June 17, 2024
Bringing a Class III medical device to market in the US requires navigating a complex regulatory landscape. The pathway for obtaining FDA approval for a Class III medical device is through the Pre-Market Approval (PMA) process. Within this process, two primary pathways exist: the traditional PMA and the modular PMA. Understanding these pathways, along with their respective advantages and challenges, is crucial for medical device manufacturers in developing their regulatory strategy for their Class III medical device. This article provides an overview of both PMA approaches, offering insights into their unique aspects, reviewing all the pros and cons, with references to relevant FDA Guidance Documents.
Traditional PMA
The traditional PMA is a comprehensive submission to the FDA that includes all necessary data to demonstrate the safety and efficacy of a Class III medical device. This process is mandatory for devices that sustain or support life, are implanted, or present potential unreasonable risk of illness or injury to the end user. PMAs are also required for devices in which a predicate device does not exist and is ineligible for a De Novo Classification Request.
Process:
1. Extensive Data Compilation: Manufacturers must compile a complete set of data, which includes:
Clinical Trial Data: Results from human clinical trials that demonstrate the device’s safety and effectiveness.
Non-clinical Studies: Laboratory and animal studies to show the initial safety profile.
Bench Testing: This includes biocompatibility testing, sterilization, shelf-life, and any other required performance testing to show the device meets specifications.
Quality System Documentation: Quality system procedures to show compliance with 21 CFR 820, specifically the information referenced in this FDA Guidance.
Manufacturing Information: Details about the manufacturing process, controls, facilities, and process validation documentation.
Design Controls: Documentation showing that the device meets its intended use and complies with 21 CFR 820.30.
Labeling and Instructions for Use: Comprehensive labeling, including intended use, contraindications, warnings, and instructions.
Risk Analysis: Evaluation of potential risks and mitigation in compliance with ISO 14971.
2. Sequential Review: The FDA reviews the entire PMA application in a linear fashion. This includes:
Acceptance Review and Filing Review: This includes an initial check to ensure the submission is administratively complete. The filing of an application means that FDA has made a threshold determination that the application is sufficiently complete to begin an in-depth review. Within 45 days after a PMA is received by FDA, the agency will notify the applicant whether the application has been filed.
Substantive Review: This is a detailed evaluation of the scientific and clinical data. FDA will begin substantive review of the PMA after it is accepted for filing.
Quality System Inspection(s): An FDA manufacturing inspection by FDA field personnel will likely be conducted for all original PMAs. Critical contract manufacturing sites could also be included in the inspection.
Bioresearch Monitoring (BIMO) Audit: This is an audit of the clinical study data.
Additional Information Requests: The FDA may request additional data or clarification at any stage of the PMA review. During the review process, FDA will notify the PMA applicant via major/minor deficiency letters of any information needed by FDA to complete the review of the application.
Panel Review: For certain devices, the application may be reviewed by an advisory panel of experts. All PMAs for the first-of-a-kind device are taken before the appropriate advisory panel for review and recommendation from key experts and stakeholders.
3. Single Decision: Upon completing the review, the FDA issues a single decision to approve or deny the PMA application. This occurs 180 days after official filing of the PMA. Approval indicates the device is safe and effective for its intended use. FDA may issue one of the following:
an approval order,
an approvable letter: if the application substantially meets the requirements of the FD&C Act, and FDA believes that it can approve the application if specific additional information is submitted or specific conditions are agreed to by the applicant
a not approvable letter: if FDA believes that the application may not be approved for one or more of the reasons given in §814.45(a) or if FDA is unable to reach an approvable decision due to a lack of significant information in the PMA
an order denying approval: if the applicant fails to follow the requirements of the PMA regulation or if FDA determines that any of the grounds for denying approval of a PMA specified in section 515(d)(2)(A)-(E) of the FD&C Act apply
Pros:
Singular process flow: Ensures thorough assessment of the device’s safety and efficacy through one singular process of communication with the Agency.
Quicker Review if all required data is readily available: Faster review cycle if all non-clinical and clinical data are ready for submission to FDA.
Cons:
Delays for PMA submission if clinical study is still underway
Unable to resolve potential review issues with bench and non-clinical testing prior to submitting clinical study data
Unable to resolve potential review issues with quality system procedures/design control documentation prior to submitting clinical study data
Modular PMA
The Modular PMA allows manufacturers to submit parts of the application, known as Modules, separately for review by the FDA. This approach is intended to streamline the review process and make it more efficient by allowing earlier Agency review and feedback and more specifically scoped submissions.
Process:
1. PMA Shell: A PMA Shell is an outline of the contents that will be included in each PMA Module and the planned timelines for submitting each Module. The PMA Shell is reviewed by FDA and agreed upon prior to submitting any Modules.
2. Modular Submission: All the information that was listed as required for a Traditional PMA is required for a Modular PMA. The difference is that manufacturers submit individual modules addressing specific segments of the required information for the PMA. Modules typically include:
Module 1: Device Description, Bench Testing, Sterilization, Shelf-Life, Biocompatibility, and Non-clinical Studies
Module 2: Manufacturing Information and Quality System Information
Module 3: Clinical Investigations and Final Labeling
3. Parallel Review: The FDA reviews each Module as it is submitted. FDA reviews each Module within 90 days and provides feedback to the sponsor. Any potential deficiencies can be addressed once they are received from FDA, instead of waiting for the entire PMA application to be completed. Upon receipt of the final module, FDA makes its official filing decision and the 180 day PMA review clock officially begins.
4. Integrated Decision: Upon completing the review of all modules, the FDA integrates the findings to make a final decision on the PMA application. The final decision options for a Modular PMA are the same as those listed above for a Traditional PMA. This approach aims to reduce the overall time to market by addressing issues earlier in the review process.
Pros:
Faster Review Process: Could result in shorter review times due to concurrent evaluation of Modules.
Flexibility: Manufacturers can submit Modules as the documentation becomes available, potentially expediting the approval process.
Earlier Awareness of Issues: With the 90 day review of Modules, sponsors can become aware of and resolve any potential deficiencies prior to waiting for a clinical study to be completed.
Cons:
Integration Challenges: Coordinating and integrating multiple Modules and potential deficiency responses could be complex and require careful planning.
Regulatory Cost: Regulatory resource fees could be more expensive than a Traditional PMA, due to the multiple filings.
Conclusion
Choosing between Traditional and Modular PMA depends on various factors, including the project timelines, clinical study timeline, available resources, and desired speed to market. Both pathways offer unique benefits and challenges, and understanding these can help manufacturers navigate the regulatory landscape more effectively. If you need support planning your PMA strategy, schedule a free, 30-minute initial consultation with our experts at Folio Consulting Group, LLC today.
For further details, refer to the FDA guidance documents:
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