BW: Mechanical circulatory support for infants and children with cardiac disease. Ann Thorac Surg
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3. Rosenthal D, Chrisant MRK, Edens E, et al: International Society for Heart and Lung Transplantation: Practice guidelines for management of heart failure in children. J Heart Lung Transplant
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4. Hetzer R, Loebe M, Potapov EV, et al: Circulatory support with pneumatic paracorporeal ventricular assist device in infants and children. Ann Thorac Surg
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5. Report to Congress: Barriers to the Availability of Medical Devices Intended for the Treatment or Diagnosis of Diseases and Conditions that Affect Children. U.S. Department of Health and Human Services, Food and Drug Administration, Rockville, MD, 2004. Available at: http://www.fda.gov/cdrh/pediatricdevices/rtc100104.html
. Accessed May 17, 2005.
6. Guidance for Industry and FDA Staff: Premarket Assessment of Pediatric Medical Devices. U.S. Department of Health and Human Services, Food and Drug Administration, Rockville, MD, 2004. Available at: http://www.fda.gov/cdrh/mdufma/guidance/1220.html
. Accessed May 17, 2005.
7. 21 Code of Federal Regulations Part 860. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=860
. Accessed June 14, 2005.