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 (240) 

276-4010 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 (240) 276-0100. 

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. FDA2007-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 240-276-3151 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

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The Least Burdensome Approach.........................................................................................2 

II. Background.............................................................................................................................. 2 

III. General Requirements for When a PMA Supplement is Needed............................................ 

IV. Determining the Type of PMA Submission ............................................................................ 

A. When to Submit a Traditional PMA...............................................................................5 

A1. Modified Device for a New Indication for Use........................................................ 

A2. Modified Device with New Clinical Effects ........................................................... 

A3. Modified Analyte and Indication/Patient Population (OIVD) .................................. 

A4. Significant Modification of Technology (OIVD) .................................................... 

B. When to Submit a Panel-Track Supplement..................................................................7 

B1. Change in Indication for Use - Different Patient Population ................................... 

B2. Change in Indication for Use - Different Patient Population ................................... 

B3. Change in Indication for Use - Different Patient Population ................................... 

B4. Change in Indication for Use - Different Patient Population (OIVD) ................... 

B5. Change in Indication for Use - Different Surgical Procedure................................ 

B6. Change in Indication for Use - Different Conditions of Use ................................. 

B7. Change in Indication for Use - Different Specimen (Sample) Type (CBER)........ 

B8. Change in Indication for Use - Different Physiological Location ......................... 

C. When to Submit a 180-Day Supplement.......................................................................11 

C1. Design Change ....................................................................................................... 

C2. New Device Feature ............................................................................................... 

C3. Modified Chemical Formulation............................................................................ 

C4. Hardware and Software Modifications .................................................................. 

C5. New Analyzer – Assay Unchanged (OIVD) .......................................................... 

C6. Design and Software Modification ........................................................................ 

C7. Modified Physical Characteristics.......................................................................... 

C8. New Device Feature ............................................................................................... 

C9. Design Change ....................................................................................................... 

C10. New Specimen (Sample) Type (CBER) ............................................................... 

D. When to Submit a Real-Time Supplement...................................................................15 

D1. Minor Modification to Correct Battery Failures..................................................... 

D2. Alternative Sterilization Method ............................................................................ 

D3. Storage Temperature Change ................................................................................. 

D4. Extended Shelf Life ................................................................................................ 

D5. Component Offered as Stand Alone System .......................................................... 

D6. Alternate Wet Shipping Solution............................................................................ 

D7. Modified Bonding Method ..................................................................................... 

E. When to Submit a Special PMA Supplement – Changes Being Effected ..................17 

E1. New Warning Added .............................................................................................. 

E2. Manufacturing Process Change .............................................................................. 
Contains Nonbinding Recommendations 

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E3. Improved Instructions ............................................................................................. 

E4. Additional Inspection Step in the Manufacturing Process...................................... 

E5. Additional Inspection Step in the Manufacturing Process...................................... 

F. When to Submit a 30-Day Notice...................................................................................19 

F1. Manual to Automated Process................................................................................. 

F2. Alternate Qualified Supplier of Critical Component (OIVD)................................. 

F3. Alternate Qualified Supplier of Critical Material ................................................... 

F4. In-Process Quality Control Step Change ................................................................ 

F5. Manual to Automated Process Conversion ............................................................. 

F6. Modified In-Process Test ........................................................................................ 

F7. Modified Sterilization Process Parameters ............................................................. 

G. When to Submit a Manufacturing Site Change Supplement .....................................21 

V. Periodic Reports..................................................................................................................... 
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. 

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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, realtime 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 FDA’s 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)). 

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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 

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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. 

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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. 

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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 steroideluting 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 prostatespecific 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 

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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. 

B. When to Submit a Panel-Track Supplement7

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. 

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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. 

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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 FDA’s 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. 

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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. 

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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 

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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. 

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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 device’s 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. 

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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. 

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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. 

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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 25°C to 30°C 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 standalone 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. 

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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 

Effected14

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. 

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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. 

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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, 

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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 inprocess 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. 

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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 CDRH’s Office of Compliance (CDRH/OC) or OIVD (for in vitro

diagnostic devices).17 Manufacturing site change supplements include those that require preapproval 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 (±0.2°C) 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 offline. 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. 
Contains Nonbinding Recommendations 

Attachment I. Types of PMA Supplements Type Panel-Track 

Supplement 

180-Day Supplement Real-Time Supplement Special PMA 

Supplement 

30-Day N

Definition "... significant change 

in design or performance of the device, or a new indication for use of the device, and for which substantial clinical data are generally necessary ..." 

"...significant change in components, materials, design, specification, software, color additives, or labeling." 

"... 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." 

Changes in labeling, quality control, or manufacturing processes “that enhance[s] the safety of the device or the safety in the use of the device ...” 

Changes manufactprocedurmethod omanufactthe applicapproved submissioa written 

Statute / Regulation Provision 

Section 737(4)(B) of the Act (as modified by the Medical Devices Technical Corrections Act (MDTCA), Public Law 108-214) 

Section 737(4)(C) of the Act 

Section 737(4)(D) of the Act (and as modified by MDTCA) 

Sections 21 CFR 814.39(d)(1) and 814.39(d)(2) 

Section 515(d)(6)the Act; 2814.39(f) 

Description A change in: 

indication for use; design; and/or performance. Substantial clinical data generally necessary to support the change. B

A significant change involving: principle of operation; control mechanism; design; or performance; labeling; and new testing or acceptance criteria. Preclinical and, in some instances, confirmatory clinical data to support the change. 

Minor changes A (e.g., for which 

clinical data or FDA inspections are not needed), such as changes in design; software; labeling (other than contraindications); and/or sterilization and packaging. Changes can be reviewed adequately by a reviewer in one scientific discipline; there is a FDA-accepted test method, FDA-recognized standard, or an applicable guidance document. 

If effectiveness is not altered, changes in: labeling to add, strengthen, or delete information; and/or manufacturing process that adds a new specification or test method or provides additional assurance of purity, identity, strength, or reliability of the device. 

Changes manufactaffect safeffectiven

A Assuming there is also an accepted test method, FDA-recognized standard, or guidance, and FDA agrees that a real-time supplemeB As discussed in Section B of this document, we have considered panel-track supplements to be most appropriate for changes in the 

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page 25 

Figure 1. Recommended Steps to Decide the Regulatory Path for a Modified PMA Device 

Step 1: 

Identify the modification and reason for it. 

New clinical & 

new preclinical 

New clinical & 

potentially 

some new 

preclinical 

Preclinical & 

potentially 

limited 

confirmatory 

clinical 

Traditional 

PMA 

Panel-Track 

Supplement 

180-Day 

Supplement 

Preclinical 

only 

Real-Time 

Supplement 

Manufacturing 

change 

affecting S&E 

30-Day Notice 

Manufacturing 

Site Change 

Supplement 

Chan

enhan

safety 

de

Sp

Suppl

Chang

Eff

Step 2: 

Conduct a risk analysis. 

Step 4: 

Choose the regulatory pathway 

from the options below.A 

Step 3: 

Define data to assess the impact of the modi

on safety and effectiveness (S&E). 

A FDA may or may not agree with your assessment as to the regulatory pathway. If we disagree with your pathway, FDA will