Contains Nonbinding Recommendations 
 
  
Real-Time Premarket Approval 
Application (PMA) Supplements 
 
Guidance for Industry and  
Food and Drug Administration Staff  
 
 
 
 
 
Document issued on December 16, 2019. 
  
Document originally issued on April 28, 2006. 
 
 
 
For questions regarding this document, contact the ORP:  Office of Regulatory Programs/Division of 
Regulatory Programs 1: Submission Support at 301-796-5640.  For questions regarding submissions to 
the Center for Biologics Evaluation and Research, contact CBERs Office of Communication, Outreach 
and Development (OCOD) at 1-800-835-4709 or 240-402-8010, or by email at ocod@fda.hhs.gov.  
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Devices and Radiological Health  
Center for Biologics Evaluation and Research  Contains Nonbinding Recommendations 
 
 
 
 
  Preface 
 
 
Public Comment 
 
You may submit electronic comments and suggestions at any time for Agency consideration 
to http://www.regulations.gov. Submit written comments to the Division of Dockets 
Management, Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), 
Rockville, MD 20852.  Identify all comments with the docket number FDA-2017-D-5971. 
Comments may not be acted upon by the Agency until the document is next revised or 
updated. 
 
 
 
Additional Copies 
 
CDRH 
 
Additional copies are available from the Internet.  You may also send an e-mail request to 
CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance.  Please include the 
document number 673 and complete title of the guidance in the request. 
 
CBER 
Additional copies are available from the Center for Biologics Evaluation and Research 
(CBER), Office of Communication, Outreach, and Development (OCOD), 10903 New 
Hampshire Ave., WO71, Room 3128, Silver Spring, MD 20903, or by calling 1-800-835-
4709 or 240-402-8010, by email, ocod@fda.hhs.gov, or from the Internet at  
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-
information-biologics/biologics-guidances.   Contains Nonbinding Recommendations 
 
 
 
Table of Contents 
I.  Purpose ........................................................................................................................ 4 
II.  Background................................................................................................................. 4 
III.  Which modifications are appropriate for a Real- Time PMA Supplement? ......... 5 
IV.  How do I request a Real-Time review?..................................................................... 6 
V.  Is there a user fee for a Real-Time PMA Supplement? ........................................... 7 
VI.  How do I submit a Real-Time PMA Supplement? .................................................. 7 
VII.  What should a Real-Time PMA Supplement contain? ........................................... 8 
VIII. What is the format of a Real-Time review meeting? .............................................. 8 
Attachment I.  Sample Real-Time Review Request ......................................................... 9 
  Contains Nonbinding Recommendations 
 
 Real-Time Premarket 
Approval Application (PMA) 
Supplements 
 
Guidance for Industry and  
Food and Drug Administration Staff  
 
This guidance represents the current thinking of the Food and Drug Administration 
(FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
binding on FDA or the public.  You can use an alternative approach if it satisfies the 
requirements of the applicable statutes and regulations.  To discuss an alternative 
approach, contact the FDA staff or Office responsible for this guidance as listed on the 
title page.  
 
 
I.  Introduction and Scope 
 
This guidance provides information about the real-time review process for premarket 
approval application (PMA) supplements and outlines the procedures for requesting and 
submitting these types of documents.   
 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agency's current thinking on a topic 
and should be viewed only as recommendations, unless specific regulatory or statutory 
requirements are cited. The use of the word should in Agency guidances means that 
something is suggested or recommended, but not required. 
 
 
II.  Background 
 
On February 4, 2003, FDA published a Federal Register notice entitled, Medical Device 
User Fee and Modernization Act of 2002, Establishment of a Public Docket1 to provide 
an  opportunity  for  interested  persons  to  share  information  and  views  on  the
 
implementation  of  the  Medical  Device  User  Fee  and  Modernization  Act  of  2002 
(MDUFMA).2   Subsequently, FDA issued a guidance entitled Assessing User Fees: 
PMA  Supplement  Definitions,  Modular  PMA Fees,  BLA  and  Efficacy  Supplement 
Definitions,  Bundling  Multiple  Devices  in  a  Single  Application,  and  Fees  for 
Combination Products3 and invited comments on its topics, which included Real-Time 
                                                           
1 68 FR 5643 
2 Public Law 107-250 
3 The PMA User Fees guidance is superseded by the following guidances: User Fees and Refunds for 
Premarket Approval Applications and Device Biologics License Applications 
  4  Contains Nonbinding Recommendations 
 
PMA Supplements.  FDA received no comments on Real-Time PMA Supplements in 
either docket. 
 
This guidance outlines the criteria for Real-Time PMA Supplements set forth in section 
737(4)(D) of the Federal Food, Drug, and Cosmetic Act (the act) and clarifies the kinds of 
device modifications we believe are appropriate for real-time review.  We continue to 
invite comments on this guidance. 
  
 
 
III.  Which modifications are appropriate for a Real- 
Time PMA Supplement? 
According to section 737(4)(D) of the act,4 a Real-Time PMA Supplement is defined as: 
 
a supplement to an approved premarket application or premarket report under 
section 515 that requests a minor change to the device, such as a minor change to the 
design of the device, software, sterilization, or labeling, and for which the applicant 
[PMA holder] has requested and the agency has granted a meeting or similar forum 
to jointly review and determine the status of the supplement. 
 
In general, we believe a Real-Time PMA Supplement is appropriate for a minor change 
that can be expected within a product line, which includes changes to: 
 
  device design 
 
  software 
 
  instructions for use, warnings, or precautions or other labeling that does not 
affect the indications or contraindications 
 
  sterilization and packaging methods. 
 
In addition, a minor change should be one that is: 
 
  expected for that device type 
 
  validated according to scientific principles we have relied on in previous 
reviews and accepted test methods or procedures for devices of that type, 
wherever applicable, such as an FDA-recognized standard or guidance 
document 
 
  adequately supported by pre-clinical or animal testing, with no new clinical data 
 
  typically involving review within a single scientific discipline, rather than 
a multidisciplinary review.5 
                                                           
(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/user-fees-and-refunds-
premarket-approval-applications-and-device-biologics-license-applications); Bundling Multiple Devices or 
Multiple Indications in a Single Submission (https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/bundling-multiple-devices-or-multiple-indications-single-submission); and Real-Time 
Premarket Approval Application (PMA) Supplements (https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/real-time-premarket-approval-application-pma-supplements). 
4 As amended by the Medical Devices Technical Corrections Act (Public Law 108-214). 
5 A review from a single scientific discipline may be, for example, an electrical engineering, mechanical 
  5  Contains Nonbinding Recommendations 
 
 
We also believe that for a Real-Time PMA Supplement to be an effective route to market, 
FDA and the PMA holder should agree that the review can be achieved in a real-time 
setting before either initiates the process. 
 
IV.  How do I request a Real-Time review? 
 
The typical request for a Real-Time review will follow these 4 steps. 
 
1. Preliminary Discussion 
 
Before submitting your request, we recommend you contact the Assistant Director 
(AD) in the appropriate Review Division in CDRH or the applications division in 
the appropriate CBER office to discuss whether the modification to your device is 
appropriate for a Real-Time PMA Supplement.6 
 
2. Your Request 
 
After you and FDA agree that the review can be achieved in a real-time setting, 
we recommend you email7,8 your request for a Real-Time review to the 
appropriate CDRH AD or CBER applications division.  We recommend that your 
request include the information outlined in the Sample Real Time Review Request 
in Attachment I. 
 
3. FDAs Response 
 
FDA plans to respond by email or fax within 14 days of receipt of Real-Time 
review requests.  Generally, if the information in your request is consistent with 
your preliminary discussion with FDA, and FDA, after evaluating the information, 
believes the modification is minor as defined in section III, FDA will generally 
agree to review your proposed change as a real-time supplement. 
 
4. Type of Interaction 
 
We intend the review process for a Real-Time PMA Supplement to be interactive, 
although a face-to-face meeting may not always be part of the process. We will 
work with you to determine the type of interaction  appropriate (e.g., face-to-face 
meeting, teleconference, written responses) based on the information in your 
request.  If you and FDA agree a meeting is appropriate, FDAs response will also 
                                                           
engineering, chemical engineering, material engineering, microbiology, or biocompatibility review. 
6 For assistance in identifying the appropriate Review Division in CDRH, the applicant may contact the 
Division of Industry and Consumer Education (DICE).  Please see https://www.fda.gov/medical-
devices/device-advice-comprehensive-regulatory-assistance/contact-us-division-industry-and-consumer-
education-dice for contact options. For assistance in identifying the appropriate division in CBER, please 
contact the Office of Communication, Training and Manufacturers Assistance at 1-800-835-4709 or please 
see  https://www.fda.gov/about-fda/about-center-biologics-evaluation-and-research-cber/center-biologics-
evaluation-and-research.  
7 For additional information about email communications with CBER, please see SOPP 8119: Use of Email for 
Regulatory Communications, available at 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/
ucm109645.htm   
8 CBER will accommodate the use of faxes. 
  6  Contains Nonbinding Recommendations 
 
confirm a meeting date, which should be within 30 days of the proposed 
submission date of the supplement or the earliest date that both you and FDA 
personnel are available to meet. 
 
V.  Is there a user fee for a Real-Time PMA 
Supplement? 
 
Yes.  As with all fee-paying submissions, the fee for a Real-Time PMA Supplement is due 
upon submission of the supplement.  If FDA receives the supplement prior to payment, we 
will place the file on hold until we receive payment and notify you by email, fax, or 
phone.9  FDA begins its review when the Office of Financial Management notifies CDRH 
or CBER that payment has been received and we have received the PMA submission, and 
a valid electronic copy (eCopy) has been received.  See https://www.fda.gov/medical-
devices/premarket-submissions/medical-device-user-fees for information on remitting 
user fees. 
 
 
VI.  How do I submit a Real-Time PMA Supplement? 
 
FDA requires all applicants to provide an eCopy of the Real-Time PMA supplement.10  The 
eCopy must be accompanied by a single paper copy of your signed cover letter submitted to 
the appropriate Center: 
 
  For devices regulated by the CDRH, send it to the current address displayed on 
the website http://www.fda.gov/cdrhsubmissionaddress. 
 
  For devices regulated by the CBER, send it to the current address displayed on the 
website 
https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTob
acco/CBER/ucm385240.htm.   
 
Each copy should be labeled REAL-TIME REVIEW REQUEST GRANTED and 
contain a copy of FDAs response granting your request for a Real-Time review. 
 
If we have scheduled a meeting with you, we recommend you submit your Real-Time 
PMA Supplement sufficiently in advance to allow FDA reviewers to adequately prepare 
their reviews.  If we have not received your submission at least 3 weeks before the meeting, 
we will typically reschedule to assure reviewers have adequate preparation time in order to 
avoid an unproductive meeting. 
 
 
                                                           
9 Section 102 of MDUFMA authorizes FDA to put the submission on hold until payment is received. 
10 Please refer to the FDA guidance, eCopy Program for Medical Device Submissions 
(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ecopy-program-medical-device-
submissions), for additional information on the eCopy program. 
  7  Contains Nonbinding Recommendations 
 
VII. What should a Real-Time PMA Supplement 
contain? 
 
A Real-Time PMA Supplement should identify all modifications planned for the device 
and labeling.  We recommend you include testing and results, along with a detailed risk 
assessment to support the continued safety and effectiveness of the modified device.  Your 
risk assessment should include a thorough review of all potential hazards associated with 
device use, taking into account the (incremental) modification proposed in your submission 
and the (cumulative) effects of any preceding modifications made since the approval of the 
original PMA.  Your risk assessment should also identify the steps you have taken to 
minimize any additional risks that may be created by incremental or cumulative 
modifications. 
 
 
VIII. What is the format of a Real-Time review 
meeting? 
 
If a Real-Time review meeting is part of the process, the meeting generally proceeds as 
follows: 
 
1.  You present the changes to your device, results of testing to support those 
changes, and your risk analysis. 
 
2.  You and FDA discuss any questions or comments about the changes, testing, or 
risk analysis. 
 
3.  The meeting briefly adjourns to allow for discussion amongst FDA staff. 
 
4.  FDA generally gives you verbal feedback that day. 
 
After the meeting, FDA will typically send our decision letter (i.e., approval, approvable, or 
not approvable letter) via mail or email to the primary correspondent identified by the 
applicant. 
  8  Contains Nonbinding Recommendations 
 
Attachment I.  Sample Real-Time Review Request 
PMA Contact Information and Submission Information 
  Date:  
  Name: 
  Address: 
  Company: 
  Phone Number: 
  Fax Number: 
  PMA Document Number: 
  Target Date for submitting to FDA: Proposed Meeting Date(s): 
 
Reason(s) for submission (check one or more) 
  Minor design changes 
  Material changes to another known material 
  Minor labeling changes 
  Software change 
  Sterilization changes to another known method 
  Packaging changes 
  Other 
 
We recommend that you attach a one-page or less explanation for the requested 
change(s) including: 
  the test methods identified in FDA guidance or recognized standard, if applicable 
  identify under what submission we have previously reviewed these test methods, if 
applicable 
  a summary of your risk analysis 
 
Specify the type of meeting you are requesting (check one or more) 
  Face-to-face 
  Telephone conference 
  Other (Explain) 
  9