Premarket Approval (PMA)

The term Premarket Approval (PMA) refers to the most stringent regulatory pathway required by the U.S. Food and Drug Administration (FDA) for marketing medical devices.

In simple terms, a Premarket Approval (PMA) is the formal regulatory application submitted to the FDA for a Class III medical device. PMA applications, which include all information submitted or incorporated by reference, implement procedures for the premarket approval of medical devices intended for human use.

The purpose of the PMA process is to establish a thorough review process to facilitate the approval of devices that have been shown to be safe and effective and meet statutory criteria for approval.

PMA is mandatory for high-risk devices because General Controls and Special Controls are insufficient to provide reasonable assurance of safety and effectiveness. PMA applications are the mechanism by which the FDA ensures the highest standards of safety before market entry.

Scope and Applicability

PMA is reserved exclusively for Class III medical devices. Devices may not be commercially distributed after the required effective date unless the manufacturer has an approved PMA or a completed Product Development Protocol (PDP) for the device.

When PMA or PDP is Required:

New Devices: Any new, not substantially equivalent device introduced into commercial distribution on or after May 28, 1976, is classified by statute into Class III without any grace period. FDA must have issued an order approving a PMA or declaring a PDP completed before such a device is commercially distributed unless it is reclassified.

Codified Classification: If FDA knows a commercially distributed device may be a "new" device due to a new intended use, FDA may codify the statutory classification of the device into Class III for that new use.

Transitional Devices: Many specific Class III devices that were in commercial distribution before May 28, 1976, are now required to have an approved PMA or PDP by a specific date, such as certain cardiovascular devices, gynecological devices, and neurological devices.

Submission Content and Documentation

A PMA must be signed by the applicant or an authorized representative residing or maintaining a place of business in the United States if the applicant is foreign.

A PMA shall include in electronic format:

Organization and Indexing: A table of contents specifying the volume and page number for each item, and separate sections on nonclinical laboratory studies and clinical investigations involving human subjects. The PMA is submitted as a single version.

Justification: A concluding discussion demonstrating that the data and information submitted constitutes valid scientific evidence and provides reasonable assurance that the device is safe and effective for its intended use.

Risk and Benefit Analysis: A discussion presenting benefit and risk considerations related to the device, including any adverse effects and any proposed additional studies or surveillance the applicant intends to conduct following approval.

Marketing History: A brief description of the foreign and U.S. marketing history, including a list of all countries where the device has been marketed or withdrawn for safety or effectiveness reasons.

Labeling: Copies of all proposed labeling for the device.

Omissions: If required information is omitted because the applicant believes it is not applicable, a statement identifying the omission and justifying it must be submitted as a separate section.

Updates (PMA Amendments): The applicant shall periodically update its pending application with new safety and effectiveness information learned from ongoing or completed studies that may reasonably affect the evaluation of the device. These updates are considered PMA amendments.

The FDA Review and Approval Process

The purpose of the review is to ensure the disapproval of PMAs for devices that have not been shown to be safe and effective or that do not otherwise meet the statutory criteria for approval.

Filing: Within 45 days after the PMA is received, FDA notifies the applicant whether the application has been filed. The date of filing is when the 180-day period for review starts. FDA may refuse to file a PMA if it is incomplete, lacks required items, or if the applicant has a pending 510(k) submission for the same device.

Review Timeframe: FDA typically reviews the PMA within 180 days after filing (unless a major amendment is submitted). The FDA may refer the PMA to an appropriate FDA advisory committee (panel) for review and a recommendation.

Amendments: FDA may extend the review period up to 180 days if the applicant submits a major PMA amendment (e.g., one containing significant new data or significant omitted information).

FDA Decisions: FDA issues one of the following:

• Approval Order: Issued if none of the reasons for denial apply. Approval may be conditioned upon incorporating specified labeling changes. Public notice of the approval order is given, and a detailed summary of information regarding the safety and effectiveness is made publicly available.
• Approvable Letter: Sent if the application substantially meets the requirements, but specific additional information (e.g., final labeling, postapproval requirements) or conditions (e.g., FDA inspection finding manufacturing compliance with part 820) are required to obtain approval.
• Not Approvable Letter: Sent if the application may not be approved due to deficiencies.
• Denial Order: Issued if the applicant fails to follow the requirements or if the device lacks reasonable assurance of safety and effectiveness. Grounds for denial include containing a false statement of material fact, failure to allow FDA inspection of facilities and records, or if key clinical investigations were not conducted in compliance with informed consent or IRB regulations.

Post-Approval Requirements (PMA Supplements)

After a PMA is approved, the device is subject to postapproval requirements, and any significant changes must be submitted to the FDA for review and approval as a supplement.

• PMA Supplement Required: An applicant shall submit a PMA supplement for review and approval by FDA before making any change that affects the safety or effectiveness of the device.
  • Changes requiring a supplement include new indications for use, changes in labeling, changes in manufacturing facilities, changes in sterilization or packaging, or changes in design specifications or components.
• PMA Supplement Process: All procedures that apply to an original PMA application also apply to PMA supplements, except the required information is limited to what is needed to support the change.
• Post-Approval Monitoring: Failure to comply with any postapproval requirement, such as restrictions on use, continuous evaluation, or maintenance of records, constitutes a ground for withdrawal of approval of a PMA.

Analogy for Understanding PMA

The Premarket Approval (PMA) process is like obtaining the definitive, highest-level building code approval for an unprecedented structure, such as a deep-sea oil platform or a new type of nuclear reactor. Since failure of this structure could cause catastrophic harm (Class III device), the regulatory body (FDA) requires the designer to submit exhaustive technical documentation, including all foundational science, complex engineering data, and test results (PMA submission). The agency doesn't just check the blueprints once; it employs panels of experts to scrutinize every detail, verify the underlying clinical data, and inspect the manufacturing facilities (180-day review). Once approved, the device receives a "permanent operating license," but any future change to the reactor's core components, operational limits, or safety protocols must first be approved via a PMA supplement before implementation, ensuring continuous, documented safety.

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