Please note: As of October 1, 2002, FDA charges a fee for review of Premarket Approvals
A PMA application involves many volumes of material to be submitted to FDA. The volumes include device description and intended use, nonclinical and clinical studies, case report forms, manufacturing methods, labeling, etc. In the traditional PMA method, the complete PMA application is submitted to FDA at once. This method is generally used if the device has already undergone clinical testing and has been approved in a country with established medical device regulations. FDA has established methods of early collaboration with the sponsor allowing devices to brought to market as early as possible. These methods include the Modular PMA, Streamlined PMA, and Product Development Protocol and are discussed below.
In a Modular PMA the complete contents of a PMA are broken down into well-delineated components (or module) and each component is submitted to FDA as soon as the applicant has completed the module, compiling a complete PMA over time. The PMA is viewed as a compilation of sections or "modules," such as preclinical, clinical, manufacturing, that together become a complete application. This method is recommended for products that are in early stages of clinical study. This method is not appropriate when the applicant is very close to being ready to submit a PMA or when the device design is in a state of flux or likely to change.
The process begins with a PMA Shell which lays out the plan for submission of the modules. The shell is an outline of modules and identifies information necessary to support the filing and approval of a specific Class III product through a combined IDE-PMA process. The review team will work with applicants to develop a customized shell for each specific product that includes module contents and suggested timelines. It is developed individually with the manufacturer for a specific device.
FDA reviews each module separately as soon as it is received allowing manufacturers to receive timely feedback during the review process. This may allow more rapid closure when the last components are submitted because much of the review work will have already been done.
Additional information on the Modular PMA process can be found in the following documents:
The streamlined PMA is a pilot program in the Division of Clinical Laboratory Devices. A complete PMA is submitted as in a traditional PMA; however, the Streamlined PMA is for a device in which the technology and use are well known to FDA. A Streamlined PMA review may be appropriate for PMAs when there is either:
- an FDA guidance document or other published methods for review which have been evaluated by FDA, or
- an FDA review history dealing with like products (two or more of a kind)
During the protocol and PMA review, the sponsor must be available for an interactive review process. Ideally, prior to beginning studies to determine the safety and effectiveness of the product to be included in this pilot program, the sponsor would submit its protocol for FDA review. Familiarity with the product and protocol as part of this up-front evaluation should streamline the review of the PMA once filed.
In the product development protocol (PDP) method for gaining marketing approval, the clinical evaluation of a device and the development of necessary information for marketing approval are merged into one regulatory mechanism. Ideal candidates for the PDP process are those devices in which the technology is well established in industry. The PDP process provides the manufacturer with the advantage of predictability once the agreement has been reached with FDA.
The PDP allows a sponsor to come to early agreement with FDA as to what would be done to demonstrate the safety and effectiveness of a new device. Early interaction in the development cycle of a device allows a sponsor to address the concerns of the FDA before expensive and time consuming resources are expended.
The PDP is essentially a contract that describes the agreed upon details of design and development activities, the outputs of these activites, and acceptance criteria for these outputs. It establishes reporting milestones that convey important information to the FDA as it is generated, where they can be reviewed and responded to in a timely manner. The sponsor would be able to execute their PDP at their own pace, keeping FDA informed of its progress with these milestone reports. A PDP that has been declared completed by FDA is considered to have an approved PMA (§814.19).
An Humanitarian Use Device (HUD) is a device that is intended to benefit patients by treating or diagnosing a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year. A device manufacturer`s research and development costs could exceed its market returns for diseases or conditions affecting small patient populations. The HUD provision of the regulation provides an incentive for the development of devices for use in the treatment or diagnosis of diseases affecting these populations.
To obtain approval for an HUD, an humanitarian device exemption (HDE) application is submitted to FDA. An HDE is similar in both form and content to a premarket approval (PMA) application, but is exempt from the effectiveness requirements of a PMA. An HDE application is not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose. The application, however, must contain sufficient information for FDA to determine that the device does not pose an unreasonable or significant risk of illness or injury, and that the probable benefit to health outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment. Additionally, the applicant must demonstrate that no comparable devices are available to treat or diagnose the disease or condition, and that they could not otherwise bring the device to market.
An approved HDE authorizes marketing of the HUD. However, an HUD may only be used in facilities that have established a local institutional review board (IRB) to supervise clinical testing of devices and after an IRB has approved the use of the device to treat or diagnose the specific disease. The labeling for an HUD must state that the device is an humanitarian use device and that, although the device is authorized by Federal Law, the effectiveness of the device for the specific indication has not been demonstrated.
Form FDA-3674, ClinicalTrials.gov Data Bank
Title VIII of the Food and Drug Administration Amendments Act of 2007 (FDAAA) included a provision that all HDE applications are required to be accompanied with certification that all applicable clinical trial information has been submitted to the ClinicalTrials.gov data bank.
Beginning December 26, 2007, HDE applications must include form FDA-3674. If your HDE includes data from a clinical trial, you must determine if your study is applicable for entry into the clinical trial registry data bank at ClinicalTrials.gov. Based on this determination, check box 9.B. or 9.C., and complete the applicable sections of the form. An applicable device clinical trial is a prospective clinical study of health outcomes comparing an intervention with a device against a control in human subjects (other than a small clinical trial to determine the feasibility of a device, or a clinical trial to test prototype devices where the primary outcome measure relates to feasibility and not to health outcomes). Currently, FDA is reviewing the legislation and developing guidance on which clinical trials meet the definition of "applicable" trials and are required to report to ClinicalTrials.gov. Until FDA issues this guidance, the HDE sponsor is responsible for determining whether its studies meet the definition of an applicable trial and, therefore, are subject to reporting requirements.
Information on how to register your clinical trial(s) in the ClinicalTrials.gov data bank is available on the National Library of Medicine (NLM) Protocol Registration System (PRS) website.