Premarket Approval (PMA)
Premarket Approval (PMA) is the most stringent type of device marketing application required by the FDA. PMA is required for Class III devices -- those that support or sustain human life, are of substantial importance in preventing impairment of human health, or present a potential unreasonable risk of illness or injury. The PMA process requires the applicant to demonstrate reasonable assurance of safety and effectiveness, typically through valid scientific evidence including clinical studies.
When PMA is Required
Under Section 515 of the FD&C Act and 21 CFR 814, PMA is required for:
- Class III devices that were on the market before the 1976 Medical Device Amendments and for which FDA has called for PMAs (preamendment devices)
- Post-amendment Class III devices for which no predicate device exists and De Novo is not appropriate (due to high risk)
- Devices found Not Substantially Equivalent (NSE) through the 510(k) process that are classified into Class III
PMA Application Contents
A PMA application must contain sufficient valid scientific evidence to demonstrate reasonable assurance of safety and effectiveness. Per 21 CFR 814.20, required sections include:
| Section | Contents |
|---|---|
| Device Description | Complete device description including pictorial representations, engineering drawings, composition, principles of operation, and each component or ingredient |
| Indications for Use | Precise statement of the conditions or diseases to be diagnosed, treated, prevented, cured, or mitigated, including the target patient population |
| Manufacturing Information | Manufacturing methods, facilities, quality control procedures; compliance with 21 CFR 820 (QSR) is expected |
| Nonclinical Laboratory Studies | Bench testing, animal studies, biocompatibility (ISO 10993), electrical safety, software verification and validation, shelf life/reliability testing |
| Clinical Investigations | Clinical study reports including study protocols, patient demographics, safety and effectiveness endpoints, statistical analysis, adverse events; must comply with 21 CFR Parts 50, 56, and 812 |
| Labeling | Proposed labeling including physician labeling, patient labeling, and IFU per 21 CFR 801 |
| Bibliography | Published reports of investigations, safety, effectiveness, and any adverse events relevant to the device |
Clinical Data Requirements
Clinical investigations for PMA typically require an approved Investigational Device Exemption (IDE) under 21 CFR 812 for significant risk devices. Key requirements include:
- IDE approval: Required before beginning a clinical study of a significant risk device in the U.S.
- IRB oversight: All clinical investigations must be approved and overseen by an Institutional Review Board (21 CFR 56)
- Informed consent: Subjects must provide informed consent per 21 CFR 50
- Good Clinical Practice: Studies should follow GCP guidelines and 21 CFR 812 requirements
- Statistical rigor: Pre-specified endpoints, adequate sample size, appropriate statistical analysis plan
- Multi-center studies: Often preferred by FDA to demonstrate generalizability of results
Advisory Panel Review
FDA may refer a PMA to an advisory panel of outside experts for review and recommendation. The panel meeting is a public proceeding where the panel reviews the PMA, hears presentations from the applicant and FDA, and provides a recommendation on approvability. The panel's recommendation is advisory; the FDA makes the final decision.
FDA typically convenes an advisory panel for novel technologies, first-of-kind devices, or when the risk-benefit assessment is complex. Panels consist of physicians, scientists, and patient/consumer representatives with relevant expertise.
PMA Supplements
After PMA approval, changes to the device, labeling, or manufacturing require PMA supplements (21 CFR 814.39). Types of supplements include:
| Supplement Type | When Required | Review Timeline |
|---|---|---|
| Original PMA Supplement | Changes that affect safety or effectiveness (e.g., new indications, design changes requiring clinical data) | 180 days |
| Panel-Track Supplement | Significant changes that may require advisory panel review | 180 days |
| 180-Day Supplement | Changes in labeling, manufacturing process, or device modifications not requiring clinical data | 180 days |
| Real-Time Supplement | Minor manufacturing changes | Reviewed during facility inspection |
| 30-Day Notice | Manufacturing changes enhancing device safety | 30 days (may implement if no objection) |
PMA vs. 510(k) Comparison
| Attribute | 510(k) | PMA |
|---|---|---|
| Legal Standard | Substantial equivalence | Reasonable assurance of safety and effectiveness |
| Typical Device Class | Class I (with 510(k)) and Class II | Class III |
| Clinical Data | Sometimes required | Almost always required (pivotal clinical trial) |
| Review Time (target) | 90 days | 180 days (plus panel review time if applicable) |
| User Fees (FY2024) | $22,550 (standard); $5,637 (small business) | $442,026 (standard); $110,507 (small business) |
| Post-Market | MDR, corrections/removals | MDR, corrections/removals, annual reports, post-approval studies |