Premarket Approval (PMA)

What is a Premarket Approval (PMA) Submission?

A Premarket Approval (PMA) is required for most Class III medical devices under section 515 of the FD&C Act before marketing in the U.S. Class III medical devices are considered high risk devices that sustain or support human life, are of substantial importance in preventing health impairment, or present a potential unreasonable risk of illness or injury.  A PMA is required for Class III medical devices, when general and special controls are not sufficient to assure safety and effectiveness.

How to Prepare a Premarket Approval (PMA) Submission?

Following is a description of the items that should be included in a Premarket Approval (PMA) submission to the FDA:

• Summary of Safety and Effectiveness (SSE) – the summary of safety and effectiveness section should be prepared according to FDA Guideline format. The SSE becomes publicly accessible following PMA approval.
• Device Characteristics and Manufacturing Section – a comprehensive description of the device is provided, including the product Design History File, Device Master Record and sample Device History Record. This section also includes a description of the methods, facilities and controls used in the manufacturing of the device according to the QMSR requirements, including the gamut of Quality Management System (QMS) Standard Operating Procedures and methods of implementation. The manufacturing section and the company’s QMS must comply with FDA QMSR requirements.
• Performance Standards or voluntary standards with which the device conforms should be addressed.
• Technical Section – all non-clinical and clinical studies are described here. Studies may include testing conducted according to the FDA Guidelines for specific devices, international standards or other methods.
• Non-Clinical Testing

-Bench and Engineering Performance Testing (as applicable)

-Mechanical and Electrical Safety according to IEC 60601-1

-Electromagnetic Disturbances (EMD) according to IEC 60601-1-2

-Mechanical Performance (e.g., fatigue, wear, tensile strength, compression)

-Functional Testing

-Durability/Reliability and Life-cycle

• Biocompatibility and Toxicology (as applicable) – for any device or component that contacts tissue, blood, or body fluids, FDA requires evidence that materials are safe according to the ISO 10993 standards.
• Sterilization, Packaging & Shelf Life (as applicable) – may include Sterilization validation, Packaging integrity, Shelf-life testing, Stability under expected storage conditions, etc.
• Preclinical (Animal) Studies (as appropriate) – particularly for implantable or high-risk devices.
• Software & Cybersecurity (as applicable) including Software verification & validation and Cybersecurity testing for connected or software-driven devices
• Clinical Testing

A Pivotal Clinical Study is routinely required for a PMA submission, including at least one adequate, well-controlled clinical trial designed to evaluate safety and effectiveness of the medical device in the relevant patient population for whom the device is intended. The study should include appropriate prespecified endpoints relevant to the device’s intended use, hypothesis testing, patient eligibility criteria, sample size calculation, pre-defined statistical analyses, etc. Usually a randomized controlled trial (RCT) is required or other rigorous designs. The clinical evidence must meet FDA’s definition of valid scientific evidence under 21 CFR 860.7, meaning it can be fairly and responsibly concluded that the device is safe and effective in the target population.

• Bibliography and Published Reports – a general bibliography of all referenced clinical articles and reports. Also all relevant published reports regarding the device or similar devices that may concern the safety and effectiveness of the device should be included.
• Labeling – copies of all proposed labeling, including instructions for use, literature, and advertising should be included in this section of the PMA.

The following FDA page links to a central index of FDA Guidance related to PMA applications, including content, review, quality systems, clinical studies, labeling, and more (https://www.fda.gov/medical-devices/premarket-approval-pma/pma-guidance-documents).

Helpful tips when submitting a Premarket Approval (PMA) Submission :

• Some pre-amendment Class III devices may have different pathways or legacy classifications.
• PMA approval may be dependent on a successful FDA QMSR inspection of the manufacturing plant, a successful BIMO inspection of the clinical sites and/or the study sponsor (as applicable) and a relatively successful panel meeting. FDA’s current approach to BIMO inspections, including types of records that may be requested, best practices for communication with FDA during inspections, and expectations for interactions before/during the audit can be found at https://www.fda.gov/media/179027/download. While not a traditional “guidance for industry” (as it is intended for FDA inspectors), this is the classic FDA document used for inspecting Quality Systems under 21 CFR Part 820 and is highly useful for companies preparing for a QMSR audit/inspection https://www.fda.gov/files/Guide-to-Inspections-of-Quality-Systems.pdf.
• Most clinical studies performed for a PMA submission are performed under an FDA approved Investigational Device Exemption (IDE) and an Institutional Review Board (IRB) under 21 CFR 812, 50, and 56.
• FDA may accept clinical data from studies conducted outside the U.S. provided that the data is representative of the US patient population and the conduct of the study is representative of clinical practice in the US. Nevertheless, it is recommended to include at least 50% of the patient data from within the US.
• FDA may impose post-market clinical studies as a condition of approval (e.g., long-term safety, pediatric use, real-world performance). These studies are separate from the clinical evidence required at the time of PMA submission but may be required to maintain marketing approval.
• The PMA may be submitted in modular format, including separate submissions for different sections. FDA PMA approvals are granted separately for each module, although the final PMA Approval letter will only be granted following receipt and review of the final PMA module. Following is a sample model of a modular PMA:

How we can help?

A. Stein Regulatory Affairs Consulting provides comprehensive support in preparing all documentation required for a Premarket Approval (PMA) submission and works directly with the FDA to define and agree on the appropriate contents for each module of the PMA. Our services are designed to help ensure a successful PMA approval, including managing interactions related to Bioresearch Monitoring (BIMO) audits and Quality Management System Regulation (QMSR) inspections throughout the PMA review process.

What is a De Novo Classification Request?

A De Novo classification request is a type of FDA premarket submission used to establish a new device classification (Class I or Class II) for a novel medical device that does not have a legally marketed predicate device and therefore, cannot use the 510(k) substantial equivalence pathway and is considered a low-to-moderate risk. Under the FD&C Act, any device that isn’t classified is automatically placed into Class III, which generally requires a Premarket Approval (PMA). A De Novo request offers an alternative pathway for certain novel devices that are low-to-moderate risk and don’t truly require PMA controls.

How to Prepare a De Novo Classification Request?

Following is a detailed description of the items included in a De Novo Classification Request:

• A coversheet clearly identifying the submission as “Request for Evaluation of Automatic Class III Designation” under 513(f)(2).
• User fee form with payment of $173,782 (or $43,446 for a small business) for FY2026.
• Administrative information including regulatory history.
• Device Description information
• The classification being recommended under section 513 of the act.
• A discussion of the potential benefits of the device when compared to the potential or anticipated risks when the device is used as intended.
• A complete discussion of the proposed general and/or special controls to ensure reasonable assurance of the safety and effectiveness of the device, including whether the product should be exempt from premarket review under section 510(k), whether design controls should be applicable, and what special controls would allow the Agency to conclude the device was reasonably likely to be safe and effective for its intended use.
• Bench, Pre-clinical and Clinical protocols and data that are relevant to the request.
• Summary of Benefits and known and potential Risks to Health, Risk and Mitigation Information and Benefit-Risk Considerations
• Device Labeling information including device brochure and Instructions for Use
• Executive Summary of the De Novo Request

The FDA Guidance document for filing a De Novo Classification Request may be found at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/de-novo-classification-process-evaluation-automatic-class-iii-designation.

Helpful tips when submitting a De Novo Classification Request:

• Before starting the De Novo request, thoroughly research FDA’s public databases (510(k), PMA, and De Novo) (https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/medical-device-databases) to ensure that no similar or predicate devices exist and the device truly qualifies for De Novo. This reduces the risk of choosing the wrong regulatory pathway.
• Engage FDA early through the Pre-Sub/Q-Sub Program to get Agency feedback and concurrence that the De Novo strategy is the correct regulatory pathway.
• Prepare comprehensive performance data including all relevant evidence, from bench testing to clinical data, as appropriate. Furthermore, as the De Novo review is fundamentally about benefit–risk, make your Benefit–Risk argument strong and clear. Use the FDA Guidance document Acceptance Review for De Novo Classification Requests, which outlines what FDA considers in the acceptance review (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/acceptance-review-de-novo-classification-requests).
• Although FDA has a 150-day target review goal under MDUFA IV, actual De Novo decision times can vary significantly based on completeness of the submission, the need for additional data, the quality of the benefit–risk discussion. So plan for variability in the timeline and allow extra time in your project planning.

How we can help?

A. Stein Regulatory Affairs Consulting has extensive expertise in guiding novel medical devices through the FDA’s De Novo Classification Request process. We can support you with a preliminary Pre-Submission (Pre-Sub/Q-Sub) that outlines a regulatory strategy justifying the use of the De Novo pathway, as well as assist with the subsequent De Novo regulatory submission.