PMA Post-Approval Study Considerations

In the US, post-market clinical studies are not required of every medical device manufacturer. However, the Food and Drug Administration (FDA) does have the authority to order post-market surveillance of any device, and for devices in the Premarket Approval (PMA) pathway, this may come in the form of a Post-Approval Study (PAS).

Devices that require a PMA have a high probability of requiring a PAS by the FDA. The PAS may be ordered to provide reasonable assurance, or the continued assurance, of safety and effectiveness of an approved device.

PMA Post-Approval Overview

What is a Post-Approval Study?

A Post-Approval Study (PAS) is one of the methods FDA may require for Post-Market Surveillance (PMS) of a medical device that has been approved or cleared and are for those devices that are using the PMA or Humanitarian Device Exemption (HDE) pathways.

Post-Approval Studies are carried out after FDA has approved a medical device to be placed on the US market. It’s used to provide more evidence for the safety and effectiveness of the device after it’s been approved. FDA may order a PAS when the agency “has uncertainty regarding certain benefits or risks of the device, but the degree of uncertainty is acceptable in the context of the overall benefit-risk profile of the device at the time of premarket approval.”

Post-Approval Study Protocol

FDA encourages manufacturers to “engage with FDA as early as possible in the PMA review to discuss the need for and details of a PAS protocol.”

If a PAS is a mandatory condition of premarket application approval, the FDA will provide details of the specific requirements to be applied, such as the intended use of the device, enrollment, completion, and reporting.

According to the guidance, a PAS study protocol shall cover the following aspects:

Background (e.g., device’s regulatory history, brief description of device, indications for use),
Purpose of study, study objectives,
Study design,
Study population (including subject inclusion and exclusion criteria and definition and source of comparator group),
Enrolment and recruitment plan (including enrolment milestones),
Sample size calculation that is statistically justified and based on study hypothesis, where applicable,
Primary and secondary endpoints, when applicable, including definitions for study endpoints and list of adverse events/complications,
Procedures for a determination of adverse events/complications relatedness with device and/or the procedure,
Length of follow-up, follow-up schedule, plans to minimize losses to follow-up, and follow-up rate targets,
Description of baseline and follow-up assessments,
Description of data collection procedures (including data management and quality control),
Data analyses and statistical tests planned (such as a statistical analysis plan including interim data release plan, when appropriate, and final data analysis),
Data collection forms, informed consent forms, and Institutional Review Board (IRB) approval forms,
Study timelines.

Post-Approval Study protocols will be subject to review by the FDA together with the initial premarket application. Once the initial PMA application has been approved, any changes to PAS protocols should be subject to additional approval.

Common Questions About Post-Approval Study Protocol

What’s the timeline for PAS Protocol Review?

There are a couple different timelines for the PAS protocol review. The first method is to review the protocol, establish milestones for enrollment and study completion timelines at the time of PMA approval:

When a PAS is likely to be required as a condition of approval of the PMA, FDA intends to review the PAS protocol interactively with the sponsor during the review of the PMA and concurrent with the review of the premarket data.

However, if the PAS protocol hasn’t been developed by the time of the PMA approval, FDA may approve the PMA with a Post-Approval Study outline (which includes objective and general study design, study population, study endpoints, sample size, length of follow-up, frequency of assessments, and enrollment milestones).

In this case, a PAS protocol is required to be submitted for approval within 30 calendar days of the PMA approval. The FDA will review the PAS protocol within 30 calendar days after receiving it, thus the PAS protocol review is completed within 60 calendar days of the PMA approval.

What is the timeline for enrolling subjects for your Post-Approval Study?

The FDA will specify the exact timelines for all the processes of the conditions of approval and PAS protocol, including enrollment, completion, and reporting. They expect the sponsor to collaborate actively in order to facilitate the review of the PAS protocol and to ensure the study objectives are agreed upon and the results achieved are accurate and reliable. In most cases, the following timelines will apply:

First subject enrolled within 6 months of the study protocol approval date,
20% of subjects enrolled within 12 months of the study protocol approval date,
50% of subjects enrolled within 18 months of the study protocol approval date,
100% of subjects enrolled within 24 months of the study protocol approval date.

What are your Post-Approval Study Reports and what is the timeline for submitting them?

There are a few different types of PAS Reports that could be required to submit to FDA over the duration of the PAS:

FDA tracks and evaluates the conduct of a PAS through review of study reports submitted to the Agency. An interim report is a written report to FDA on the status of the PAS prior to its completion. Generally, FDA recommends submitting two types of interim reports: “Enrollment Status Report” and “PAS Progress Report.” 

The different reports and their timelines:

The Enrollment Status Report is a document that shows progress toward meeting the enrollment milestones of the PAS.
The PAS Progress Report describes the status of the Post-Approval Study before completion and includes subject accountability, device performance, and safety and effectiveness data. If delays have occurred or are anticipated, FDA should be notified in the next PAS Progress Report.
The Final PAS Report is the documentation of a completed or terminated Post-Approval Study.

What are the timelines for submitting your PAS reports?

The timelines for submitting these reports will be different for each Post-Approval Study. A specific reporting timeline will be agreed upon with FDA prior to the start of the Post-Approval Study. “FDA intends for the PMA approval order to include a submission timeline for PAS reports.”

The timeline for the Enrollment Status Reports will likely be based on the deadlines for the subject enrollment milestones.
The PAS Progress Reports are generally required every six months until all subjects have been enrolled and then submitted annually until the Post-Approval Study is complete or terminated.
The Final PAS Report is generally submitted “no later than three months after the study is complete (i.e., last subject’s last follow-up date), unless a different reporting schedule post study completion is agreed upon.”

Key Considerations for Post-Approval Studies

Post-Approval Study begins with early communication with FDA on the development and design of the protocol. Conducting a successful study includes meeting enrollment requirements, collection of needed data, maintaining adequate follow-up and adherence to the protocol. Collecting data on a medical device in the post-market stage can be more challenging than in pre-market studies, because Investigators tend to forget that the device is still under observation.

Need Help Navigating Post-Approval Studies?

At ProPharma, we specialize in helping medical device manufacturers successfully manage Post-Approval Studies to meet FDA requirements. Our experts can assist with designing protocols, data collection, monitoring, and reporting to ensure compliance and the continued safety and effectiveness of your device. Whether you're preparing for your first PAS or need support with ongoing post-market surveillance, ProPharma is here to help. Contact us today to learn how we can guide you through your Post-Approval Study and regulatory processes with ease.

Post-Approval References

Author

Peter Weiman

Director, Clinical Programs

TAGS: PMA MedTech Post-Approval Study