US FDA Premarket Approval(PMA) 21 CFR 814

 Premarket Approval (PMA) is a scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices.

515 of the FD&C Act

• It is a marketing approval application. Manufacturer shall receive FDA approval of its PMA application prior to marketing the device.
• Devices fails to meet PMA requirements is adulterated under section 501(f) of the FD&C Act and may not be marketed.

Types of PMA

Traditional PMA

• Common method for achieving FDA approval.
• Ideal method for devices with already completed clinical studies.
• complete PMA application is submitted to FDA at once.

Modular PMA 

• Ideal method for devices with not completed clinical studies.
• PMA contents are divided into modules (example modules are preclinical, clinical, manufacturing etc.). Each module is submitted to FDA as soon as the applicant has completed the module

 Product Development Protocol

• Ideal method for devices in which the technology is well established in industry
• Manufacturer can have an early agreement with FDA as to what would be done to demonstrate the safety and effectiveness of a new device

Humanitarian Device Exemption

A Humanitarian Use Device (HUD) is a medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in not more than 8,000 individuals in the United States per year (Section 3052 of the 21st Century Cures Act (Pub. L. No. 114-255)

 PMA can be amended before approval.

Click here to know more about HUD/HDE

PMA supplements: Any significant changes in approved PMA may require PMA supplements

Types of PMA supplements:

1. Panel-Track supplement: Significant change requiring new substantial clinical data
2. 180-Day supplement: Significant change requiring new preclinical test data, no clinical data required.
3. Real-Time supplement: Minor changes supported by pre-clinical or animal testing, with no new clinical data. Involves review within a single scientific discipline.
4. Special PMA supplement: Changes Being Effected: This change Must enhance safety. Change may be implemented prior to FDA approval order
5. Manufacturing site change supplement: Use of a different site or moving the manufacturing site require a 180-day PMA supplement (referred to as a “site change supplement”). Supplement must demonstrate compliance with QS regulation.
6. 30-Day Notice: Written notification of change in manufacturing procedure or method, affecting safety and effectiveness

Annual (periodic) Report or 30-day Supplements: FDA will notify the manufacture for certain changes to be reported in an annual report instead of a PMA supplement submission

 Common documents included in PMA

There is no pre-printed form for a PMA Application. Required elements are listed in 814.20

PMA content consists of below listed administrative and technical data.

1.       The name and address of the applicant.

2.       A table of contents

3.       The summary shall contain the following information:

a.       Indications for use.

b.       Device description.

c.       Alternative practices and procedures.

d.       Marketing history.

e.       Summary of non-clinical and clinical studies.

f.        Conclusions drawn from the studies.

4.       Device Description of device and functional components or ingredients

5.       Manufacturing

6.       Reference to any performance standard

7.       Q-Submission(s)

8.       Results of Nonclinical Laboratory Studies: results of the nonclinical laboratory studies with the device including microbiological, toxicological, immunological, biocompatibility, stress, wear, shelf life, and other laboratory or animal tests as appropriate.

9.       Results of clinical investigations involving human subjects Conducted inside US and Outside US

10.   Statements of Compliance for Clinical Investigations

11.   FORM FDA 3674, Certification with Requirements of ClinicalTrials.gov Data Bank?

12.   A bibliography of all published reports not submitted

13.   Sample of device, if practical

14.   Copies of all proposed Labeling for the device. Such Labeling may include, e.g., instructions for installation and any information, literature, or advertising that constitutes Labeling

15.   Environmental assessment

16.   A financial certification or disclosure statement or both

a.       A signed and dated Certification Form (3454)

b.       A signed and dated Disclosure Form (3455)

17.   Information concerning uses in pediatric patients.

Documents issued by FDA for Product PMA Approval

Once FDA approve the PMA, Manufacturer will receive an Approval Order and Summary of Safety and Effectiveness Data (SSED)

The following are posted on the FDA’s public PMA database:

·       Approval Order

·       Summary of Safety and Effectiveness Data (SSED)

·       Labeling

FDA Review

1.Sponsor submits the ecopy to FDA CDRH's or CBER’s Document Control Center (DCC). FDA will send the acceptance status. (15 days) Assess administrative completeness of application and required elements per 21 CFR 814.20.

Decision: Accepted or Not accepted

2.FDA Filing Review: Threshold determination that application is sufficiently complete to review.

Manufacturer can use Acceptance and Filing Reviews for PMAs

Within 45 calendar days FDA will notify below to manufacturer: Decision: Accepted or Not accepted

3. Substantive Review: Lead reviewer will assess the application and share the below information to manufacturer (Day 90)

·       Interactive review

·       Issue Major Deficiency Letter.PMA request will be placed on hold.

·       Advisory Panel Meeting.Public meeting to review the PMA in accordance with 21 CFR 14.

·       Manufacturing facility inspection

·        Day 100 Meeting (Requested by Applicant)

Decision:

Approval Order:Device may be marketed.Identifies conditions of approval
Approvable Pending Deficiencies Letter: Device can not be marketed.deficiencies to be addressed
Approvable Pending GMP Letter: Device can not be marketed.GMP not confirmed  Not Approvable Letter:Device can not be marketed

References:

PMA : https://www.fda.gov/medical-devices/premarket-submissions/premarket-approval-pma

 PMA database: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm

PMA Guidance: https://www.fda.gov/medical-devices/premarket-approval-pma/pma-guidance-documents