# Presentation: 782451

## Overview of Premarket Approval Regulations and Review Processes 

- Patricia Beverly
- Office of the Director
- Premarket Approval Section
- Office of In Vitro Diagnostic Device (OIVD) Evaluation and Safety

## PMA Regulations

- Class III Medical Devices
- Safety and Effectiveness
- Valid Scientific Evidence
- Contents of an Application
- Acceptance of Foreign Clinical Data
- PMA Definitions

## PMA Review

- PMA Review Phases
- FDA/CDRH Letters
- PMA Supplements
- Expedited Review
- User Fees

## Class III

- General Controls/Special Controls/Performance Standards Are Not Sufficient
- Supports or Sustains Human Life
- Substantial Importance in Preventing Impairment of Human Health
- Potential Unreasonable Risk of Illness or Injury

## Safety and Effectiveness	(21 CFR 860.7)

- Considerations
- Persons for Whose Use the Device is Intended
- Conditions of Use for the Device
- Possible Benefit to Health vs Probable Injury or Illness from Use
- Reliability of the Device
- Reliance on Valid Scientific Evidence Only

## Valid Scientific Evidence	(21 CFR 860.7)

- Well-Controlled Investigations
- Partially Controlled Studies
- Studies and Objective Trials without Matched Controls
- Well-Documented Case Histories by Qualified Experts
- Reports of Significant Human Experience with a Marketed Device

## Valid Scientific Evidence Is Not:

- Isolated Case Reports
- Random Experience
- Unsubstantiated Opinions
- Reports Lacking Sufficient Details to Permit Scientific Evaluation

## Valid Scientific Evidence

- Randomized Control Trial
- Historical Control (Literature)
- Objective Performance Criteria

## Contents of Application (21 CFR 814.20)

- Applicant's Name and Address
- Signature of U.S. Representative
- Table of Contents
- Summary of Safety and Effectiveness Data
- Device Description and Manufacturing Section
- Voluntary Performance Standards
- Non-clinical and Clinical Data

## Contents of Application (Continued)

- Justification for Sole Investigator
- Bibliography and Other Relevant Information
- Samples of Device (if requested by FDA)
- Proposed Draft Labeling
- Environmental Assessment or Claim of Categorical Exclusion
- Other Information Requested by FDA or Panel

## Acceptance of Foreign Clinical Data

- Greater Protection: Declaration of Helsinki or Laws/Regulations of that Country
- Applicable to U.S. Population/Medical Practice
- Clinical Investigators of recognized Competence
- Valid Scientific Evidence (21 CFR 860.7)

## Premarket Approval Application Definitions

- Original
- Supplement
- Amendment
- Report
- Masterfile

## PMA Review Phases and Associated Letters

- Filing Review           Filing/Not Filing
- Substantive Review  Major
- Status			    90 day letter/						100 day meeting
- Panel Meeting            Panel Status
- Decision                    Approvable 						Not Approvable						Approval					    	        Denial

## PMA Letters				

- Major Deficiency
- Approvable
- Not Approvable
- Approval Order

## Major Deficiency Letter	

- Major Deficiency
- Significant new or updated data
- Significant previously omitted data
- Reset 180 day clock

## Approvable Letter		

- Pending QSR inspection
- Pending minor deficiencies (clarification, labeling, etc.)
- Agreeable to “Conditions of Approval”
- Agreeable to post-approval study

## Not Approvable Letter	

- Identify what is needed to put the application in approvable form
- Response resets 180 day clock

## Approval Order

- Decision Based on FDA Review, Panel Recommendation, GMP and BioResearch Monitoring Inspections
- If Approval Order Issues = Go to Market
- Federal Register Notice of Approval Decision
- Availability of Summary of Safety and Effectiveness Data (SSED)
- Opportunity to Petition for Administrative Review of the Decision

## PMA Supplements

- Submit For Changes That Affect Safety and Effectiveness
- Types of Supplements:
- Panel track
- 180 day
- Real time
- Special PMA supplements – Changes Being Affected
- 30 day Notices/135 day supplements

## Panel Track Supplements	

- Panel-track Supplement:
- New indication for use
- Significant change in device design or performance
- Substantial clinical data are necessary to provide a reasonable assurance of safety and effectiveness

## Panel Track Supplements - Examples

- Examples:
- A glucose monitoring system for detecting trends and tracking patterns in glucose levels in adults to expand the indication for use to add pediatric patients (age 7 to 17 years) .
- A modification to the indication for use using the same device but a different patient population.
- Heart valves approved for use in the aorta will require a submission of a panel track supplement to expand the indication for use to include usage in the mitral positions.

## Panel Track Supplements	

- Consider As Original PMAs
- Require New SS & E
- 180 Day Review Clock

## 180 – Day Supplement

- 180-Day Supplement is submitted for a _significant_ change in:
-  components
-  materials
-  designs
-  specification
-  software
-  labeling, or
-  color additive
- 180 day review clock

## 180-Day Supplements - Examples

**Examples:**
- The addition of a new analyzer – assay remained unchanged. The PMA holder conducts new analytical performance testing to demonstrate that the new analyzer does not alter the performance of the assay.
- A change in the continuous glucose monitoring system that uses wireless RF telemetry
- Design Change - Pre-clinical Data and Limited Confirmatory Clinical Studies

## Real Time Supplement

- Real-time Supplement is submitted for a _minor_ change to the device, such as a minor change to the:
- design of the device,
- software,
- sterilization, or
- Labeling, and
- The applicant has requested and the agency has granted a meeting or similar forum to jointly review and determine the status of the supplement.”

## Real Time Supplement - Examples

- Examples:
- minor design modifications (e.g., new lengths, diameters, and curve types) for cardiac ablation catheters,
- a change in the storage temperature and expiration dating for an injectable gel,
- extension of the shelf life of the autosensor for a continuous glucose measuring device from 6 months to 18 months (if protocol was not approved previously)

## Special PMA Supplements - Changes Being Effected

- Submit For Changes Which Enhance The Safety of The Device Or The Safe Use of the Device
- Changes May Be Implemented Prior to Receipt of Approval Letter

## Special PMA Supplement -Changes Being Affected	

- Labeling Changes That Add or Strengthen:
- Contraindication, Warning, Precaution, or Information About An Adverse Reaction
- Instruction That Enhance the Safe Use of the Device
- Labeling Changes That Delete Misleading, False, or Unsupported Indications

## Special PMA Supplement - Changes Being Affected			

- Changes in Quality Control or Manufacturing Process That
- Add New Specification or Test Method
- Provide Additional Assurance of Purity, Identity, Strength, or Reliability of the Device

## 30-Day Notices/135 Day PMA Supplements	

- Modifications to Manufacturing Processes
- Modifications to Methods of Manufacturing
- 30 Day Clock / 135 Day Clock

## Typical Manufacturing Changes

- Change in Sterilization Method or Process
- Change From Manual to Automated Manufacturing Process
- Change in Manufacturing Materials

## Expedited Review Criteria

- Is intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition, _and_
- No Approved Alternatives Exist
- Alternatives Exist but the Device May Offer Earlier Diagnosis or Significant Advances
- Breakthrough Technologies
- Availability is in best interest of the patients

## Expedited - Procedures

- Receive priority review before other pending applications
- If multiple PMA meets expedited qualification, First In First Review

## Expedited - Procedures

- When one is approved:
- Remaining PMA lose expedited status
- Retain place in the review queue for the current cycle
- Subjected to standard FIFR procedures applicable to non-expedited submissions

## FY 06 User Fee

- Original PMA & PT Supplement –
- $259,600 ($98,648)
- Other PMA Supplements –
- $55,841 - $18,691 ($21,209 - $7,103)
- Small Business - $100 million in gross receipts or sales

## FY 06 User Fee

- _First_ PMA from firms with gross receipts or sales ≤ $30 million – Fee is waived
- Any application for a device intended solely for _pediatric_ use.

## How to Get Further Information

- World Wide Web
- http://www.fda.gov/cdrh/index.html
- PMA Staff
- Lisa Fisher/Wanda Sawyer Major/Laura Byrd/Pat Beverly/Marsha Melvin
- 301-594-2186 or 240-276-0504

## Thanks

- Thinh Nguyen
- Director, Premarket Approval Section
- Office of Device Evaluation
- PMA Staff
- Lisa Fisher, Laura Byrd, Marsha Melvin