- For changes that request a significant change in design or performance of the device, or a new indication for use of the device.
- Substantial clinical data are necessary to provide a resonable assurance of safety and effecitveness.
- A full PMA review which may include a review by an outside advisory panel will be required.
- For changes that affect the safety and effectiveness of the device.
- For significant change in components, materials, design, specification, software, color additves, or labeling.
- In general, the clinical data provided in support of the traditional device approval should still be applicable in supporing the approval of the changed device. In most cases, only new preclinical testing is needed to support safety and effectiveness.
- In-depth review and approval by FDA is required before implementation of the change
- A full PMA review 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.
- For 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.”
- For any change that enhances the safety of the device or the safety in the use of the device.
- For certain labeling and manufacturing changes that enhance 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:
- PMA supplement and its mailing cover letter are plainly marked "Special PMA Supplement -- Changes Being Effected;"
- PMA supplement provides a full explanation of the basis for the changes;
- applicant has received acknowledgment that the application qualifies as a "Special PMA Supplement -- Changes Being Effected" from FDA for the supplement;
- PMA supplement specifically identifies the date that such changes are being effected; and
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)
- 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 30-day 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 (§814.39(a)(3)
- For the use of a different facility or establishment to manufacture, process, or package the device.
- FDA considers use of a different site ormoving the manufacturing site of a finished device to require a 180-day PMA supplement (referred to as a “site change supplement”) if :
- the change affects the safety and effectiveness of the finished device and
- the site was not approved as part of the original PMA or a PMA supplement, or
- the site was approved as part of original PMA or PMA supplement, but only for the performance of different manufacturing activities.
The information submitted to the FDA in the “site change supplement” must demonstrate compliance with the Quality System (QS) Regulation (§820). A preapproval inspection may be necessary to evaluate the firm’s implementation of the QS regulation requirements. The following factors are considered when determining whether to conduct a preapproval inspection for the “site change supplement”:
- the dates of the last inspection of the current site and the new/different site;
- the classifications of the last inspections of the current site and new/different site;
- the relevance of the last QS regulation inspection (for example, whether similar products or processes were inspected);
- a review of relevant recalls and adverse events associated with manufacturing processes for devices manufactured, processed, or packaged at this site; and
- the risk to the safety or effectiveness of the device associated with the manufacturing activities performed at the new/different site.
- Annual (periodic) Report or 30-day Supplements-§814.39(e)
- FDA may allow certain changes to be reported in an annual report instead of a PMA supplement submission. (If this method is utilized, FDA will typically request that the information be reported in the annual report.)
- 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. In written correspondence, FDA will identify the type of information that is to be included in the report.
If FDA requires that the change be reported in a periodic report, the change may be made before it is reported to FDA.
For additional information regarding PMA annual reports please see the Guidance for Industry and Food and Drug Administion Staff: Annual Reports for Approved Premarket Approved Applications (PMA).
- 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 review office.
- 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.
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 information about the device that is 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 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
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.
- PMA supplements submitted 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 timeframes for review of a PMA supplement depend on the supplement type. For more information on review timeframes, please refer to the FDA and Industry Actions on Premarket Approval Applications (PMAs): Effect on FDA Review Clock and Goals - Guidance for Industry and Food and Drug Administration Staff.
The applicant should submit a valid eCopy of their PMA Supplement. The eCopy should be sent to CDRH’s or CBER’s 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.
Applicants should also clearly identify on the CDRH Premarket Review Submission Cover Sheet the type of PMA supplement.
General Suggestions
- 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 Q-submission, Premarket Notification, Investigational Device Exemption, reclassification petition, De Novo Application, or color additive petition submitted by the applicant and relevant to the submission.
- 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.
Suggested Formats
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].
[Signature]
[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].
PMA Manufacturing Site Change Supplement Cover Letter
SUBJECT: 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.
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
References for PMA Supplements and Amendments
- 21 CFR 814.37
- 21 CFR 814.39
- Modifications to Devices Subject to Premarket Approval (PMA) - The PMA Supplement Decision-Making Process
- Real-Time Premarket Approval Application (PMA) Supplements - Guidance for Industry and FDA Staff (PDF - 82KB)
- 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 and FDA Staff (PDF - 80KB)
- Supplements to Approved Applications for Class III Medical Devices: Use of Published Literature, Use of Previously Submitted Materials, and Priority Review - Guidance for Industry
- FDA and Industry Actions on Premarket Approval Applications (PMAs): Effect on FDA Review Clock and Goals - Guidance for Industry and Food and Drug Administration Staff
- User Fees and Refunds for Premarket Approval Applications and Device Biologics License Applications - Guidance for Industry and Food and Drug Administration Staff
- Guidance: Manufacturing Site Change Supplements: Content and Submission
