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.
Note: This terminology varies slightly for Investigational Device Exemption
(IDE) submissions. An IDE supplement is any additional submission to an
IDE after approval of the IDE. An IDE amendment is any additional
submissions to an IDE before approval of the IDE.
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).]
Additional guidance on when a PMA Supplement is required can be found in the
following document:
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.
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. The criteria
for taking supplements to the outside advisory panel for review
are discussed in Criteria for Panel Review of PMA Supplements http://www.fda.gov/cdrh/p863.html
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" Review Program for Premarket Approval Application
(PMA) Supplements. http://www.fda.gov/cdrh/ode/realtim2.html
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.
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.
Additional information on the Express PMA Supplement process
can be found in the guidance document "Draft Guidance: Likelihood
of Facilities Inspections When Modifying Devices Subject to Premarket
Approval" http://www.fda.gov/cdrh/comp/likehood.html
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.
New PMA
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.
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.
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.
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).
PMA supplements and amendments should be mailed to the following address:
Food and Drug Administration
Center for Devices and Radiological Health
Document Mail Center (HFZ-401)
9200 Corporate Blvd.
Rockville, MD 20850
General Suggestions
Use the applicant's letterhead or that of the applicant's authorized
representative.
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.
See Chapter 3 of the PMA Manual, "Environmental Impact Considerations,"
for additional guidance. http://www.fda.gov/cdrh/dsma/pmaman/sec03.html#P1127_59655
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.
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
[Date]
Food and Drug Administration
Center for Devices and Radiological Health
Document Mail Center (HFZ-401)
9200 Corporate Blvd.
Rockville, MD 20850
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].
Sincerely yours,
[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].
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, HFZ-306,
ATTN: 30-day Notice, 9200 Corporate Blvd., Rockville, MD 20850. 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, Field Programs Branch, HFZ-306,
9200 Corporate Blvd., Rockville, MD 20850. 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].
Guidance to Industry Supplements to Approved Applications for Class
III Medical Devices: Use of Published Literature, Use of Previously Submitted
Materials, and Priority Review; Final http://www.fda.gov/cdrh/modact/evidence.html
