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The purpose of this FDA workshop was to describe the regulatory process for pediatric ventricular assist device approval as well as indicate to the community that effective pediatric device development is an important issue for FDA. FDA staff presented on the regulatory topics and outside experts presented on the medical and surgical topics.
Dr. Joanne Less, Associate Director of Clinical Research and Government Affairs at the Center for Devices and Radiological Health, discussed the new pediatric provisions, such as the guidance on data necessary to support device approval and on the protection measures for pediatrics in clinical trials. She also indicated that FDA was required to submit a report to Congress regarding the barriers to the development of pediatric devices. FDA requested outside comment regarding the unmet pediatric device needs and what possible barriers exist for pediatric device development. From these comments, it was determined that we do not yet know the scope of the unmet pediatric needs. Some of the proposed solutions include enhancing information exchange between FDA and the clinical community, encouraging pediatric discussions at Pre-IDE meetings, and clarifying the marketing requirements for pediatric devices. The challenge will be to encourage the development of pediatric devices without increasing the risk to pediatric patients, unduly increasing burden on industry or FDA, or delaying device approval for adults.
Sarah Linde-Feucht, MD, Director of Humanitarian Use Device (HUD) Designation Program in the Office of Orphan Products Development (OOPD), described what a HUD was and how a Humanitarian Device Exemption (HDE) compared to a Pre-Market Approval (PMA) Application. She described that an orphan product is a drug, biologic, device, or medical food that is used in the diagnosis and/or treatment of patients with rare diseases. The HUD and HDE program encourages the development of devices for use in patients with rare diseases. That is, if a disease or condition exists in fewer than 4,000 patients per year in the United States, and if a sponsor is able to demonstrate that the device is safe and of probable benefit to the patient, FDA would approve the device without the sponsor having to demonstrate that the device is effective. In other words, the sponsor of a HUD is exempt from the requirement to prove effectiveness as mandated in the Safe Medical Devices Act. A request for HUD designation is submitted to OOPD for review. If HUD designation is granted, then the manufacturer must submit an HDE application to the Office of Device Evaluation in CDRH. Both HDE and PMA applications are marketing applications, but the data in the HDE application must demonstrate safety and probable benefit while the data in the PMA application must demonstrate safety and effectiveness. Profit-making is not allowed for an HDE.
Sheila Brown, RN, CCRC, Investigational Device Exemptions (IDE) and Humanitarian Device Exemption (HDE) program, presented on the regulatory process for conducting clinical trials with medical devices and how to collaborate with FDA through Pre-IDE meetings. The purpose of IDEs was to encourage the discovery and development of useful medical devices for human use to the extent consistent with the protection of public health and safety and with ethical standards. The sponsor of an IDE could be a manufacturer, government agency, individual investigator, etc. and the sponsor assumes all legal responsibilities for the IDE. Pre-IDE meetings allow for early discussion with FDA regarding clinical trial design, preclinical testing, and proof of concept animal studies.
Thinh Nguyen, Director of PreMarket Approval (PMA) Program in the Office of Device Evaluation, presented on what types of devices require PMAs. Class III devices are those devices that support or sustain human life, have substantial importance in preventing impairment of human health, and those with potential unreasonable risk of illness or injury require PMAs. The data in a PMA must demonstrate reasonable assurance of safety and effectiveness. The data should generally be collected through well controlled investigations that provide valid scientific evidence.
Sheila Brown, RN, CCRC, IDE and HDE program, presented on the HDE application process by which the manufacturer must demonstrate the safety and probable benefit of their device. The HDE regulation exempts the sponsor of a device for orphan diseases from the effectiveness requirement of the medical device law, provided that the device meets the safety conditions and does not expose patients to significant or unreasonable risk. The HDE application must contain an explanation why another device would not otherwise be available or why no comparable device exists. Multiple HDEs can exist with the same indication but once a PMA is approved for that indication, FDA may rescind the HDEs. This issue would be a case-by-case basis. An HDE application is a marketing application and informed consent is not an FDA requirement but could be a state, local or institutional requirement.
Dr. Michael Berman, Leader of Division of Solid and Fluid Mechanics in the Office of Science and Engineering Laboratories, presented on the preclinical testing for pediatric VADs. The use of computational and experimental testing of devices could be part of the preclinical testing which will be used to obtain an IDE to start a clinical trial. Similarly, animal testing is appropriate for these types of devices in order to obtain data on how the device will function within a foreign host. The type of animal that will be used should also be considered. With regard to computational modeling, one must choose an appropriate CFD code and validated CFD model. Similarly, flow visualization and blood damage are important issues. Finally, there should be consistency among the CFD, flow visualization, and blood damage results.
Christopher Almond, MD, Senior Fellow Heart Failure / Transplant Children’s Hospital Boston, provided a pediatric cardiologist’s perspective. He provided an overview of the need for pediatric mechanical circulatory support devices, an outline of the primary challenges likely to face these devices during the regulatory process, and discussed a clinicians perspective on clinical trial design and pitfalls. The problem with pediatric devices now is that ECMO is the mainstay of mechanical circulatory support for infants and children, but it is not suitable for long-term support. Currently, pediatric circulatory support devices are currently being developed in the U.S. and abroad. It appears that the HDE pathway permits market access without requiring sponsors to perform large-scale clinical trials, but findings from a smaller clinical trial may be necessary. Challenges that could affect the approval of these pediatric devices are limited experience among pediatric specialists with clinical trial design, difficulty in describing an objective patient population that could benefit with a VAD, limited sample size on which to perform a clinical trial, and ethical considerations.
Richard Jonas, MD, Chief of Cardiovascular Surgery and Co-Director of the Children’s National Heart Institute, provided a surgeon’s perspective. He provided an overview of the different surgical techniques that are required to repair congenital heart disease in infants such as the Mustard Procedure, fontan track for single ventricle, etc. He reviewed the necessity of having an ECMO team that is able to respond quickly and has a portable ECMO circuit available at short notice. He further provided results on the use of pulsatile pediatric ventricular assist devices in an acute right heart failure model. Similarly, he presented on the use of the Medos VAD and Berlin Heart VAD.
Eric Chen, MS, Team Leader for VADs, provided a summary of the workshop. He indicated that device development is a total product life cycle process where manufacturers would continuously be refining their devices in hopes of providing more efficient devices. The creation of a pediatric working group consisting of expert cardiologists and surgeons to continue discussions regarding the development of standard definitions and effective clinical trial designs is important. The use of novel technology such as CFD and flow visualization is valuable. And, market entry begins early, so the use of Pre-IDE meetings with the FDA is encouraged.
Updated February 23, 2006
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