Please note: As of October 1, 2002, FDA charges a fee for review of Premarket Approvals
- When to submit a PMA supplement (§814.39)
- Types of PMA Supplements
- PMA Amendments (§ 814.37)
- Withdrawal and Resubmission (§ 814.37)
- Suggested Format For PMA Supplement Cover Letters
Amendments (§ 814.37) or supplements (§814.39) are submitted to FDA for changes or revisions to the original PMA submission. Although a PMA supplement applies to an approved PMA, in many cases there will be amendments to the PMA or to the PMA supplement before it is approved. In addition PMA reports may also have amendments if the applicant is requested to submit additional information on a report. That is,
A PMA supplement is the submission required for a change affecting the safety or effectiveness of the device for which the applicant has an approved PMA; additional information provided to FDA for PMA supplement under review are amendments to a supplement
A PMA amendment includes all additional submissions to a PMA or PMA supplement before approval of the PMA or PMA supplement OR all additional correspondence after PMA or PMA supplement approval.
When to submit a PMA supplement (§814.39)
Changes that Require a PMA Supplement
After FDA has approved a PMA, an applicant must submit a PMA supplement for review and approval by FDA before making any change affecting the safety or effectiveness of the device unless FDA has advised that an alternate type of submission is permitted for a particular change. All changes must meet the requirements of the Quality System regulation (Good Manufacturing Practices) under 21 CFR Part 820 including the design control requirement under §820.30. Changes for which an applicant must submit a PMA supplement include, but are not limited to, the following types of changes if they affect the safety or effectiveness of the device:
- new indication for use of the device;
- labeling changes;
- the use of a different facility or establishment to manufacture, process, sterilize, or package the device;
- changes in manufacturing facilities, methods, or quality control procedures;
- changes in sterilization procedures;
- changes in packaging;
- changes in the performance or design specifications, circuits, components, ingredients, principles of operation, or physical layout of the device; and
- extension of the expiration date of the device based on data obtained under a new or revised stability or sterility testing protocol that has not been approved by FDA. [If the protocol has been previously approved by FDA, a supplement is not submitted but the change must be reported to FDA in the postapproval periodic reports as described in the §814.39(b).]
Changes without a PMA Supplement 814.39(b)
An applicant may make a change in a device after FDA's approval of the PMA without submitting a PMA supplement if (1) the change does not affect the device's safety or effectiveness, and (2) the change is reported to FDA in a postapproval periodic report (annual report) required as a condition of approval of the device, e.g., an editorial change in labeling which does not affect the safety or effectiveness of the device. Trivial changes, such as changes in the color of a label, would not have to be included in the postapproval periodic report.
Types of PMA Supplements
The methods of notification and FDA involvement of changes to a PMA approved medical device depend on the type of change made. A summary of the types of notification and FDA involvement is outlined below.
PMA supplement (180 days) - §814.39(a)
- for significant changes that affect the safety and effectiveness of the device
- in-depth review and approval by FDA is required before implementation of the change
A full PMA review including a review by an outside advisory panel may be required. The criteria for a full PMA review includes changes in the device that may raise different types of safety and effectiveness questions or changes in which there may be no accepted test methods for evaluating the issues of safety or effectiveness.
Some 180-day PMA supplements may be reviewed using the Real-Time Review process. In this process the supplement is reviewed during a meeting or conference call with the applicant. FDA will fax its decision to the applicant within five working days after the meeting or call. The change must meet certain criteria to be eligible for this type of review. Supplements with detailed clinical data are generally not considered for this program. The criteria and process for the Real Time Review program are outlined in Real-Time Premarket Approval Application (PMA) Supplements.
Special PMA Supplement -- Changes Being Effected - §814.39(d)
- for any change that enhances the safety of the device or the safety in the use of the device
may be placed into effect by the applicant prior to the receipt of a written FDA order approving the PMA supplement.
After FDA approves a PMA, any change described below that enhances the safety of the device or the safety in the use of the device [§814.39(d)(2)] may be placed into effect by the applicant prior to the receipt of a written FDA order approving the PMA supplement, but after the applicant receives specific acknowledgment that the application qualifies for review under §814.39(d)(2) provided that:
- 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 acknowledgment that the application qualifies as a "Special PMA Supplement -- Changes Being Effected" from FDA for the supplement;
- the PMA supplement specifically identifies the date that such changes are being effected; and
- the change is made according to the good manufacturing practices regulation.
The following changes are permitted [§814.39(d)(1)]:
- labeling changes that add or strengthen a contraindication, warning, precaution, or information about an adverse reaction;
- labeling changes that add or strengthen an instruction that is intended to enhance the safe use of the device;
- labeling changes that delete misleading, false, or unsupported indications; and
- changes in quality controls or the manufacturing process that add a new specification or test method, or otherwise provide additional assurance of purity, identity, strength, or reliability of the device.
The applicant is encouraged to contact the PMA Staff to assist in determining if the change meets the requirements of §814.39(b).
30-day Notice and 135 PMA Supplement - §814.39(f)
- Used for modifications to manufacturing procedures or methods of manufacture that affect the safety and effectiveness of the device.
- Changes in a manufacturing/sterilization site or to design or performance specifications do not qualify
If the change qualifies as a 30day Notice, the change may be made 30 days after FDA receives the 30day notice unless FDA informs the PMA holder that the 30-day Notice is not adequate and describes the additional information or action required. If the 30-day Notice was not adequate, but contained data meeting appropriate content requirements for a PMA supplement, then the 30-day Notice will become a 135-day PMA Supplement.
Additional guidance can be found in "30-Day Notices and 135-Day PMA Supplements for Manufacturing Method or Process Changes, Guidance for Industry and CDRH".
Note: 30-day Notice is not the same as a 30-day Supplement. See below for information regarding the 30-day Supplement.
PMA Manufacturing Site Change Supplement
- For moving the manufacturing site if certain conditions apply.
- Manufacturing site must have received a Quality System/GMP inspection within the last two years.
- If requirements are not met, 180-day PMA Supplement must be submitted.
Annual (periodic) Report or 30-day Supplements-§814.39(e)
- FDA may allow certain changes to be reported in an annual report or 30-day supplement an instead of a PMA supplement submission. (If this method is utilized, FDA will typically request that the information be reported in the annual report and not as a 30-day supplement.)
FDA will notify applicants of this alternative through an advisory opinion to the affected industry or in correspondence with the applicant.
FDA will identify a change to a device for which the applicant has an approved PMA and for which a PMA supplement is not required under 814.39(a). FDA will identify such a change in an advisory opinion under §10.85, if the change applies to a generic type of device. Such changes will be identified in written correspondence to each PMA holder who may be affected by FDA's decision.
FDA will require that a change, for which a PMA supplement under §814.39(a) is not required, to be reported to FDA in a periodic (annual) report or a 30-day PMA supplement. In written correspondence, FDA will identify the type of information that is to be included in the report or 30-day PMA supplement.
If FDA requires that the change be reported in a periodic report, the change may be made before it is reported to FDA. If FDA requires that the change be reported in a 30-day PMA supplement, the change may be made 30 days after FDA files the 30-day supplement, unless FDA informs the PMA holder that additional information is required, the supplement is not approvable, or the supplement is denied. The 30-day PMA supplement must follow the instructions in the correspondence or advisory opinion. Any 30-day PMA supplement that does not meet the requirements of the correspondence or advisory opinion will not be filed and, therefore, will not be deemed approved 30 days after receipt.
The applicant is encouraged to contact the PMA staff to assist in determining if the change meets the requirements of §814.39(e).
Document to file
- for changes that do not affect the safety or effectiveness of the device
very limited or no FDA involvement prior to implementation of the change
Minor manufacturing changes and minor quality control changes can be documented to file. Examples of changes that can be documented to file include editorial changes to a Standard Operating Procedure (SOP) to make instructions clearer and combining two SOPs into one.
- Certain changes may require the submission of a complete new PMA. If any of the following changes occur, the applicant should consult the appropriate reviewing branch in the Office of Device Evaluation if:
- the design change causes a different intended use, mode of operation, and technological basis of operation,
- there will be a change in the patient population that will be treated with the device, or
- the design change is so significant that a new generation of the device will be developed.
- Certain changes may require the submission of a complete new PMA. If any of the following changes occur, the applicant should consult the appropriate reviewing branch in the Office of Device Evaluation if:
PMA Amendments (§ 814.37)
An applicant may amend a pending PMA or PMA supplement to revise existing information or provide additional information. FDA may request that the applicant amend their PMA or PMA supplement with any necessary information about the device that FDA considers necessary to complete the review of the PMA or PMA supplement.
If the applicant submits a major PMA amendment on his or her own initiative or at FDA's request, the review period may be extended up to 180 days. A major amendment is one that contains significant new data from a previously unreported study, significant updated data from a previously reported study, detailed new analyses of previously submitted data, or significant required information previously omitted.
A PMA amendment must include the PMA or PMA supplement number assigned to the original submission and the reason for submitting the amendment.
Withdrawal and Resubmission (§ 814.37)
Applicants may voluntarily withdraw their PMA or PMA supplement. If FDA requests an applicant to submit a PMA amendment, and a written response to FDA's request is not received within 180 days, FDA will consider the pending PMA supplement to be withdrawn voluntarily by the applicant (abandoned).
An applicant may resubmit a PMA or PMA supplement that was withdrawn, that FDA has refused to accept for filing, or that FDA has disapproved. A resubmitted PMA or PMA supplement must comply with the requirements of §814.20 or §814.39, respectively, and must include the PMA number assigned to the original submission as well as the applicant's reason for resubmission.
Suggested Format For PMA Supplement Cover Letters
An applicant's cover letter should accurately identify the type of PMA submission and include information needed for FDA tracking purposes. To expedite its processing, the following suggestions and formats have been prepared.
All procedures and actions that apply to a PMA application under §814.20 also apply to PMA supplements, except that the information required in a supplement is limited to that needed to support the change. A summary is required only if there are new indications for use of the device, significant changes in the performance or design specifications, circuits, components, ingredients, principles of operation, or physical layout of the device, or when otherwise required by FDA.
Three copies of a PMA supplement are required and must include information relevant to the proposed changes in the device. A PMA supplement must include a separate section that identifies each change for which approval is being requested and explains the reason for each change. The applicant must submit additional copies and information if requested by FDA. The timeframes for review of a PMA supplement are the same as those provided for a PMA (§814.40).
Please refer to the eCopy guidance for current information on the number of copies and the format (paper versus eCopy) you must send to the Document Control Center (DCC). The current mailing address for CDRH’s DCC and a link to CBER’s DCC’s mailing address are provided on the eCopy Program for Medical Device Submissions webpage.
- Use the applicant's letterhead or that of the applicant's authorized representative. Provide a valid email address since all letters from FDA will be sent via email to the applicant.
- Address the cover letter as indicated under "PMA Supplement Cover Letter" below. To minimize misrouting, do not include an FDA staff member's name in the address.
- If submitted by someone other than the applicant (e.g., lawyer or consultant), the identity of the applicant must be included.
- In the case of a PMA supplement for a new model or revised indication, specify the indication for use for which FDA approval is requested.
- If applicable, include the reference numbers for any Premarket Notification, Investigational Device Exemption, reclassification petition, or color additive petition submitted by the applicant.
- Indicate whether the submission includes an environmental assessment. Please note that an environmental assessment is typically not required.
- In the case of a PMA supplement, specify the location of the following information required by 21 CFR 814.39(c): identification of each change for which approval is requested and an explanation of the reason for each change.
- In the case of a "Special PMA Supplement - Changes Being Effected" under 21 CFR 814.39(d), identify the submission as such, provide a full explanation of the basis for the changes and identify the date that such changes are being effected.
- In the case of a 30-day PMA supplement under 21 CFR 814.39(e), specify the date of the FDA advisory opinion or correspondence providing for the change(s) to be reported in this manner and identify the submission as specified in the FDA advisory opinion or correspondence. In the cover letter for the 30-day supplement, provide a statement that confirms only changes identified in the advisory opinion or previous FDA correspondence are being requested via the supplement.
- Date and sign the cover letter and include a copy in the first volume of each copy of the PMA submission.
To minimize delays in processing of PMA submissions, it is important that the applicant's cover letter correctly identify the type of submission, i.e., a PMA supplement, an amendment to a pending PMA or PMA supplement, or a required periodic report to an approved original PMA, PMA supplement or report amendment. Although FDA correspondence requesting additional information or approving a PMA submission identifies the form in which a subsequent submission is to be made, the incidence of incorrectly identified submissions has been significant. Delays in FDA processing occur when a document is misidentified and the submission must be reprocessed.
The general full format of the cover letter for a PMA supplement appears below. Only the subject section and opening sentence(s) are provided for the various types of PMA supplement submissions. In several instances, alternative opening statements are included to address specific situations.
PMA Supplement Cover Letter
SUBJECT: PMA Supplement to [original PMA reference number] for [new device trade name or present device trade name if not being revised as a result of the modification]
To Whom It May Concern:
[Applicant's name] is submitting this supplement to our approved Premarket Approval application for the [present device trade name] to request approval to [identify the changes or modifications to be made in the device].
[If the supplement involves a new manufacturing or sterilization facility, indicate whether the facility is prepared for an FDA inspection. If not prepared, provide the expected date when the facility will be ready for inspection.]
If another document is incorporated by reference, e.g., a master file, please include the original letter of authorization as an attachment to this cover letter.
The existence of this PMA supplement and the data and other information that it contains are confidential, and the protection afforded to such confidential information by 18 USC 1905, 21 USC 331(I), 5 USC 552, and other applicable laws is hereby claimed. [Note: confidentiality claims cannot be made unless the applicant has complied with the applicable requirements.
If there are questions regarding this submission, [name] may be contacted at [give telephone number including area code].
[Name and title of applicant's representative]
Special PMA Supplement - Changes Being Effected" Cover Letter
SUBJECT: Special PMA Supplement-Changes Being Effected" to [original PMA reference number] for [present device trade name]
[Applicant's name] is submitting this "Special PMA Supplement-Changes Being Effected" to our approved Premarket Approval application to place into effect the following change(s) described in 21 CFR 814.39(d)(2) that enhance(s) the [safety of/safety in the use] of [device trade name].
[As required by 21 CFR 814.39(d)(1), provide a full explanation of the basis for the changes and the date that such changes are being effected.]
30-day Notice PMA Supplement Cover Letter
SUBJECT: 30-day Notice PMA supplement to [original PMA reference number] for [present device trade name]
[Applicants name] is submitting this 30-day Notice PMA supplement to our approved Premarket Approval application for the [present device trade name] to request approval to [identify the manufacturing change or modification to be made in the device].
Note: Two copies should be sent to CDRH's Office of Device Evaluation. At the same time, a duplicate copy should be sent directly to CDRH's Office of Compliance, Field Programs Branch, PMA Document Mail Center – WO66-G609, ATTN: 30-day Notice, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002. The duplicate copy should be flagged: "Office of Compliance Copy."
PMA Manufacturing Site Change Supplement Cover Letter
SUBJECT: Express PMA supplement to [original PMA reference number] for [present device trade name]
[Applicant's name] is submitting this PMA Manufacturing Site Change Supplement to our approved Premarket Approval application for the [present device trade name] to request approval for a new [manufacturing or sterilization] facility.
Note: Two copies should be sent to CDRH's Office of Device Evaluation. At the same time, a duplicate copy should be sent directly to CDRH's Office of Compliance, PMA Document Mail Center – WO66-G609, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002. The duplicate copy should be flagged: "Office of Compliance Copy."
30-day PMA Supplement Cover Letter
SUBJECT: 30-day PMA supplement to [original PMA reference number] for [present device trade name]
[Applicant's name] is submitting this 30-day PMA supplement to our approved Premarket Approval application for the [present device trade name] to request approval to [identify the change or modification to be made in the device]. As provided in the FDA [letter/advisory opinion] dated [date], this change may be reported to FDA in a 30-day PMA supplement and implemented 30 days after FDA files the 30-day PMA supplement under the conditions described in 21 CFR 814.39(e).
Amendment to Original PMA or PMA Supplement Cover Letter
SUBJECT: Amendment to [original PMA or PMA supplement reference number] for [device trade name]
Unsolicited submission of additional information
[Applicant's name] is submitting this amendment to its [Premarket Approval application or PMA supplement] [original PMA or PMA supplement reference number] for the [device trade name] to provide [identify the additional information being provided].
References for PMA Supplements and Amendments
21 CFR 814.37 21 CFR 814.39 Real-Time Premarket Approval Application (PMA) Supplements Guidance for Industry and FDA Staff - 30-Day Notices, 135-Day Premarket Approval (PMA) Supplements and 75-Day Humanitarian Device Exemption (HDE) Supplements for Manufacturing Method or Process Changes Guidance for Industry - Supplements to Approved Applications for Class III Medical Devices: Use of Published Literature, Use of Previously Submitted Materials, and Priority Review (Text Only)