Guidance for Industry and FDA Staff 
 
Modifications to Devices Subject to 
Premarket Approval (PMA) - The PMA 
Supplement Decision-Making Process 
 
Document Issued on: December 11, 2008 
 
 
This document supersedes Modifications to Devices Subject to Premarket 
Approval (PMA) - The PMA Supplement Decision-Making Process dated 
March 9, 2007. 
 
For questions regarding the use or interpretation of this guidance in the review of PMAs and 
PDPs, please contact the Nicole L. Wolanski, CDR, USPHS, Director, PMA Program at (301) 
796-6570 or nicole.wolanski@fda.hhs.gov. For questions regarding the 30-day notice or 
manufacturing site change supplement program, please contact Director, Office of Compliance 
in CDRH at (301) 796-796-5504. 
 
For questions regarding the application of this guidance to devices regulated by the Center for 
Biologics Evaluation and Research (CBER), please contact the Office of Communication, 
Training and Manufacturers Assistance at 1-800-835-4709 or 301-827-1800.  
  
 
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 
 
Written comments and suggestions may be submitted at any time for Agency consideration to the 
Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, Room 
1061, (HFA-305), Rockville, MD, 20852.  Alternatively, electronic comments may be submitted 
to http://www.regulations.gov.  When submitting comments, please refer to Docket No. FDA-
2007-D-0025.  Comments may not be acted upon by the Agency until the document is next 
revised or updated. 
 
Additional Copies 
 
Additional copies are available from the Center for Devices and Radiological Health (CDRH) 
through the Internet at: http://www.fda.gov/cdrh/ode/guidance/1584.pdf.  You may also send an 
e-mail request to dsmica@fda.hhs.gov to receive an electronic copy of the guidance document or 
send a fax request to 301-847-8149 to receive a hard copy.  Please use the document number 
(1584) to identify the guidance document you are requesting.  
 
Additional copies of this guidance document are also available from the Center for Biologics 
Evaluation and Research (CBER), Office of Communication, Training and Manufacturers 
Assistance (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, or by 
calling 1-800-835-4709 or 301-827-1800, or from the Internet at 
http://www.fda.gov/cber/guidelines.htm. 
 
 
  Contains Nonbinding Recommendations 
Table of Contents 
I. Introduction................................................................................................................ ..............1 
The Least Burdensome Approach.........................................................................................2 
II. Background ..............................................................................................................................2 
III.  General Requirements for When a PMA Supplement is Needed............................................3 
IV. Determining the Type of PMA Submission............................................................................4 
A.  When to Submit a Traditional PMA...............................................................................5 
A1.  Modified Device for a New Indication for Use........................................................5 
A2.   Modified Device with New Clinical Effects...........................................................6 
A3. Modified Analyte and Indication/Patient Population (OIVD)..................................6 
A4.  Significant Modification of Technology (OIVD)....................................................7 
B.  When to Submit a Panel-Track Supplement..................................................................7 
B1.  Change in Indication for Use - Different Patient Population...................................8 
B2.  Change in Indication for Use - Different Patient Population...................................9 
B3.  Change in Indication for Use - Different Patient Population...................................9 
B4.  Change in Indication for Use - Different Patient Population (OIVD)...................10 
B5.  Change in Indication for Use - Different Surgical Procedure................................10 
B6.  Change in Indication for Use - Different Conditions of Use.................................10 
B7.  Change in Indication for Use - Different Specimen (Sample) Type (CBER)........11 
B8.  Change in Indication for Use - Different Physiological Location.........................11 
C.  When to Submit a 180-Day Supplement.......................................................................11 
C1.  Design Change.......................................................................................................12 
C2.  New Device Feature...............................................................................................12 
C3.  Modified Chemical Formulation............................................................................13 
C4.  Hardware and Software Modifications..................................................................13 
C5.  New Analyzer  Assay Unchanged (OIVD)..........................................................13 
C6.  Design and Software Modification........................................................................13 
C7.  Modified Physical Characteristics..........................................................................14 
C8.  New Device Feature...............................................................................................14 
C9.  Design Change.......................................................................................................14 
C10.  New Specimen (Sample) Type (CBER)...............................................................15 
D.  When to Submit a Real-Time Supplement...................................................................15 
D1.  Minor Modification to Correct Battery Failures.....................................................15 
D2.  Alternative Sterilization Method............................................................................16 
D3.  Storage Temperature Change.................................................................................16 
D4.  Extended Shelf Life................................................................................................16 
D5.  Component Offered as Stand Alone System..........................................................16 
D6.  Alternate Wet Shipping Solution............................................................................17 
D7.  Modified Bonding Method.....................................................................................17 
E.  When to Submit a Special PMA Supplement  Changes Being Effected..................17 
E1.  New Warning Added..............................................................................................18 
E2.  Manufacturing Process Change..............................................................................19 
  Contains Nonbinding Recommendations 
E3.  Improved Instructions.............................................................................................19 
E4.  Additional Inspection Step in the Manufacturing Process......................................19 
E5.  Additional Inspection Step in the Manufacturing Process......................................19 
F.  When to Submit a 30-Day Notice...................................................................................19 
F1.  Manual to Automated Process.................................................................................20 
F2.  Alternate Qualified Supplier of Critical Component (OIVD).................................20 
F3.  Alternate Qualified Supplier of Critical Material...................................................20 
F4.  In-Process Quality Control Step Change................................................................20 
F5.  Manual to Automated Process Conversion.............................................................21 
F6.  Modified In-Process Test........................................................................................21 
F7.  Modified Sterilization Process Parameters.............................................................21 
G.  When to Submit a Manufacturing Site Change Supplement.....................................21 
V. Periodic  Reports.....................................................................................................................22 
  Contains Nonbinding Recommendations 
Guidance for Industry and FDA Staff 
 
Modifications to Devices Subject to 
Premarket Approval (PMA) - The PMA 
Supplement Decision-Making Process 
 
This guidance document represents the Food and Drug Administration's (FDA's) current 
thinking on this topic.  It does not create or confer any rights for or on any person and does 
not operate to bind FDA or the public.  You can use an alternative approach if the approach 
satisfies the requirements of the applicable statutes and regulations.  If you want to discuss an 
alternative approach, contact the FDA staff responsible for implementing this guidance 
document.  If you cannot identify the appropriate FDA staff, call the appropriate number 
listed on the title page of this guidance document.  
I.  Introduction 
This guidance document has been developed to provide the underlying principles and examples 
to establish a clear and consistent way to approach the decision-making process you follow to 
determine the type of regulatory submission, if any, that may be required when you modify your 
lawfully marketed PMA device.   
 
This guidance applies to class III devices that are subject to premarket approval application 
(PMA) requirements of section 515 of the Federal Food, Drug, and Cosmetic Act (the Act) (21 
U.S.C. 360e).  This guidance provides the criteria for industry and Food and Drug 
Administration (FDA) staff to use in determining the type of PMA submission (i.e., traditional 
PMAs, panel track supplements, 180-day supplements, real-time supplements, Special PMA 
Supplements-Changes Being Effected, 30-day notices, manufacturing site change supplements, 
or periodic reports) that you should submit to FDA when you modify the design or labeling of 
your PMA device; its manufacturing process; or the location of manufacturing, processing, or 
packaging.  The guidance also provides examples of various types of device modifications, 
describes the types of testing that were performed to support the safety and effectiveness for each 
device modification, and the type of PMA submission that was submitted.  It does not address 
how to test a specific device to determine the effects of modifications. 
 
This guidance applies to PMAs reviewed by CDRH and CBER. This guidance also applies if you 
modify your PMA device in response to a recall or field corrective action to assure the continued 
safety and/or effectiveness of the device.  
 
This guidance is not intended to replace existing, device-specific guidance or other guidance 
documents related to the PMA program.1   
 
                                                 
1 All CDRH guidance documents are available at http://www.fda.gov/cdrh/guidance.html using the online 
search feature there.    
page 1  Contains Nonbinding Recommendations 
FDA's guidance documents, including this guidance document, do not establish legally 
enforceable responsibilities.  Instead, guidance documents 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 guidance documents means that 
something is suggested or recommended, but not required. 
 
The Least Burdensome Approach 
We believe we should consider the least burdensome approach in all areas of medical device 
regulation.  This guidance reflects our careful review of the relevant scientific and legal 
requirements and what we believe is the least burdensome way for you to comply with those 
requirements.  However, if you believe that an alternative approach would be less burdensome, 
please contact us so we can consider your point of view.  You may send your written comments 
to the contact person listed in the preface to this guidance or to the CDRH Ombudsman.  
Comprehensive information on CDRH's Ombudsman, including contact information, can be 
found on the Internet at http://www.fda.gov/cdrh/ombudsman/.  
II. Background 
The PMA regulation (21 CFR Part 814) sets forth general criteria for determining when you 
must submit a PMA supplement or a 30-day notice for a device modification or manufacturing 
change (21 CFR 814.39).  Subpart B Premarket Approval Application of the PMA regulation 
in Part 814 describes PMA amendments and supplements. Subpart E -Post Approval 
Requirements describes requirements for continuing evaluation (post-approval studies), 
periodic reporting, and other requirements related to the continued reasonable assurance of safety 
and effectiveness of an approved PMA device.  The Act defines different types of PMA 
supplements that are used to request approval of a change to a device that has an approved PMA 
(see section 737(4) of the Act (21 U.S.C. 379i(4)) for definitions of 180-day supplements, real-
time supplements, panel-track supplements).  These definitions form the basis for the 
recommendations provided in this guidance document.   
 
The draft version of this guidance document, which was issued on March 9, 2007, was the result 
of an extensive effort by a working group consisting of regulatory and scientific experts from 
CDRH and CBER.  That March 2007 draft guidance replaced the August 6, 1998 draft guidance 
entitled, Modifications To Devices Subject to Premarket Approval  The PMA Supplement 
Decision Making Process.2  Comments by the industry on the August 1998 draft and comments 
we received at subsequent meetings on this issue were considered by FDA during the 
development of the March 2007 draft guidance document. 
 
In response to the comment period for the March 2007 draft guidance, FDA received the 
following five general categories of comments from industry.  Each category of comment, 
below, is followed by FDAs response.   
                                                 
2 The 1998 guidance, Modifications To Devices Subject to Premarket Approval  The PMA 
Supplement Decision Making Process was withdrawn on January 5, 2005 (70 FR 824) because of 
amendments made to the Act after 1998 that affected our recommendations (i.e., the amendments made 
by the Medical Device User Fee and Modernization Act of 2002 (MDUFMA) (Pub. L. 107-250), which 
added specific definitions for 180-day supplement, real-time supplement, and panel-track supplement 
(section 737(4) of the Act)).  
page 2  Contains Nonbinding Recommendations 
  Industry requested clearer interpretation of the PMA regulation as to when a supplement 
is necessary (i.e., when a change to a device impacts or could impact safety and/or 
effectiveness).  Our response to this is included in Sections III and IV below.   
  Industry requested a detailed flowchart that would identify the type of supplement to be 
submitted based on any specific change for any device.  FDA understands that there is a 
general desire among PMA applicants for such a detailed flowchart or easy-to-use 
paradigm.  However, FDA believes the complexity and variability of class III devices 
makes it unfeasible to develop such a flowchart.   
  Industry requested specific definitions for some terms, such as substantial clinical data, 
significant change, and limited confirmatory clinical data.  Where possible, FDA 
provided additional clarity for some terminology.  Again, because of the complexity and 
variability of class III devices, we do not believe it is feasible to provide detailed 
definitions for certain terms and instead use examples to help illustrate the meaning of 
these terms.   
  Industry requested that the guidance address 30-day supplements (21 CFR 814.39(e)).  
However, FDA has chosen not to include 30-day supplements within the scope of the 
guidance document, in part, because we have not identified cases for which this provision 
can be effectively applied.  
 
  Industry requested the addition of examples to illustrate the various supplement types as 
well as periodic reports.  While industry provided a number of examples, many such 
examples did not contain sufficient details for inclusion in this guidance document.  
However, examples that provided further clarification on the underlying principles were 
added.  In addition, the periodic report section was significantly increased in detail and 
includes examples.   
III.  General Requirements for When a PMA Supplement is 
Needed  
Examples of the types of modifications that require a PMA supplement (21 CFR 814.39(a)), if 
such changes affect the safety or effectiveness of the device, include, but are not limited to, the 
following:  
  new indications for use of the device;  
  labeling changes;  
  the use of a different facility or establishment to manufacture, process, or package the 
device;  
  changes in sterilization procedures;  
  changes in packaging;  
  changes in the performance or design specifications, circuits, components, ingredients, 
principle of operation, or physical layout of the device; and  
page 3  Contains Nonbinding Recommendations 
  extension of the expiration date of the device based on data obtained under a new or 
revised shelf life testing protocol that has not been approved by FDA.  If FDA has 
approved your protocol, the change should be reported in a periodic report (21 CFR 
814.39(b)).  
 
Under 21 CFR 814.39(f), you may submit, instead of a PMA supplement, a 30-day notice for 
changes to manufacturing procedures or methods of manufacture that affect the safety and 
effectiveness of your device.  We recommend that you carefully assess whether a PMA 
supplement (21 CFR 814.39(a)) or a 30-day notice (21 CFR 814.39(f)) is appropriate for any 
modification you plan to undertake.  The Quality System (QS) regulation (21 CFR Part 820) 
requires that you have in place a system to document and assess design changes (21 CFR 
820.30).  Part of the assessment for all changes should include a risk analysis and validation (or, 
where appropriate, verification) of the changes to the design or manufacturing process and 
subsequent assessment of the need for regulatory submission. (More information regarding 30-
day notices is provided in Section F of this guidance document.) 
IV.  Determining the Type of PMA Submission 
A primary indicator of what type of PMA submission is needed is the nature of the data, if any, 
that is needed to demonstrate the safety and effectiveness of the modified device.  Each of the 
following sections describes one of the various types of PMA submissions that may be submitted 
to FDA (traditional PMA, a panel-track supplement, a 180-day supplement, a real-time 
supplement, a Special PMA Supplement  Changes Being Effected, 30-day notice, and 
manufacturing site change supplement).  For each type of PMA submission, we discuss the kinds 
of changes we would consider to be appropriate for the type of submission, the general nature of 
test data we believe are needed to support the safety and effectiveness of such changes, and 
criteria we may use when determining whether that type of submission should be submitted.   
 
We also provide, in each section, examples of device modifications submitted to CDRH/Office 
of Device Evaluation (ODE), CDRH/Office of In Vitro Diagnostic Device Evaluation and Safety 
(OIVD), and CBER to illustrate what we believe are appropriate submissions for the type of 
PMA submission discussed in that section.  For each example, we provide the specific changes 
that were made to the approved device, the impact that changes had on the intended patients or 
on the use of the device, and the test data that FDA believes are needed to demonstrate that the 
modified device remains safe and effective.  
 
The examples below illustrate how FDA determines which particular supplement type is 
warranted.  These examples are straightforward in nature to demonstrate the underlying 
principles.  We expect that there may be more complex situations.  If you need additional input 
from FDA to determine the appropriate supplement type, please contact the appropriate review 
branch or division.   
 
Figure 1 at the end of this guidance document illustrates the steps we recommend you follow in 
selecting the appropriate regulatory path for a modification to your PMA device. 
 
page 4  Contains Nonbinding Recommendations 
A.  When to Submit a Traditional PMA 
 
In general, a traditional PMA (rather than a PMA supplement) is appropriate when the 
modifications you make to your approved PMA device result in a new device.  We would 
consider a new device to be one where a modification results in a device design so different from 
the original version that the preclinical3 (analytical for in vitro diagnostics (IVDs)) and clinical 
data4 you previously submitted on your original device are not applicable (i.e., not supportive) 
for the specific change in demonstrating a reasonable assurance of the safety and effectiveness of 
the modified device.  
 
In deciding whether to submit a supplement to your approved traditional PMA or to submit a 
new traditional PMA5 for a modified device, we recommend you first ascertain whether, and to 
what extent, you can rely on the preclinical testing and clinical data submitted in your traditional 
PMA to support the safety and effectiveness of your modified device.  If you need to conduct 
both new preclinical testing and new clinical testing to demonstrate reasonable assurance of 
safety and effectiveness of the modified device, you should assume that this is a new device that 
will require a submission of a new traditional PMA.6 
 
The examples below illustrate when FDA has considered a traditional PMA to be appropriate for 
a device modification based on the types of changes made and the testing that was necessary to 
demonstrate a reasonable assurance of safety and effectiveness.  Each example describes a 
device reviewed in ODE, unless indicated as reviewed in OIVD or CBER. 
 
A1.  Modified Device for a New Indication for Use 
 
FDA approved a PMA for the TransMyocardial Revascularization (TMR) holmium laser for 
surgical treatment of stable patients with angina that is refractory to medical treatment and not 
amenable to direct coronary revascularization.  In this procedure, the chest is opened by surgical 
incision.  Once the heart is exposed, the surgeon places the end of a fiber light guide onto the 
surface of the epicardium and the laser is activated making a hole through the ventricular wall, 
penetrating entirely through the wall into the ventricular cavity.  This is repeated at several 
locations in the region to be treated. 
 
The PMA applicant modified its laser system by incorporating it into a fiber optic guide to make 
it suitable for percutaneous use.  The PMA applicant also modified the indication for use to 
                                                 
3 For purposes of this guidance document, the term preclinical testing refers to non-clinical testing that 
is used to characterize a device (e.g., animal, bench, biocompatibility, electrical safety, software, 
reproducibility, reliability, accuracy, limit of detection, analytical testing).  
4 For purposes of this guidance document, the term clinical data refers to data derived from a study 
using a patient population with a defined clinical condition to determine the safety and effectiveness of 
the device, including clinical performance characteristics (e.g., clinical specificity, clinical sensitivity).  
Clinical data are not limited to data obtained from an investigational device exemption (IDE) study and 
could include foreign data and literature. 
5 In lieu of a traditional PMA, you may submit a modular PMA. The criteria and process for the modular 
review program are discussed in Premarket Approval Application Modular Review Program 
available at http://www.fda.gov/cdrh/mdufma/guidance/835.html. 
6 For the purposes of this guidance document, new preclinical or clinical data are those collected in 
accordance with an existing or different protocol.   
page 5  Contains Nonbinding Recommendations 
include percutaneous myocardial revascularization (PMR), a non-surgical procedure.  In PMR, 
the surgeon percutaneously places a catheter containing a fiber optic light guide into the left 
ventricle and uses the laser to make several gouges in the endocardium (inside) ventricular wall. 
 
The TMR device creates a hole that penetrates the inside ventricular wall and the PMR device 
creates a gouge that scoops out tissue, but does not penetrate through the ventricular wall (i.e., 
the injury to the myocardial tissue is different).  To assess the impact of this change, new 
preclinical testing was necessary to demonstrate that the performance of the device, such as 
maneuverability, and reliable deployment and retraction, were adequate for percutaneous use.  
New clinical data were also necessary because of the possibility of differences in the clinical 
outcome that could result from the differences in the indication for use of the devices (TMR vs. 
PMR), as well as to assess the difference in risk between an open surgical procedure and a 
percutaneous procedure. 
 
Because new preclinical and clinical data were necessary to demonstrate a reasonable assurance 
of safety and effectiveness for the modification, FDA determined that the changes resulted in a 
new device and as such, a submission of a traditional PMA was appropriate for this modification.  
 
A2.   Modified Device with New Clinical Effects 
 
FDA approved a PMA for an implantable cardiac pacemaker system consisting of a pulse 
generator and a lead.  The system is indicated for patients who have bradyarrhythmias or other 
cardiac conduction abnormalities.  The PMA applicant modified the lead by adding a steroid 
eluting piece to the distal lead tip to reduce the inflammatory process (where the lead comes in 
contact with the endocardial tissue) and the impedance between the lead and the tissue.  As a 
result, the amount of energy (the stimulation threshold) needed to achieve heart pacing was 
reduced, and the battery life was improved.  The indication for use for the modified device 
remained the same as the original device. 
 
The modified lead design raised questions related to device performance such as longer battery 
life and lower stimulation threshold, as well as questions of clinical safety and effectiveness.  To 
adequately assess these changes, it was necessary for the PMA applicant to conduct new 
preclinical testing to characterize the electrical performance and biocompatibility of the modified 
lead, as well as animal studies to demonstrate the in vivo effect of the steroid on pacing 
stimulation thresholds.  New clinical data were also needed to demonstrate that the steroid-
eluting lead remained as safe and effective as the approved non-steroid lead.  Because new 
preclinical and clinical data were needed to demonstrate a reasonable assurance of safety and 
effectiveness of the modified design, FDA determined that this change resulted in a new device 
and as such, a submission of a traditional PMA was appropriate for this modification.  
 
A3. Modified Analyte and Indication/Patient Population (OIVD)  
 
FDA approved a PMA for an in vitro diagnostic immunoassay for the detection of total prostate-
specific antigen (total PSA) in serum to aid in detection of prostate cancer in conjunction with 
the digital rectal exam (DRE).  Free prostate-specific antigen (free PSA) is a component of the 
total PSA.  The PMA applicant modified the device to detect free PSA in serum, which was 
considered a new analyte, and added a new indication, to distinguish prostate cancer from benign 
prostate disease.  The PMA applicant also intended that the device be used in a new patient 
population with defined total PSA levels and specific DRE characteristics.  Consequently, the 
page 6  Contains Nonbinding Recommendations 
original preclinical and clinical data were no longer adequate to support a finding of safety and 
effectiveness of the modified device.  The analytical performance characteristics, (e.g., precision, 
reproducibility, and sensitivity) of the two assays differ.  In addition, the clinical performance 
characteristics (e.g., clinical sensitivity and specificity) also differ. 
 
To demonstrate reasonable assurance of the safety and effectiveness of the modified device in 
the new patient population, new analytical (i.e., preclinical testing) and clinical data were 
necessary.  Therefore, FDA determined that a traditional PMA was appropriate for this 
modification.  
 
A4.  Significant Modification of Technology (OIVD)  
 
FDA approved a PMA for the in vitro detection of bladder cancer in urine that used microwell 
enzyme immunoassay (EIA) technology (i.e., the reagents and analyte react in solution).  The 
PMA applicant modified the technology to a membrane-bound EIA (i.e., the reagents are bound 
to a membrane and the urine specimen is applied to the membrane).  Because of the differences 
in the two technologies, the analytical performance characteristics (e.g., precision, 
reproducibility, and sensitivity) and the clinical performance characteristics (e.g., clinical 
sensitivity and specificity) of the two assays differ.  Therefore, to demonstrate a reasonable 
assurance of safety and effectiveness for this new technology, new analytical and clinical data 
were necessary.  Therefore, FDA determined that the submission of a traditional PMA was 
appropriate for this modification.  
 
7
B.  When to Submit a Panel-Track Supplement   
 
The FDA regulation 21 CFR 814.39(c) refers to any type of PMA supplement.  However, 
specific types of PMA supplements are defined under the Act.  The term "panel-track 
supplement" is defined in section 737(4)(B) of the Act (21 U.S.C. 379i(4)(B)), (added by 
MDUFMA, as amended by the Medical Devices Technical Corrections Act (MDTCA) (Pub. L. 
108-214 (2004))), as: 
a supplement to an approved premarket application or premarket report under section 515 
that requests a significant change in design or performance of the device, or a new indication 
for use of the device, and for which substantial clinical8 data are necessary to provide a 
reasonable assurance of safety and effectiveness.  
 
We consider panel-track supplements to be the most appropriate supplement type for changes in 
the indication for use requiring substantial clinical data (i.e., new clinical data), with or without 
limited new preclinical testing.  A change in the indication for use may incorporate a change to 
                                                 
7 21 CFR 814.44 describes when a Panel meeting may be held.  Not all panel-track supplements require a 
Panel meeting or input.  For more guidance on Panel meetings, please use our online search feature for 
CDRH guidance documents at http://www.fda.gov/cdrh/guidance.html. 
8 For the purposes of this guidance only, FDA considers the term "substantial clinical data" in the 
definition of panel-track supplement to refer to a new clinical data set that is intended to provide valid 
scientific evidence necessary to support the safety and effectiveness of the modified device (i.e., the 
clinical data provided in support of the original device approval is no longer applicable in supporting the 
approval of the modified device).  Human factors data are not considered substantial clinical data because 
they are specifically focused on evaluating the interaction between the device and the user and not to 
answer whether the device does what it is intended to do.  
page 7  Contains Nonbinding Recommendations 
the intended patient population, disease state, or to other clinical aspects of the device use, such 
as duration of use, anatomical site, or surgical procedure.  Changes in these clinical aspects 
would generally require significant labeling changes for which new clinical data are generally 
needed to support those changes.  We also consider a panel-track supplement to be the most 
appropriate supplement type for a change to, or removal of, a contraindication.9 
 
A panel-track supplement, therefore, should be submitted for a change in indication for use or a 
change to (or removal of) a contraindication of the device because: 
  substantial clinical data (i.e., new clinical data) are necessary to provide reasonable 
assurance of safety and effectiveness for that change; and  
  indication or contraindication changes generally either do not require or require very 
limited new preclinical testing (i.e., all or most of the preclinical data previously 
submitted and reviewed in the traditional PMA are still applicable for the change in 
indication).  
 
The following examples illustrate when FDA has considered a panel-track supplement to be 
appropriate for a modification based on the types of changes made and the testing that was 
necessary to demonstrate a reasonable assurance of safety and effectiveness. 
 
B1.  Change in Indication for Use - Different Patient Population 
 
FDA approved a PMA for a ventricular assist device (VAD) indicated for the temporary, 
mechanical circulatory support of nonreversible left ventricular failure in patients awaiting 
cardiac transplant (as a temporary bridge to transplantation).  The PMA applicant modified the 
indication for use to include patients not eligible for cardiac transplantation (i.e., destination 
therapy).  No modifications were made to the device itself.  In destination therapy, the VAD is 
permanently implanted. 
 
There are significant differences in the clinical conditions of these two patient populations.  For 
example, destination therapy patients are precluded from a transplant because they do not meet 
the age requirement or they have one or more co-morbid conditions (e.g., diabetes).  The PMA 
applicant conducted clinical studies for the proposed change to the indication for use to 
demonstrate safety and effectiveness in this new patient population. 
 
In addition, destination therapy patients will use the device for a much longer period (years) 
compared to patients who use it as a temporary bridge to transplantation where the device may 
be used only for a few weeks or months, and rarely longer than 1 year.  New clinical data were 
needed to demonstrate reasonable assurance of safety and effectiveness for longer term 
implantation.  Although the device itself was not modified, the new conditions of use raise a new 
preclinical concern regarding device reliability.  Therefore, the reliability test that was conducted 
for the original PMA had to be repeated to support the safety and effectiveness for use in the new 
patient population.  The test conditions were modified to reflect the new clinical use conditions.  
 
                                                 
9 For example, the original contraindication specified all pediatric patients, but the applicant wants to 
modify the contraindication so that only neonate patients are contraindicated. 
page 8  Contains Nonbinding Recommendations 
FDA determined that a panel-track supplement was appropriate for this modification because 
new clinical data were needed to support the safety and effectiveness of the device and, although 
some additional preclinical testing was needed to address the new conditions of use, the full 
battery of preclinical testing was not needed because the device itself was not modified.  
 
B2.  Change in Indication for Use - Different Patient Population 
 
FDA approved a PMA for a urethral stent indicated to relieve urinary obstruction secondary to 
recurrent bulbar urethral strictures.  The PMA applicant requested FDAs approval to market the 
identical device for the treatment of urinary obstruction secondary to benign prostate hyperplasia 
(BPH).  In the original indication for urethral strictures, the device is inserted into the bulbar 
urethra in order to improve urine flow and prevent recurrence of strictures.  In the new indication 
for BPH, the urethral stent compresses the enlarged prostatic tissue widening the urinary tract 
within the prostatic urethra in order to relieve urinary symptoms.  The use of the permanent stent 
in this new urethral location (i.e., the prostate) introduces different safety concerns as compared 
to the traditional indication because the new target patient population has different risks related 
to age, overall health and anatomical location where the device is to be used.  Strictures typically 
occur in younger healthy men, whereas patients with BPH are generally men greater than 60 
years of age and who may have more health problems.  The different anatomical location also 
presents new risks (e.g., adverse tissue response due to the presence of the stent in hyperplastic 
tissue, ejaculatory impairment, and associated reduced fertility).  
 
Because of the clinical differences related to age, overall health, and anatomical location where 
the device is to be used between the new and traditional patient populations, new clinical data 
were needed to support the safety and effectiveness of the new indication for use.  No new 
preclinical data were needed because the device was not modified and the conditions of use (e.g., 
implant duration) were similar.  Therefore, FDA determined that a panel-track supplement was 
appropriate for this modification.  
 
B3.  Change in Indication for Use - Different Patient Population 
 
FDA approved a PMA for a high frequency oscillatory ventilator (HFOV) indicated for 
ventilatory support and treatment of respiratory failure and barotrauma in low birth weight 
neonates.  The PMA applicant modified the indication to include ventilatory support and 
treatment in adult patients with (adult) respiratory distress syndrome.  The device itself was not 
modified.  The patients in the original PMA consisted of infants with respiratory failure 
associated with lung immaturity, or other causes of respiratory failure in newborns.  The new 
indication was for adults with adult respiratory distress syndrome, which is a condition 
associated with trauma and sepsis.  Although both groups suffered from respiratory failure, the 
underlying lung pathology, the cause of the lung pathology, and the potential clinical outcomes 
for the two populations are different.  Because of these clinical differences between these two 
patient populations, new clinical data were needed to evaluate the safety and effectiveness of the 
device in the new population.  Since the device and the conditions of use remained the same, no 
new preclinical testing was necessary.  Therefore, FDA determined that a panel-track supplement 
was appropriate for this modification. 
 
page 9  Contains Nonbinding Recommendations 
B4.  Change in Indication for Use - Different Patient Population (OIVD) 
 
FDA approved a PMA for a glucose monitoring system for detecting trends and tracking patterns 
in glucose levels in adults with diabetes.  The PMA applicant modified the indication for use to 
add pediatric patients.  The differences between adults and children, in body surface area, daily 
activities, physiology, and underlying disease may affect clinical outcomes in the two patient 
populations.  For this reason, it was necessary to conduct new clinical testing to demonstrate that 
the device provided reasonable assurance of safety and effectiveness for the new pediatric patient 
population.  Since the device and the conditions of use remained the same, no new preclinical 
testing was necessary.  Therefore, FDA determined that the submission of a new panel-track 
supplement was appropriate for this modification. 
 
B5.  Change in Indication for Use - Different Surgical Procedure 
 
FDA approved a PMA for an excimer laser system for photorefractive keratectomy (PRK) for 
the reduction or elimination of myopia (nearsightedness).  The PMA applicant modified the 
indication to add laser assisted in-situ keratomileusis (LASIK), a different procedure, for the 
reduction or elimination of myopia using the identical laser system.  PRK uses laser ablation on 
the surface of the cornea to reshape it, whereas LASIK involves cutting a flap in the cornea and 
using laser ablation underneath the flap.  The new indication involves a more invasive procedure 
with different risks associated with the creation, replacement, and maintenance of the flap.   
 
There were also new risks and clinical effectiveness concerns associated with the intrastomal 
ablation used in the new indication.  These concerns include a different healing response, longer 
recovery times, different ablation profiles and deeper ablation into the cornea, potentially leaving 
it thinner, which may affect the physical integrity of the eye.  Therefore, new clinical data were 
needed to demonstrate reasonable assurance of safety and effectiveness for the new indication 
for use.  No preclinical testing was necessary because the device was not modified and the 
conditions of use remained the same.  Therefore, FDA determined that the submission of a 
panel-track supplement was appropriate for this modification.  
 
B6.  Change in Indication for Use - Different Conditions of Use 
 
FDA approved a PMA for a soft silicone hydrogel extended wear (1 to 7 days) contact lens 
indicated for the correction of myopia or hyperopia.  The PMA applicant modified the indication 
to include extended wear up to 30 days.  The device remained unchanged and the intended 
patient population remained the same; however, the conditions of use changed.  The extended 
time of wear raised new safety concerns including increased risk of ocular adverse events, such 
as corneal microbial keratitis, and corneal infiltrated lesions.  To evaluate the risks associated 
with extended wear from 7 days to up to 30 days, substantial clinical data were necessary to 
demonstrate a reasonable assurance of safety and effectiveness.  No new preclinical testing was 
needed because the testing previously performed adequately addressed the new conditions of 
use.  Therefore, FDA determined that the submission of a panel-track supplement was 
appropriate for this modification. 
 
page 10  Contains Nonbinding Recommendations 
B7.  Change in Indication for Use - Different Specimen (Sample) Type (CBER) 
 
FDA approved a PMA for an HIV diagnostic (whole blood specimens).  The PMA applicant 
modified the indication to oral fluid specimens without any modification to the device itself, i.e., 
a new sample type only.  The characteristics of oral fluid specimens are different from that of 
whole blood specimens.  Therefore, clinical data were necessary to determine the safety and 
effectiveness of the device.  However, while the specimen matrix changed, the actual analyte 
(HIV antibodies) did not.  In this case, limited analytical studies were sufficient to examine 
specimen matrix effects.  A panel-track supplement would be appropriate for this modification 
because only new clinical data and limited additional analytical data would be needed to support 
the safety and effectiveness of the device.  
 
B8.  Change in Indication for Use - Different Physiological Location 
 
FDA approved a PMA for a prosthetic heart valve for use in the aortic position.  The PMA 
applicant modified the indication to include the mitral position.  No changes were made to the 
device itself.  In the mitral position, the valve is subjected to different physiological conditions, 
such as valve closing pressures and flow rates, from the aortic position.  These conditions can 
affect the performance of the valve by affecting the hemodynamics (e.g., forward flow pressure 
drop (gradient) and regurgitation).  These conditions can also affect the complication rates for 
thrombosis, thromboembolism, and hemolysis.  The physiological and potential performance 
differences between the two positions may significantly impact clinical outcome.  Therefore, 
new clinical data were needed to ensure that the heart valve remained safe and effective when 
implanted in the new location.  Additional preclinical testing was not needed because the test 
data provided in the original PMA to support the valve for use in the aortic position were 
sufficient to support the valve for use in the mitral position.  Therefore, FDA determined that the 
submission of a panel-track supplement was appropriate for this change. 
 
C.  When to Submit a 180-Day Supplement  
 
According to section 737(4)(C) of the Act (21 U.S.C. 379i(4)(C)), "180-day supplement" is 
defined as: 
a supplement to an approved premarket application or premarket report under section 515 
that is not a panel-track supplement and requests a significant change in components, 
materials, design, specification, software, color additives, or labeling. 
 
Submission of a 180-day supplement is required for certain types of significant changes to the 
approved device that affect safety or effectiveness of the device.  In general, for a change to be 
submitted as a 180-day supplement, the clinical data provided in support of the traditional device 
approval should still be applicable in supporting the approval of the modified device.   
 
In most cases, for such modifications, only new preclinical testing is needed to demonstrate 
reasonable assurance of safety and effectiveness of the modified device.  In some instances, 
however, additional limited confirmatory clinical data may be necessary to provide a bridge 
between the clinical data set for the original device and the expected clinical performance of the 
modified device.  Confirmatory clinical data typically involve a limited number of patients, 
shorter study duration, and/or a subset of endpoints as compared to the clinical data set for a 
traditional PMA.  In these situations, FDA believes that a 180-day supplement, rather than a 
page 11  Contains Nonbinding Recommendations 
panel-track supplement, is appropriate because of the limited nature of the supplementary 
clinical data.   
 
The applicant should submit a 180-day supplement for certain significant changes, including the 
following changes:  
  the principle of operation;  
  the control mechanism;  
  the device design or performance;  
  the labeling; and  
  new testing requirements or acceptance criteria.  
 
Below are examples illustrating when FDA has considered a 180-day supplement to be 
appropriate for a device modification, based on the types of changes made and the testing that 
was necessary to demonstrate a reasonable assurance of safety and effectiveness.  
 
C1.  Design Change   
 
FDA approved a ventricular assist device (VAD) intended as temporary mechanical circulatory 
support for patients awaiting a cardiac transplant.  The applicant changed the design of the 
percutaneous ventricular lead in order to improve the interaction between the lead and the patient 
by making the lead more flexible and smaller in diameter.  This design change was intended to 
reduce the physical damage to the lead at the site where it exits the patient.  No change was made 
to the indication for use and the patient population.  To demonstrate that the modified device 
remained safe and effective, only mechanical tests, such as pull/bend/twist testing were needed.  
Since FDA determined that this change could be evaluated with mechanical tests and no new 
clinical data were needed, the submission of a 180-day supplement was appropriate for this 
change.  
 
C2.  New Device Feature  
 
FDA approved a PMA for an excimer laser system indicated for wavefront-guided LASIK to 
reduce or eliminate myopia and astigmatism.  The PMA applicant added an iris identification 
and registration system to the device to control for torsional movement of the eye.  No changes 
were made to the indication for use, the intended patient population, the ablation characteristics 
of the excimer laser, or the intended clinical outcome.  For this change, FDA determined that 
preclinical testing such as engineering tests, visual optics evaluation, and software validation 
along with the revised labeling were adequate to demonstrate reasonable assurance of the safety 
and effectiveness of the modification.  Therefore, FDA determined that the submission of a 180-
day supplement was appropriate. 
 
page 12  Contains Nonbinding Recommendations 
C3.  Modified Chemical Formulation 
 
FDA approved a PMA for a hydrophilic contact lens.  The PMA applicant modified the chemical 
formulation of the lens by adding an ultraviolet (UV) light blocking material and also modified 
the manufacturing process.  For this change, FDA determined that preclinical testing to assess 
the modified manufacturing processes, biocompatibility, shelf-life, UV light transmission, and 
materials characterization, including an assessment of leachability, was sufficient to demonstrate 
a reasonable assurance of the safety and effectiveness of this modification.  Therefore, FDA 
determined that the submission of a 180-day supplement was appropriate for this change. 
 
C4.  Hardware and Software Modifications  
 
FDA approved a PMA for a transurethral microwave system that is indicated to relieve 
symptoms associated with benign prostatic hyperplasia (BPH).  The PMA applicant modified 
several critical components of the system, including the computer motherboard, computer 
operating system, and software for the user interface screens.  To demonstrate that the modified 
device met the specifications of the original device (and remained safe and effective), 
comparative bench testing was needed, including software, electromagnetic compatibility 
(EMC), electrical safety, shock, vibration, and functional testing.  The treatment parameters and 
algorithm remained unchanged such that clinical data were not needed to evaluate the 
performance of the modified device.  Therefore, FDA determined that the submission of a 180-
day supplement was appropriate for this change. 
 
C5.  New Analyzer  Assay Unchanged (OIVD)  
 
FDA approved a PMA for a total prostate-specific antigen (total PSA) immunoassay using an 
automated analyzer.  The PMA applicant developed a new automated analyzer to perform the 
total PSA assay.  The indications for use and the technology of the total PSA assay remained 
unchanged, and no new clinical data were warranted.  The PMA applicant conducted new 
analytical performance testing at internal and external sites to demonstrate that the new analyzer 
does not alter the performance of the assay.  Therefore, FDA determined that a submission of a 
180-day supplement was appropriate for this change. 
 
C6.  Design and Software Modification 
 
FDA approved a PMA for a bone growth stimulator for use as an adjunct to primary lumbar 
spinal fusion surgery.  The PMA applicant changed the type of battery used and modified the 
LCD display, which required modifications to the housing, the printed circuit board, and the 
software.  Because these changes impacted the electrical characteristics of the device, it was 
necessary to conduct preclinical testing, including EMC, electrical safety, shock and vibration, 
battery life, software and functionality to verify that the modified device operated within the 
original devices specifications.  Clinical data were not necessary to support the safety and 
effectiveness of the modified device.  Therefore, FDA determined that the submission of a 180-
day supplement was appropriate for this change. 
 
page 13  Contains Nonbinding Recommendations 
C7.  Modified Physical Characteristics 
 
FDA approved a PMA for an endovascular stent graft system for the treatment of infra- renal 
abdominal aortic or aorto-iliac vessels.  The PMA applicant modified the physical characteristics 
of the material used in the manufacture of the stent graft.  The modified material had the same 
chemical composition as the original material; however, the weaving process was different.  The 
new graft was woven into a denser weave configuration, which was intended to enhance the 
robustness of the graft material.  Bench testing (e.g., dimension verification, joint strength, burst 
strength, tensile strength, fatigue, and water permeability) was needed to demonstrate that the 
new weaving process did not adversely affect the physical performance properties of the device.  
Animal testing was also needed to compare the vessel healing and patency of the new material 
with the material used in the original device.  Preclinical testing, including animal testing, was 
adequate to demonstrate a reasonable assurance of the safety and effectiveness of the device.  
Therefore, FDA determined that the submission of a 180-day supplement was appropriate for 
this change. 
 
C8.  New Device Feature 
 
FDA approved a PMA for a cardiac radiofrequency (RF) ablation system.  The PMA applicant 
modified the system by adding a feature that allows the physician to visualize catheter navigation 
during the procedure.  The modification did not change the delivery of RF energy to the tissue, 
and therefore, the clinical performance of the device was not impacted by this modification. 
Consequently, clinical data were not necessary to support this change.  However, verification and 
validation testing were needed to assess the performance of the modified device.  This 
assessment consisted of bench testing including functionality, EMC, lesion qualification, 
compatibility testing (between the generator, which has the new feature, and the approved 
catheters) and animal testing.  Bench testing and animal testing were adequate to demonstrate a 
reasonable assurance of safety and effectiveness of the modified device.  Therefore, FDA 
determined that the submission of a 180-day supplement was appropriate for this change.  
 
C9.  Design Change  
 
FDA approved a PMA for a pneumatic ventricular assist device (VAD) intended as temporary 
mechanical circulatory support for patients with heart failure awaiting a cardiac transplant.  The 
PMA applicant modified the system from a pneumatically driven system to an electrically driven 
one by replacing the original controller with a new device controller.  The PMA applicant was 
asked to conduct bench testing to demonstrate the similarities and differences between the 
performance characteristics (e.g., flow pattern, pressures, alarm functions) of the new controller 
and the original controller.  A limited confirmatory clinical study was also needed to confirm that 
the modification did not raise new safety and effectiveness questions.  The new bench testing and 
the limited confirmatory clinical study of the modified device, along with the original clinical 
data set, were sufficient to demonstrate reasonable assurance of safety and effectiveness of the 
modified device.  Therefore, FDA determined that the submission of a 180-day supplement was 
appropriate for this change.  
 
page 14  Contains Nonbinding Recommendations 
C10.  New Specimen (Sample) Type (CBER)  
 
FDA approved a PMA for an HIV diagnostic intended for fingerstick, whole blood specimens. 
The PMA applicant modified the device for use with venipuncture, whole blood specimens. 
Specimen characteristics of venipuncture blood and fingerstick blood are not significantly 
different.  The PMA applicant conducted analytical (e.g., reproducibility) and limited clinical 
data (e.g., clinical sensitivity and specificity) to confirm adequate performance of the 
modification to demonstrate reasonable assurance of safety and effectiveness for the 
modification.  The clinical data necessary to support this modification was limited.  Therefore, 
FDA determined that the submission of a 180-day supplement was appropriate for the change. 
 
D.  When to Submit a Real-Time Supplement  
 
According to section 737(4)(D) of the Act (21 U.S.C. 379i(4)(D)) (added by MDUFMA, as 
amended by MDTCA), a "real-time 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 has requested and the 
agency has granted a meeting or similar forum to jointly review and determine the status of 
the supplement.  
 
For additional information about the type of changes that qualify for a real-time supplement, as 
well as the process for the real-time review program, please refer to the guidance document, 
Real-Time Premarket Approval Application (PMA) Supplements.10  
 
The following examples illustrate when FDA has considered a real-time PMA supplement to be 
appropriate, based on the types of changes made, the testing that was necessary to demonstrate a 
reasonable assurance of safety and effectiveness, and other applicable criteria.  Please note that 
FDA is not aware of a situation in which a real-time supplement would be appropriate for 
changes that affect an indication for use; therefore, there are no discussions of changes to 
indications in the examples below. 
 
D1.  Minor Modification to Correct Battery Failures 
 
The PMA applicant made minor modifications to the circuitry associated with the battery 
supervisor chip in the portable driver used with its ventricular assist device (VAD). The 
modification was intended to correct a battery failure problem.  The bench testing was conducted 
using a test method that was previously accepted by FDA and was sufficient to support the 
change to the device.  In addition, the supporting test data for this change were within the single 
scientific discipline of electrical engineering.  Therefore, FDA determined that a real-time 
supplement was appropriate for this change.  
 
                                                 
10 Refer to guidance at http://www.fda.gov/cdrh/ode/guidance/673.pdf. 
page 15  Contains Nonbinding Recommendations 
D2.  Alternative Sterilization Method 
 
The PMA applicant employed an alternative sterilization method for its cardiac ablation catheter. 
The sterilization method used was a method that was previously reviewed and approved by FDA 
for this type of device.  Validation testing alone was sufficient to ensure the alternative method 
adequately sterilized the ablation catheter.  In addition, the supporting test data for this change 
were within the single scientific discipline of sterilization.  Therefore, FDA determined that a 
real-time supplement was appropriate for this change.11   
 
D3.  Storage Temperature Change 
 
The PMA applicant increased the upper limit for the storage temperature from 25C to 30C for 
its bone graft (i.e., recombinant human bone morphogenetic protein).  This is a minor change to 
the storage condition and device labeling.  Stability data at the new higher temperature was 
sufficient to support the change and was conducted using an accepted test method.  In addition, 
the supporting data for this change were within the single scientific discipline of materials 
engineering.  Therefore, FDA determined that a real-time supplement was appropriate for this 
change.  
 
D4.  Extended Shelf Life 
 
The PMA applicant modified the labeling of its injectable gel for facial wrinkles and folds to 
extend the shelf life from 24 months to 36 months.  Accelerated and long-term testing was 
performed to evaluate the physical, chemical, and biological stability of the device during 
storage.  This is a minor change to the labeling and the stability studies are well understood and 
have a well defined protocol.  In addition, the supporting data for this change were within the 
single scientific discipline of microbiology.  Therefore, FDA determined that a real-time 
supplement was appropriate for this change.12  
 
D5.  Component Offered as Stand Alone System 
 
The PMA applicant proposed to modify an excimer laser system by offering the wavefront 
system and the surgery planning software included in the original system as a stand-alone system 
to allow the surgeon to prepare for surgical cases in advance.  There were no actual changes to 
the wavefront system or the surgery planning software, and both were included in the original 
PMA.  Verification and validation of data transfer from the excimer laser system to the stand-
alone system was sufficient to support this minor change.  In addition, the supporting data for 
this change were within the single scientific discipline of electrical engineering.  Therefore, FDA 
determined that a real-time supplement was appropriate for this change. 
 
                                                 
11 Changes in sterilization method (e.g., dry heat sterilization to gamma radiation) should not be reviewed 
under the 30-day notice program because a change in sterilization method could impact the device 
specifications and/or performance.   
12 If a shelf life protocol was approved for extended shelf life testing in an approval order for a traditional 
PMA (or an approval order for a subsequent supplement), then the shelf life testing results can be reported 
as part of the annual report. 
page 16  Contains Nonbinding Recommendations 
D6.  Alternate Wet Shipping Solution 
 
The PMA applicant proposed to use an alternate wet shipping solution for its permeable 
extended wear contact lenses.  This solution was one that was previously approved by the FDA 
for other contact lenses.  The concerns with this type of change included biocompatibility of the 
new solution, compatibility with the contact lens, adequate preservative efficacy (i.e., ability to 
maintain low bioburden), and adequate labeling (identification of solution and preservative).  
The supporting data for this change were within the single scientific discipline of microbiology.  
Therefore, FDA determined that a real-time supplement was appropriate for this change. 
 
D7.  Modified Bonding Method 
 
The PMA applicant modified the method of bonding the retention balloon to the catheter in its 
transurethral microwave system to enhance balloon reliability.  This was a minor change, 
adequately supported by bench testing using the test method previously described in the original 
approved PMA.  In addition, the supporting data for this change were within the single scientific 
discipline of mechanical engineering.  (Note that it was also determined that this particular 
change in bonding method could impact the device specifications and/or performance.13)  
Therefore, FDA determined that a real-time supplement was appropriate for this change. 
 
E.  When to Submit a Special PMA Supplement  Changes Being 
14
Effected   
 
Sections 21 CFR 814.39(d)(1) and (d)(2) provide that certain labeling and manufacturing 
changes that enhance the safety of the device or the safety in the use of the device may be 
submitted as a supplement marked Special PMA Supplement  Changes Being Effected.  The 
Special PMA Supplement is a narrow exception to the general rule that prior FDA approval of 
changes to a PMA, including the labeling for a device, is a condition of lawful distribution and, 
therefore, may only be utilized when (1) the applicant has newly acquired safety-related 
information; (2) the information in question was not previously submitted to the FDA; and (3) 
the information involves labeling changes that add or strengthen a contraindication, warning, 
precaution, or information about an adverse reaction for which there is reasonable evidence of a 
causal association. .  
 
Prior to approving a PMA, the FDA undertakes a detailed review of the proposed labeling, 
allowing only those safety-related warnings for which there is reasonable evidence of a causal 
association.  Allowing the applicant to add a safety-related warning using a Special PMA 
Supplement based on information that was known to the FDA during the rigorous PMA review 
process would undermine that important process.  For the same reason, the applicant may not 
add a safety-related warning to avoid potential liability under state tort law if there is not 
reasonable evidence of a causal association for the new warning.  Instead, the applicant may 
                                                 
13 If the change in bonding method had no potential impact on the device specifications and/or 
performance, then this type of change may be appropriate for review under the 30-day notice program. 
14 FDA recently published a final rule entitled, Supplemental Applications Proposing Labeling Changes 
for Approved Drugs, Biologics, and Medical Devices (73 Fed. Reg. 49603, August 22, 2008, 
http://www.fda.gov/OHRMS/DOCKETS/98fr/E8-19572.htm).  This final rule, in part,  amends 21 CFR 
 814.3, 814.39(d)(1) and (2).  The recommendations in this guidance are consistent with the final rule. 
page 17  Contains Nonbinding Recommendations 
utilize the limited Special PMA Supplement only when it possesses new information that 
provides a scientifically legitimate foundation for modifying the FDA-approved labeling.   
For these types of changes, the applicant may place the change in effect prior to receipt of a 
written FDA order approving the supplement, provided that the following exist: 
  the PMA supplement and its mailing cover are plainly marked Special PMA Supplement 
 Changes Being Effected;  
  the PMA supplement provides a full explanation of the basis for the changes;  
  the applicant has received acknowledgement from FDA of receipt of the supplement; and  
  the PMA supplement specifically identifies the date that such changes are being effected.  
 
Although the applicant may place a change into effect prior to the receipt of a written FDA order 
approving the change, any such change should be considered temporary while FDA reviews the 
supplement, including the basis for how the change enhances the safety of the device or the 
safety in the use of the device.  Design changes are not considered appropriate for a Special 
PMA Supplement.  For example, if the applicant attempted to change the design of an 
implantable cardiac device so that it can be more securely held in place inside the patient's chest 
cavity, such a change would be inappropriate for a Special PMA Supplement.  
 
Although the regulation allows both labeling and manufacturing changes that enhance the safety 
of the device or the safety in the use of the device to be submitted as a Special PMA Supplement, 
FDA believes that labeling changes (as described in 21 CFR 814.39(d)(2)) are most appropriate 
for a Special PMA Supplement.  However, changes to the quality control or manufacturing 
process may fall under the scope of this provision.  The manufacturing changes that may be 
reviewed as a Special PMA Supplement are generally those that add a step to the quality control 
or manufacturing processes to enhance safety but not to impact effectiveness.  
 
If the quality control or manufacturing process modification enhances safety and also impacts 
effectiveness, then we believe that change is not appropriate for a Special PMA Supplement and, 
instead, a 30-day notice is more appropriate.  However, a PMA supplement (e.g., real-time 
supplement, 180-day supplement) may be more appropriate if the quality control or 
manufacturing process change impacts the device specifications and/or performance of the 
device. 
 
Below we provide examples to illustrate when FDA has considered a Special PMA Supplement 
to be appropriate, based on the types of labeling and manufacturing changes made.  
 
E1.  New Warning Added 
 
The PMA applicant made a labeling change in the technical manual for its neurological 
implantable programmer, by adding a warning against using the device in the presence of any 
flammable anesthetic mixture in conformance with the FDA-recognized standard (i.e., 
International Electrotechnical Commission (IEC) 60601-1 Medical Electrical Equipment - Part 1: 
General Requirements for Safety).  Because this modification to the warning of the labeling 
enhanced safety with no impact on effectiveness, a Special PMA Supplement was appropriate. 
 
page 18  Contains Nonbinding Recommendations 
E2.  Manufacturing Process Change 
 
The PMA applicant made a modification to its manufacturing process for the source wire 
component of its intravascular brachytherapy system, by adding a secondary wipe station to the 
manufacturing process.  The PMA applicant made this change as a result of detecting incidental 
radioactive contamination during routine cartridge exchanges.  This change was made to provide 
an additional safeguard to ensure effective removal of contaminants from the wire surface prior 
to transfer in a production cartridge.  Because this modification enhanced safety with no impact 
on effectiveness, a Special PMA Supplement was appropriate. 
 
E3.  Improved Instructions 
 
The PMA applicant made a labeling change to its urethral stent to improve the instructions for 
device removal after urothelial coverage.  Because this modification enhanced safety with no 
impact on effectiveness, a Special PMA Supplement was appropriate. 
 
E4.  Additional Inspection Step in the Manufacturing Process 
 
The PMA applicant added an additional incoming inspection step (i.e., measuring the outer 
diameter of the distal end of the stopcock) to the manufacturing process of a duett sealing device 
(sealing femoral arterial puncture site).  The purpose of this step was to ensure that there was a 
tight fit between the two mating parts: the distal end of the stopcock and the proximal end of the 
hub sleeve knob.  This change enhanced the reliability of the catheter by more reliably ensuring a 
proper fit when the user attached these two components together.  Since the change enhanced the 
safety in the use of the device with no impact on effectiveness, a Special PMA Supplement was 
appropriate. 
 
E5.  Additional Inspection Step in the Manufacturing Process 
 
The PMA applicant added an additional inspection step to the manufacturing process for its bone 
growth stimulator as a result of observing an increased frequency of a particular error message.  
A greater than normal air gap between two inductors on one of the circuit boards was the source 
of the error.  The process was modified to assess the air gap between the conductors, thereby 
better ensuring the reliability of the device.  Since the change enhanced the safety of the device 
and did not impact effectiveness, a Special PMA Supplement was appropriate. 
 
F.  When to Submit a 30-Day Notice  
 
Section 515(d) of the Act (21 U.S.C. 360e), as amended by the Food and Drug Administration 
Modernization Act of 1997 (FDAMA)(Pub. L. 105-115), permits a PMA applicant to submit 
written notification to the agency of a modification to the manufacturing procedure or method of 
manufacture affecting the safety and effectiveness of the device rather than submitting such 
change as a PMA supplement.  The applicant may distribute the device 30 days after the date on 
which FDA receives the notice, unless FDA finds such information in the 30-day notice is not 
adequate, notifies the applicant that the submission has been converted to a 135-day supplement 
(21 CFR 814.39(f)), and describes further information or action that is required for acceptance of 
the modification.  For additional information about the type of changes that qualify for a 30-day 
notice and for information on when FDA may convert a 30-day notice to a 135-day supplement, 
page 19  Contains Nonbinding Recommendations 
refer to the guidance document entitled 30-Day Notices and 135-Day PMA Supplements for 
Manufacturing Method or Process Changes.15 
 
Below, we provide examples of the types of changes that FDA has considered to be appropriate 
for the submission of a 30-day notice.  In some cases, the 30-day notice was converted to a 135-
day supplement because the supporting information was inadequate.  For those cases, we have 
included an explanation for the conversion.  
 
F1.  Manual to Automated Process 
 
The PMA applicant has a specified manufacturing process for a cardiac resynchronization 
therapy pacemaker (CRT-P).  As part of its manufacturing process, there is a manual process for 
applying medical adhesive.  The PMA applicant made a change that involved automating the 
process of applying the medical adhesive to the device header and affixing the header to the 
device case.  Adequate information was submitted to support the 30-day notice for the 
manufacturing change. 
 
F2.  Alternate Qualified Supplier of Critical Component (OIVD) 
 
The PMA applicant has a qualified supplier for the manufacture of a critical component used in 
the calibrator of its Hepatitis B surface antigen assay.  The change in manufacturing process 
involved identifying a different qualified supplier for this component that met the same 
specifications.  Adequate information was submitted to support the 30-day notice for the change 
in supplier.  This included, but was not limited to, specifications for the raw material, supplier 
evaluation procedures, and a description of the type and extent of control over the raw 
material/supplier for the old and new material/supplier. 
 
F3.  Alternate Qualified Supplier of Critical Material  
 
The PMA applicant has a qualified supplier for polymethylmethacrylate (PMMA) material, a 
critical material used in the manufacture of a single-piece intra-ocular lens.  The PMA applicant 
submitted a 30-day notice identifying a different qualified supplier for the PMMA material that 
met the same specifications.  This 30-day notice was converted to a 135-day supplement because 
the submission did not contain all the tests necessary to qualify the new supplier, such as optic 
tilt test and axial displacement test.  
 
F4.  In-Process Quality Control Step Change 
 
The PMA applicant has numerous quality control steps for the manufacture of an inflatable 
penile prosthesis.  An in-process quality control monitoring step for endotoxin testing is part of 
the manufacturing process.  The PMA applicant made a change that included moving the in-
process quality control monitoring step for endotoxin to a different location in the process flow.  
The PMA applicant provided adequate documentation in the 30-day notice to support this change 
in the manufacturing process of the prosthesis. 
 
                                                 
15 Refer to the guidance at http://www.fda.gov/cdrh/modact/daypmasp.html. 
page 20  Contains Nonbinding Recommendations 
F5.  Manual to Automated Process Conversion 
 
The PMA applicant submitted a change to the manufacturing process for forming and folding the 
balloon wings of an Over-the-Wire Percutaneous Transluminal Angioplasty (PTCA) catheter 
from a manual process to an automated process.  This 30-day notice was converted to a 135-day 
supplement because the submission did not contain all of the appropriate testing (e.g., balloon 
fatigue test, rated burst pressure test, and validation data) to support the change.  
 
F6.  Modified In-Process Test 
 
The PMA applicant of a vascular closure device submitted a 30-day notice to incorporate an 
alternate backup deployment test methodology in its manufacturing process.  The notice was 
converted to a 135-day supplement because the test methods and acceptance criteria used to 
support this change were either not clearly explained or not provided in the submission. 
 
F7.  Modified Sterilization Process Parameters 
 
The PMA applicant submitted a change to allow sterile product release based on demonstration 
of conformity to pre-defined sterilization parameters (parametric release) rather than release 
based on demonstrating no growth of biological indicators (conventional release). The PMA 
applicant provided adequate documentation in the 30-day notice to support this change in the 
sterilization process. 
 
G.  When to Submit a Manufacturing Site Change Supplement 
 
After approval of a PMA, an applicant shall submit a PMA supplement for review and approval 
by FDA before making a change that affects the safety or effectiveness of the device, including a 
change that uses a different facility or establishment to manufacture, process, or package the 
device.16  Such a PMA supplement for a move to a different facility or establishment is called a 
manufacturing site change supplement. 
 
Manufacturing site change supplements are 180-day supplements (21 CFR 814.39(c) and 
814.40) that are reviewed by CDRHs Office of Compliance (CDRH/OC) or OIVD (for in vitro 
diagnostic devices).17  Manufacturing site change supplements include those that require pre-
approval inspection, as well as those that do not.18  CDRH intends to issue a separate guidance 
document for manufacturing site change supplements that describes the criteria for 
manufacturing site change supplements and when an inspection would likely occur.  
Accordingly, this information is not included in this guidance document.  Applicants should 
contact CDRH/OC or OIVD in advance of the submission to discuss what information should be 
provided.   
                                                 
16 See 21 CFR 814.39(a). 
17 If the applicant submits a supplement that includes both a design change and a manufacturing site 
change, then ODE or OIVD will be the lead review office and will consult with OC. 
18 In previous guidance to industry, FDA described express supplements as manufacturing site change 
supplements that did not require pre-approval inspection.  However, FDA no longer uses the express 
supplement terminology to distinguish these supplements from the other types of manufacturing site 
change supplements.  Nevertheless, the expectation is that for a manufacturing site change supplement 
that does not require a pre-approval inspection, the review process is shorter. 
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V. Periodic Reports 
In accordance with 21 CFR 814.82(a)(7), FDA may require as a condition of approval 
submission to FDA at intervals specified in the approval order of periodic reports containing the 
information required by 21 CFR 814.84(b).  In most cases, after the PMA is approved, the PMA 
applicant is required to submit reports to FDA annually unless a different time frame is specified 
in the approval order.  Accordingly, periodic reports are typically referred to by FDA and 
industry as annual reports.   
 
For changes that do not require the submission of a traditional PMA or a PMA supplement, you 
should provide this information as part of your annual report.19  However, it should be noted that 
simple changes related to the device documentation or manufacturing process documentation, 
such as rewording or expanding for clarification, translating from one language to another, 
correcting typographical errors, and moving component characteristics from an engineering 
drawing note to a different document (e.g., standard operating procedure), do not need to be 
reported in the annual report.   
 
Below, we provide examples of the types of changes that FDA has considered to be appropriate 
to be submitted as part of an annual report because the Agency did not believe that these impact 
safety or effectiveness.   
  Extension of the expiration date of the device based on data obtained under an approved 
protocol, as specified in an approval order. 
  Lowered the clean room temperature shutdown limit to provide a comfortable 
environment for personnel per environmental, health, and safety requirements.  Reducing 
a maximum temperature specification does not impact the safety and effectiveness of the 
device. 
  Increased the number of products sampled for release testing.  Increasing the number 
better assures that product released meets the specifications. 
  Tightened the allowed viscosity range for the balloon dipping process from 27.0  157.0 
to 78  82.  The larger range is acceptable, but the restricted range is optimal for low 
processing times and high yields. 
  Changed the in-process testing data collection form to record actual resistance readings 
for the continuity failure test rather than recording pass/fail.  
  Added a clarification to include a minimum cure time to the manufacturing instructions 
for the boot adhesive step.  The prior manufacturing instructions contained no minimum 
cure time. 
  Updated the processing instructions to incorporate an alert limit (0.2C) and tolerance 
  
limit ( 0.4 C) around the processing temperature (35 C).  Although the processing 
temperature is unchanged, these limits are new.  Per industry standards, the limits are 
                                                 
19 Refer to the annual report guidance document at http://www.fda.gov/cdrh/ode/guidance/1585.pdf for 
more details. 
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based on the calibration tolerance of the thermocouple used to control this process.  The 
alert and tolerance limits provide additional assurance of device quality, and were set 
using industry standards.  
  Updated the in-process test procedures to re-implement a back-up method for testing 
poppet pressure and pump flow rate.  The primary test method uses an automated test 
procedure.  This specific change re-implements the non-automated (mechanical) test 
method, to be used as an alternate method in the event that the automated method is off-
line.  The non-automated test evaluates the same performance characteristics as the 
automated test.  Also, since the non-automated test was previously validated and 
incorporated in the pump manufacturing process, re-implementation of this change 
restores the manufacturing procedures to their previous state.  
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Attachment I.  Types of PMA Supplements  
Type   Panel-Track  180-Day Supplement   Real-Time Supplement   Special PMA  30-Day Notice   Manufacturing Site 
Supplement   Supplement   Change Supplement 
Definition   "... significant change "...significant change in  "... minor change to the device,  Changes in labeling,  Changes to a  The use of a different 
in design or  components, materials,  such as a minor change to the  quality control, or  manufacturing  facility or 
performance of the  design, specification,  design of the device, software,  manufacturing processes  procedure or  establishment to 
device, or a new  software, color additives, sterilization, or labeling, and for  that enhance[s] the  method of  manufacture, 
indication for use of  or labeling."   which the applicant has  safety of the device or  manufacturing,and process, or package 
the device, and for  requested and the agency has  the safety in the use of  the applicant of the the device.  
which substantial  granted a meeting or similar  the device ...   approved 
clinical data are  forum to jointly review and  submissionsubmits 
generally necessary  determine the status of the  a written notice. 
..."  supplement."  
Statute /  Section 737(4)(B) of  Section 737(4)(C) of the  Section 737(4)(D) of the Act  Sections 21 CFR  Section  Section 21 CFR 
Regulation  the Act (as modified  Act   (and as modified by MDTCA)   814.39(d)(1) and  515(d)(6)(A)(ii) of  814.39(a)(3)  
Provision   by the Medical  814.39(d)(2)   the Act; 21 CFR 
Devices Technical  814.39(f)  
Corrections Act 
(MDTCA), Public 
Law 108-214)  
Description  A change in:  A significant change  Minor changes A (e.g., for which  If effectiveness is not  Changes in  A move to a different 
indication for use;  involving:   clinical data or FDA inspections  altered, changes in:   manufacturing that  manufacturing 
design; and/or  principle of operation;  are not needed), such as changes  labeling to add,  affect safety and  facility or 
performance.   control mechanism;  in design; software; labeling  strengthen, or delete  effectiveness.   establishment.  
Substantial clinical  design; or  (other than contraindications);  information; and/or 
data generally  performance; labeling;  and/or sterilization and  manufacturing process 
necessary to support and new testing or  packaging.   that adds a new 
the change. B  acceptance criteria.   Changes can be reviewed  specification or test 
Preclinical and,in some adequately by a reviewer in one  method or provides 
instances, confirmatory scientific discipline; there is a  additional assurance of 
clinical data to support  FDA-accepted test method,  purity, identity, strength, 
the change.   FDA-recognized standard, or an  or reliability of the 
applicable guidance document.    device.  
A Assuming there is also an accepted test method, FDA-recognized standard, or guidance, and FDA agrees that a real-time supplement is appropriate. 
B As discussed in Section B of this document, we have considered panel-track supplements to be most appropriate for changes in the indication for use.  
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Figure 1.  Recommended Steps to Decide the Regulatory Path for a Modified PMA Device  
 
Step 1: 
Identify the modification and reason for it. 
Step 2:    Step 3: 
Conduct a risk analysis.  Define data to assess the impact of the modification 
on safety and effectiveness (S&E). 
Step 4: 
Choose the regulatory pathway 
from the options below.A 
New clinical &  New clinical &  Preclinical &  Preclinical  Manufacturing  Manufacturing  Change that  Change that 
new preclinical  potentially  potentially  only  change  Site Change  enhances the  doesnot affect 
some new  limited  affecting S&E  Supplement  safety of the  S&E 
preclinical  confirmatory  device 
clinical 
Traditional  Panel-Track  180-Day  Real-Time  30-Day Notice  Special  Annual Report
PMA  Supplement  Supplement  Supplement    Supplement: 
Changes Being 
Effected 
 
A FDA may or may not agree with your assessment as to the regulatory pathway.  If we disagree with your pathway, FDA will provide the reasons. 
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