The FDA Refuse to
Accept Policy/Acceptance
Review Process
Erika Huffman, MSBME, RAC
Regulatory
The FDA Refuse to Accept
Policy/Acceptance Review Process
NAMSA White Paper
So you have a 510(k) or PMA submission prepared and are ready to send it to FDA for
review…or are you? On December 31, 2012, the US Food and Drug Administration (FDA)
released two final guidance documents outlining new acceptance review processes that
apply to 510(k) Premarket Notifications and Premarket Approval (PMA) applications. In the
time since the release of the documents, we have come to understand more about this
new step in FDA’s review process and how to ensure you meet their requirements.
The two new final guidance documents are:
• Refuse to Accept Policy for 510(k)s: Guidance for Industry and Food and Drug
Administration Staff1
• Acceptance and Filing Reviews for Premarket Approval Applications (PMAs):
Guidance for Industry and Food and Drug Administration Staff2
Erika Huffman, MSBME, RAC
([email protected]),
Medical Research Manager–
Regulatory, joined NAMSA
in 2010. She holds an MS in
Biomedical Engineering from
the University of Iowa and has
over 18 years of experience
in the medical device
industry, having worked
in Regulatory, Quality, and
Management roles with both
US and international focus.
Her experience includes
premarket submissions and
post-marketing surveillance
for Class II and III devices,
including software/firmware
and active implantables. Ms.
Huffman holds a current
Regulatory Affairs Certification
(RAC).
These guidance documents provide detail and definition around the first step in the
FDA 510(k) and PMA submission review processes – the 510(k) Refuse to Accept policy/
designation and the PMA Acceptance Review. They supersede previous guidance and
were implemented as a means for FDA to meet their commitment to performance
goals related to the timeliness of reviews as spelled out in the Medical Device User Fee
Amendments of 2012 (MDUFA III).3,4
What is an Acceptance Review?
Acceptance reviews are intended to encourage quality submissions to the Agency and
ensure a minimum threshold of acceptability is met before the formal substantive review
begins. A quality submission is one that includes all required information per applicable
guidance documents and special controls, is clearly organized, easy to understand, and is
supported by appropriate test and/or clinical data as applicable. The acceptance review,
or Refuse to Accept designation as it is called for 510(k) Premarket Notifications, is an
early, time-bound review against specific pre-defined acceptance criteria. This allows the
Agency to appropriately concentrate resources on complete submissions and improve
submission review efficiency and turnaround times. The aim of the acceptance review is
to limit the assessment to the general completeness of the submission, while saving the
appraisal of the quality of the submitted information for the subsequent 510(k) substantive
or Premarket Approval (PMA) filing review. In actual practice, however, the acceptance
review process gives the Agency some “off the clock” time to start the more significant
review of the submission, thereby helping them meet their MDUFA performance goals.
What submission types are subject to an Acceptance Review?
Acceptance reviews are performed for all Traditional, Special, and Abbreviated 510(k)s,
as well as all original PMAs and panel-track PMA supplements. The specific acceptance
criteria for each of these five submission types are defined in comprehensive checklists
provided in the corresponding guidance document.
When does the Acceptance Review happen?
The acceptance review begins immediately after your 510(k) or PMA submission is
received and successfully processed by the FDA’s Document Control Center (DCC).
Successful processing by the DCC means that following criteria have been met:
• The appropriate user fee has been paid (and user fee payment identification number
has been adequately provided)
• The correct number of copies have been provided, including one valid eCopy5
• In the case of PMAs, the application is signed or countersigned by a US
representative per 21 CFR 814.20(a)
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The acceptance review for both 510(k) notifications and PMAs should be completed by
the FDA within 15 calendar days of receipt/acceptance of your submission to the DCC. If
the Agency does not complete the review within this time, you will be notified in writing
that the acceptance review was not completed and that the 510(k) or PMA submission is
under substantive or filing review, respectively.
“A quality submission
is one that includes all
Does the Acceptance Review replace the PMA filing review?
required information
per applicable guidance No, the acceptance review does not replace the PMA filing review. Rather, it is now a
part of the filing review. The criteria for PMA filing, previously outlined in the superseded
documents and special
2003 guidance,2 has been separated into 1) acceptance criteria and 2) filing criteria. The
acceptance criteria are applied during the 15-calendar-day acceptance review discussed
controls, is clearly
above and pertain to whether the file is administratively complete. The filing review
organized, easy to
criteria aim to determine the basic adequacy of the technical elements of the PMA (eg ,
understand, and is
whether the data are consistent with the final device design and proposed indications) in
supported by appropriate preparation for the substantive review.
The filing review, and the preceding acceptance review, will be completed by the Agency
test and/or clinical data
within 45 calendar days of receipt of a complete PMA and you will be notified of the filing
as applicable.”
status (“filed” or “not filed”) per 21 CFR 814.42(a).6 Note that the filing criteria outlined in
the latest guidance are not significantly different than those described in earlier guidance
documents, as PMA filing criteria defined in the regulation have not changed. Refer to the
PMA regulation (21 CFR 814.42[e])6 for reasons why FDA may refuse to file a PMA.
How are Modular PMAs handled? Do I have to go through an acceptance
review with each module?
Modular PMAs will also be subject to acceptance and filing reviews, which will occur at
the time of receipt of the final clinical module that completes the PMA submission, and
will be an assessment of all information in all modules received to date. Refer to the FDA
guidance document “Premarket Approval Application Modular Review”7 for additional
details.
How does the Acceptance Review affect the FDA’s decision-making process or
review clock?
For 510(k) notifications, the acceptance review policy does not alter FDA’s substantial
equivalence decision-making process once the submission has been accepted for review;
however, for those submissions that are not accepted for substantive review the first
time and instead receive a “Refuse to Accept” designation letter, it alters the start of the
FDA review clock for purposes of the Agency’s MDUFA performance goals. For example,
if your submission is accepted during the initial acceptance review (within the first 15
calendar days of receipt of the submission), the FDA review clock start date is the date
of receipt of the submission. However, if your submission is not accepted and additional
information is requested by the Agency, the FDA clock has not started yet and will not
start until all required data has been received and the submission is accepted for review
(Figure 1).
For PMA applications, once the Agency has both “Accepted” and “Filed” an original PMA
application or panel-track PMA supplement, the FDA review clock begins as of the date
of receipt of the most recent submission or amendment that made the PMA complete.
What can I do to ensure my submission meets the acceptance criteria?
NAMSA encourages manufacturers to complete the appropriate checklist for their
submission and retain it in their project files. A practical walk-through of the checklist
accomplishes two things: confirms all required information has been provided in the
submission, and provides documentation that can be referred back to in the event of a
The FDA Refuse to Accept
Policy/Acceptance Review Process
NAMSA White Paper
dispute. Inclusion of a completed checklist as part of your submission is not required by
the Agency, but may be helpful to the FDA reviewer. Electronic checklists for Traditional,
Abbreviated, and Special 510(k) submissions are available on the FDA website.8
“Merely listing
the differences
between the
subject device
and the predicate
device(s) is not
enough. An analysis
of the differences
must be presented,
or if there are none,
include a statement
as such.”
What do I need to know to meet the 510(k) Refuse to Accept policy criteria?
The following items on the Refuse to Accept checklist are most commonly missed when
preparing a 510(k) and lead to a Refuse to Accept designation (specific checklist item
numbers in parentheses):
• Submission contains a 510(k) Summary or Statement (#4).
{{It is critical that the 510(k) Summary or Statement contain all of the required
elements as specified in 21 CFR 807.92 or 21 CFR 807.93, respectively.6
• The submission identifies prior submissions or states that there were no prior
submissions for the subject device (#9).
{{Consider including a direct statement in your cover letter regarding prior
submissions/FDA feedback for the same device. Either include prior submission
numbers—eg, submission numbers for Pre-Submission meetings, Investigational
Device Exemptions (IDE), prior 510(k)s for the same device that were withdrawn or
designated Not Substantially Equivalent (NSE)—or clearly state there were no prior
submissions for the device.
Section F (prior related submissions section) of the CDRH Premarket Review
Submission Coversheet (FDA Form 3514) may also be used to list submission
numbers to address this criterion. However, you should note that leaving this
section of the form blank is not considered to be a statement that there were no
prior submissions.
{{
• Device Description missing engineering drawings or information identified in device
specific guidance (#s 10-13).
{{You should be intimately familiar with all applicable guidance documents and
special controls applicable to the device in question and ensure that all required
elements are discussed in the submission. It may be helpful to indicate in your
cover letter that the submission was prepared in accordance with the applicable
guidances/standards/documents and list them by title.
• Submission includes an analysis of differences between subject device and predicate
device(s) (#16).
{{The comparison to a predicate device must include what is similar and what is
different.
Merely listing the differences between the subject device and the predicate
device(s) is not enough. An analysis of the differences must be presented, or if
there are none, include a statement as such.
{{
• Indications for use are stated in labeling and are identical to Indications for Use form
and 510(k) Summary (#17).
{{This concept also applies to the device name. You should ensure the device name
is the same everywhere it is used (cover letter, 510(k) Summary, labeling).
• Submission includes summary of methods used for storage conditions and aging
(#28).
{{Include conditions used for accelerated aging and/or real-time aging conditions.
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FDA
substantive/
filing review
starts
Submission
arrives at FDA
Document
Control
Center
Submission
FDA
Acceptance
Review - Up
to 15 calendar
days
S M
T W
T S
pted
n acce
Submissio
Refuse to
Submission
number
assigned
Figure 1. FDA Acceptance Review Clock
“Delayed
manufacturing
information would
not preclude
filing a PMA per
the old 2003
guidance; however
manufacturing
information
is now an
acceptance review
requirement. ”
FDA
Clock
Starts*
Accept d
ecision
* If submission is accepted during first
15 days (i.e., during first acceptance
review), FDA clock starts on date on
submission receipt.
Repeat FDA Acceptance Review
Applicant
provides missing
info to FDA
Submission
accepted
FDA
Clock
Starts
FDA
substantive/
filing review
starts
• Submission includes a list of patient contacting materials (including color additives),
material contact classification (eg, transient), and biocompatibility assessment of
patient contacting components (#s 29-31)
{{NAMSA recommends including a table titled “Patient Contacting Materials” where
you minimally list each component of the device and the associated material(s).
The duration of contact for each material may also be included.
• Submission includes legible reprints or a summary of each literature article
referenced in the submission (#38).
{{Include copies of all literature referenced in both the paper copies and electronic
(eCopy) copies of the submission.
Copies of standards, guidance documents, and such do not need to be provided.
{{
• Confirm that the eCopy of the document and the electronic file properties (eg, size,
filename, etc.) conform to the criteria specified in the FDA eCopy guidance.5
What do I need to know to meet the PMA Acceptance Review criteria?
The following items on the PMA acceptance review checklist lead to a Refuse to Accept
decision when they are not properly included in your PMA submission (specific checklist
item numbers in parentheses):
• Submission includes a Device Manufacturing section if new manufacturing site or
substantially different manufacturing procedures (A7 ).
{{Delayed manufacturing information would not preclude filing a PMA per the old
2003 guidance; however manufacturing information is now an acceptance review
requirement. Refer to FDA guidance regarding Quality System information for
more detail about the preparation of PMA manufacturing information.9
• Submission includes full test reports (A8).
{{A full test report includes the objective of the test, a description of the test
methods and procedures, the study endpoint(s), predefined pass/fail criteria, a
summary of the results, and a discussion of conclusions.
• Submission includes copies of clinical protocols and related statistical analyses (A9,
A10).
{{Final FDA-approved versions of the clinical protocols used for the relevant clinical
studies must be provided, including any Notices of Changes for Investigational
Device Exemptions (IDE).
The results of all statistical analyses identified in the protocol(s) must be included
in the submission.
{{
The FDA Refuse to Accept
Policy/Acceptance Review Process
“Section F (prior
related submissions
section) of the
CDRH Premarket
Review Submission
Coversheet (FDA
Form 3514) may
also be used to
list submission
numbers to
address this
criterion. However,
you should note
that leaving this
section of the
form blank is not
considered to be
a statement that
there were no prior
submissions.”
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• Submission includes appropriate draft labeling.
{{Physician labeling is required for all PMA submissions and must contain indications
for use, contraindications/warnings/precautions, and instructions for use.
Patient labeling is also required for most devices.
{{
• Submission contains documentation to establish that applicable performance
standards, voluntary standards and/or FDA guidance have been followed (A12).
{{You should be intimately familiar with all standards and guidance documents
applicable to your device and ensure that all required elements are discussed in the
submission. It may be helpful to indicate in your cover letter that the submission
was prepared in accordance with the applicable guidances/standards/documents
and list them by title.
• Submission contains all required FDA forms (A12).
{{Either FDA Form 3454 or Form 3455 pertaining to investigator financial disclosure
is required to be included in the submission.
FDA Form 3674 related to certification requirements of ClinicalTrials.gov Data Bank
is required.
{{
An environmental assessment is not required unless the device presents new
environmental concerns.
{{
• The submission identifies prior submissions or states that there were no prior
submissions for the subject device (B1).
{{Consider including a direct statement in your cover letter regarding prior
submissions/FDA feedback for the same device. Either include prior submission
numbers—eg, submission numbers for Presubmission meetings, Investigational
Device Exemptions (IDE)—or clearly state there were no prior submissions for the
device.
Section F (prior related submissions section) of the CDRH Premarket Review
Submission Coversheet (FDA Form 3514) may also be used to list submission
numbers to address this criterion. However, you should note that leaving this
section of the form blank is not considered to be a statement that there were no
prior submissions.
{{
Complete copies of meeting minutes from any and all Presubmission meetings
with the Agency must also be included.
{{
What happens if my submission does not meet the Acceptance Review
criteria?
If one or more items on the 510(k) Refuse to Accept checklist or on the PMA Acceptance
Checklist are not present in the submission, the Agency will notify in writing the person
listed as the submission contact. This notice will indicate that the submission was not
accepted and will include a copy of the completed acceptance review checklist to
indicate the specific information that was missing or inadequate.
When responding to an unsuccessful acceptance review, do not resend the entire
submission, create a new submission, or pay another user fee unless stipulated by
FDA. The new information should be submitted under the originally issued submission
number. Providing a timely response to the Agency is important; if a response is not
received within 180 calendar days of the date of non-acceptance, FDA will consider the
submission withdrawn and it will be closed in the system.
When additional information is provided to the FDA in response to deficiencies noted
during an acceptance review, the acceptance review process begins again and there are
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another 15 calendar days for the Agency to complete the ensuing review(s); note that
although multiple acceptance reviews are allowed, they do not reflect favorably on the
applicant and should be avoided.
“Every manufacturer
wants to receive
FDA clearance or
approval for their
medical device
“yesterday.” To
make sure you
minimize delays
in getting your
product to market,
remember to
plan ahead and
allow time to
walk through the
acceptance review
checklist.”
How do I know my submission passed the Acceptance Review?
Assignment of a 510(k) or PMA number does not indicate that the submission has
been accepted for review; it just means that the DCC has successfully processed the
submission. When a submission meets the acceptance review criteria, FDA staff should
notify you in writing that the submission has been accepted for review. At this point,
the reviewer should begin either the substantive review of your 510(k) to determine
substantial equivalence, or the filing review of your PMA. FDA may request information
required as part of the acceptance review during these subsequent review periods even if
the acceptance review was successful.
Key Points to Remember
Every manufacturer wants to receive FDA clearance or approval for their medical device
“yesterday.” To make sure you minimize delays in getting your product to market,
remember to plan ahead and allow time to walk through the acceptance review checklist.
This extra effort will pay off in an administratively complete submission that is not unduly
delayed during the FDA acceptance review process.
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REFERENCES
1. US Food and Drug Administration. Refuse to Accept Policy for 510(k)s: Guidance
for Industry and Food and Drug Administration Staff. December 31, 2012. Available
at: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/UCM315014.pdf. [Supersedes Center for Devices and
Radiological Health’s Premarket Notification (510(k)) Refuse to Accept Policy, June
30, 1993; and 510(k) Refuse to Accept Procedures (K94-1) blue book memo, May 20,
1994].
2. US Food and Drug Administration. Acceptance and Filing Reviews for Premarket
Approval Applications (PMAs): Guidance for Industry and Food and Drug
Administration Staff. December 31, 2012. Available at: http://www.fda.gov/
downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/
UCM313368.pdf [Supersedes Guidance for Industry and Staff: Premarket Approval
Application Filing Review, May 1, 2003].
3. US Food and Drug Administration. Medical Device User Fee Amendments
2012 (MDUFA III). Available at: http://www.fda.gov/MedicalDevices/
DeviceRegulationandGuidance/Overview/MDUFAIII/default.htm
4. US Food and Drug Administration. MDUFA III Commitment Letter.
Available at: http://www.fda.gov/downloads/MedicalDevices/NewsEvents/
WorkshopsConferences/UCM295454.pdf
5. US Food and Drug Administration. eCopy Program for Medical Device Submissions:
Guidance for Industry and Food and Drug Administration Staff. Available at:
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/UCM313794.pdf
6. Code of Federal Regulations. Title 21: Food and Drugs. Available at: http://www.fda.
gov/MedicalDevices/DeviceRegulationandGuidance/Databases/ucm135680.htm
7. US Food and Drug Administration. Premarket Approval Application Modular Review.
Available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/ucm089764.htm
8. US Food and Drug Administration. Acceptance Checklists for 510(k)s. Available
at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/
HowtoMarketYourDevice/PremarketSubmissions/PremarketNotification510k/
ucm071360.htm
9. US Food and Drug Administration. Quality System Information for Certain
Premarket Application Reviews: Guidance for Industry and FDA Staff. Available at:
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/ucm070899.pdf
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