re: docket no. fda-2012-d-0523; draft guidance for ... · substantive review will help achieve that...

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September 27, 2012

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

Re: Docket No. FDA-2012-D-0523; Draft Guidance for Industry and Food and Drug

Administration Staff; Refuse to Accept Policy for 510(k)s

Dear Sir/Madam:

The Advanced Medical Technology Association (AdvaMed) provides these comments in

response to a request for comments regarding the Food and Drug Administration (FDA)

Center for Devices and Radiological Health Draft Guidance for Industry and Food and Drug

Administration Staff; Refuse to Accept Policy for 510(k)s. Notice of this draft guidance and

request for comments were published in Fed. Reg. Vol.77, No. 156 (August 13, 2012).

AdvaMed is the world’s largest association representing manufacturers of medical devices,

diagnostic products, and health information systems that are transforming health care through

earlier disease detection, less invasive procedures and more effective treatments. Our

members range from the largest to the smallest medical technology innovators and

companies. More than 70 percent of our members have less than $30 million in domestic

sales annually. We welcome the opportunity to comment on this guidance and look forward

to working with FDA to ensure the revised guidance meets the needs and expectations of

both FDA and industry.

AdvaMed supports FDA’s effort to provide industry with more clarity and transparency on

FDA’s requirements for the content and format of 510(k) submissions. We agree with FDA

that such clarity will enable industry to better meet FDA’s expectations, and has the potential

to improve overall review time. It is essential that FDA resources are used wisely and

effectively. Allowing only well-organized and complete 510(k) submissions to undergo

substantive review will help achieve that goal.

AdvaMed encourages its members to prepare well-organized and complete 510(k)

submissions. The AdvaMed educational division (Medical Technology Learning Institute—

MTLI) conducts two annual workshops on how to prepare good quality 510(k) submissions.

Division of Dockets Management

September 27, 2012

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These workshops are open to all industry personnel and benefit from participation by key

CDRH staff who provide information on submission organization and content as well as the

510(k) process itself.

AdvaMed agrees that the purpose of the 510(k) acceptance review, as stated in the

“Background” of the draft guidance, should be “to assess whether a submission is

administratively complete in that it includes all of the information necessary for FDA to

conduct a substantive review and to reach a determination regarding substantial

equivalence…” AdvaMed also agrees with the statement in the Purpose section of the draft

guidance that states “It is critical to distinguish between the completeness of the regulatory

submission, and the quality of the data provided and any studies conducted in support of the

submission. The assessment of the completeness of the 510(k) occurs during the acceptance

review, while the assessment of the quality of the submitted information occurs during the

substantive review.”

However, despite these very clear and concise explanations of the purpose of the acceptance

review stated in the draft guidance, some items in the Acceptance Checklists require

responses that could only be provided if a substantive review has been conducted. For

example, Item G. “Shelf Life” on page 13 of the Traditional 510(k) Checklist asks whether

the storage conditions impact the device safety and effectiveness and if so, does the

submission provide certain information. It would be very difficult for the reviewer

conducting the acceptance assessment to determine if the device could be adversely affected

by the storage conditions. The review should be limited to determining if certain information

is present. Additionally, item 21 in section D “Proposed Labeling” on page 9 requires the

reviewer to determine if there is a device specific guidance, special control or regulation and

that the submitter has followed the applicable guidance, special control or regulation.

Determining if there is a device specific labeling requirement and then assessing if the

submitted labeling meets the requirement goes beyond the bounds of an acceptance review.

The acceptance review should determine that the required elements of a 510(k) are present,

that they are legible and provided in English. It should verify that the submission is

organized in a manner that allows efficient substantive review. In the “Adequacy of

information” section of the draft guidance, it states “…FDA should consider only the

presence or omission of the element or a rationale for the omission of the element…” This

very accurately states the checklist criteria objective.

It is critical that FDA limit its acceptance review to prescreening of 510(k) submissions, that

is, to determining whether an element is present and not whether it is substantively

acceptable. As detailed in Attachment A, the checklists contain some items that could be

interpreted as needing a substantive review. Such substantive review should not occur at this

early phase, when FDA is merely determining whether a 510(k) submission contains all of

the required elements.

Division of Dockets Management

September 27, 2012

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Attachment A provides specific comments on the draft guidance and on the three Acceptance

Checklists. These comments reference line numbers applied to the draft guidance text so a

copy of the line-numbered document is provided in Attachment B.

In conclusion and as previously stated, AdvaMed supports the FDA efforts to improve the

clarity and transparency of FDA’s requirements for the content and format of a 510(k)

submission. AdvaMed believes it is important to ensure the most efficient and effective use

of FDA resources and that by ensuring only well-organized and complete 510(k) submissions

are accepted for review, the goal will be achieved. We appreciate the extraordinary efforts

taken by FDA personnel in preparing this draft guidance and support the goals of developing

a guidance that serves the mission of FDA, the needs of industry and the common goal of

benefiting public health.

Sincerely,

Ruey C. Dempsey

Associate Vice President

Technology and Regulatory Affairs

ATTACHMENT A

ADVAMED COMMENTS

Draft Guidance for Industry and FDA Staff

Medical Devices: Refuse to Accept Policy for 510(k)s

of 15

Line(s) No. – Line or lines numbers of the guidance

Change – Proposed change to the guidance

Reason – Reason for proposed change

Line(s) No. Change Reason

General

Throughout, modify documents to support intent

as described in lines 47-51; a process to determine

if all the required documents are present, not a

determination if they are present and adequate.

Determination of adequacy of information is not

appropriate.

The guidance is not always consistent. For example, lines 47-

51 explain the difference between completeness and data

quality, and that this guidance is to assess the completeness, not

the quality of the submitted data (quality is assessed during the

substantive review). However, several items in the checklist

require that an assessment be made as to the quality of the data

submitted. Please see Item #21, page 9 of the Acceptance

Checklist for Traditional 510(k)s. Here, during the check in

process, the item requires that a determination be made if the

submission contains data that satisfies any device-specific

guidance, special controls, or regulations, and that the submitter

has followed the recommendations in these documents, or has

otherwise met the applicable statutory or regulatory criteria

through an alternative approach. The underlined portion of this

requirement can only be determined through a review and

understanding of the submission as a whole. This requirement

goes beyond a mere determination if the submission is

complete. Please see item #34, page 15 of the Acceptance

Checklist for Traditional 510(k)s. Here, the checklist requires

that, “All appropriate categories of software verification and

validation documentation provided based on stated level of

concern, as described in Guidance for the Content of Premarket

Submissions for Software Contained in Medical Devices, or the

ATTACHMENT A

ADVAMED COMMENTS



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submitter has provided documentation that it has otherwise met

the applicable statutory or regulatory criteria through an

alternative approach.” Again, a determination if the appropriate

items are provided should be completed during the substantive

review. For the check-in process, one should merely determine

if software verification / validation documents are present.

53

State the requirements for submitting an electronic

copy of the submission both before and after the

issuance of the required guidance. Clarify if the

absence of an electronic copy is a cause for not

accepting a submission (both before and after the

issuance of the electronic copy guidance).

It is our understanding that submission of an electronic copy of

the submission is required after a guidance is issued. Stating

the requirements before and after the guidance is issued will

avoid having to revise this guidance after electronic guidance is

issued. The FDASIA legislation states:

(Sec. 1136(b)):

‘‘(b) DEVICES.—

‘‘(1) IN GENERAL.—Beginning after the issuance of final

guidance implementing this paragraph, presubmissions and

submissions for devices under section 510(k), 513(f)(2)(A),

515(c), 515(d), 515(f), 520(g), 520(m), or 564 of this Act or

section 351 of the Public Health Service Act, and any

supplements to such presubmissions or submissions, shall

include an electronic copy of such presubmissions or

submissions.

‘‘(2) GUIDANCE CONTENTS.—In the guidance under

paragraph (1), the Secretary may—

‘‘(A) provide standards for the electronic copy required

under such paragraph; and

‘‘(B) set forth criteria for waivers of and exemptions

from the requirements of this subsection.’’.

ATTACHMENT A

ADVAMED COMMENTS



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135

Add:

“The start of the FDA review clock for those

submissions accepted for review after the first 15-

calendar-day acceptance review is the date the

FDA received the submission from the sponsor.”

Clarify the initial acceptance review process is part of the FDA

review clock. Refer to lines 237-239.

180-181

Modify the sentence (add underlined wording):

“The acceptance review which occurs prior to the

substantive review will be conducted…”

Ensure that review process and time are clearly stated. Ensure

consistency with line 226.

194 Clarify “in writing”. We suggest that this

communication be done by e-mail.

Email will move the process more quickly.

194

At the end of the sentence in line 194, add the

information provided in the footnote.

Add: “The review clock will not start until the

510(k) submission is accepted for review.

This is important information that should not be buried in the

citation in the footnote.

206

Modify to read: “Upon receipt of the newly

submitted information, FDA staff will ensure the

new information meets the checklist requirements

and complete the screening process within 15

calendar days.”

There is no need to the reviewer to repeat the screening process.

The reviewer needs to determine that the new information

corrects the deficiency found in the original review.

225-227

Revise as follows (modified words are

underlined): “Should FDA fail to complete the

acceptance review within 15 calendar days, the

submission will be considered accepted, the

submitter will be notified in writing, and FDA will

commence with substantive review.”

Include a copy of the Refuse to Accept Checklist.

The use of “should” implies that the reviewer has discretion in

meeting these requirements.

Provide clarity and demonstrate supervisory concurrence.

ATTACHMENT A

ADVAMED COMMENTS



of 15


227-229

Delete sentence beginning “Once a submission has

been accepted. . .

Add: FDA will make every effort to determine

whether all required elements of the 510(k) exist.

On the rare occasion in which FDA

unintentionally overlooks information that should

have been included, FDA may request such

information during the substantive review.

Although we understand that there will be occasions in which

FDA overlooks a missing element during the acceptance

review, this should be a rare occurrence. Otherwise, the

acceptance review will be meaningless, and could result in

increased overall review time.

238-240

Add after line 240:

“The start of the FDA review clock for those

submissions accepted for review after the first 15-

calendar-day acceptance review is the date the

FDA received the submission from the sponsor.”

This section is unclear as to the date the review clock starts for

510(k)s that are accepted without any RTA.

310-319 Move footnote text to body of guidance This is important information and shouldn’t be buried in a

footnote.

341-346

Remove This is sometimes a very subtle question and should not be part

of the acceptance review. A 510(k) may require significant

review to determine whether 510(k) or PMA is the correct

regulatory submission.

449-457

Insert: “This is not a reason to refuse to accept the

submission.” after sentence beginning “It is

likely…

The reviewer should not be assessing the adequacy of the

information during the acceptance review. We believe stronger

text is needed in this section to avoid such practices.

ATTACHMENT A

ADVAMED COMMENTS



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463-468

Replace example.

As discussed with respect to lines 121-126 above, FDA must be

careful not to conduct a substantive review during this

acceptance “pre-screening”. The example provided arguably

requires a substantive review and subjective determination by

the FDA reviewer as it requires an assessment of whether it

complies with applicable guidance. This is problematic in two

ways: (1) it bogs down the prescreening process; and (2) it

effectively turns guidance recommendations into requirements,

without notice and comment rulemaking.

ATTACHMENT A

ADVAMED COMMENTS



of 15

Acceptance Checklist for Traditional 510(k)s Question

Number Change Reason

General

Format the checklist consistent with the format

requested in the FDA guidance document “Format

for Traditional and Abbreviated 510(k)s”.

Provide consistency and easy verification that all elements are

present.

Pg 1 #3 Remove item #3 See comments on lines 341-346

Pg 4 #7

Remove current language and replace with,

“Submission contains Standards Data Report for

510(k)s (FDA Form 3654) or detailed information

on the use of standards.”

Impossible to tell if the submission relies on standards as part of

the demonstration of SE until the substantive review has started.

Also, without FDA checking the entire document during this

phase, impossible to know all the standards referenced in the

submission.

Pg 4 #8

Add statement to address IVD products that use

clinical specimens to generate data.

IVD manufacturers may use clinical specimens on-site to

generate data. Although it is “clinical data” this type of clinical

data is generally exempt from the requirements of traditional

clinical trials.

Pg 5 #10

Remove. The CDRH coversheet already requires the sponsor to reference

any prior related submissions. If #10 is not removed, add the

CDRH coversheet to the checklist as a required document. This

guidance should consider the FDA guidance on Format for

Traditional and Abbreviated 510(k)s for items to include in the

checklist.

Pg 6 #12

Replace all sections a., b. and c. of #12 with,

“Submission contains descriptive information.”

As written, the substantive review would have to begin in order

for the RTA reviewer to determine if “all” description

information is present and “all conditions of use such as

surgical technique…” are met. Each of the items in #12 is too

detailed for just the acceptance process.

ATTACHMENT A

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Pg 6 #13

Delete:

“Where applicable…dimensions,”

Replace with:

“If the submission contains engineering

drawing(s), schematics, illustrations and/or figures

of the devices, these items are clear and legible.”

As written, the substantive review would have to begin in order

for the RTA reviewer to determine if criteria are met. For

acceptance, merely determine if illustrations are legible. It is

for the substantive reviewer to determine what information is

needed for a determination of SE (e.g., dimensions, illustrations

for each model).

Pg 7 #14a Modify to, “A list of each component or accessory

is provided.”

For components or accessories included in the submission, a

description as detailed as 12a, b, and 13 should not be required.

Only for components or accessories that are part of the system

and under review as part of the 510(k) should require details of

that nature.

This should apply to only those items that are medical devices.

Pg 7 #14b

Modify to, “Each component or accessory that is a

medical device is identified with a 510(k) number,

as 510(k) exempt, or is identified as associated

with the 510(k) under review.”

Pg 8 #17

Remove. This should be part of the substantive review. Additionally, text

is not aligned with statutory language of 513(i) because of

reference to “any differences” language when referring to the

comparison between the device and predicate in determining

NSE.

Pg 8 #18

Delete “advertisements” or add “if available” after

“advertisements”.

The check should merely be for the presence of labeling. The

substantive review should determine what labeling is required

for a determination of SE.

Pg 8 #18b

Remove. This should be part of the substantive review. The check should

merely be to determine if labeling has been included in the

submission.

ATTACHMENT A

ADVAMED COMMENTS



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Pg 9 #21

Remove. This should be part of the substantive review. The wording is

too specific for merely a check-in process; it implies adequate

documentation, which may only be determined during the

substantive review. Here, the reviewer is asked whether the

labeling complies with all of the device-specific guidance,

special controls or regulations, which requires a substantive

review of the content of the labeling. The acceptance review

should be limited to whether the labeling is included in the

510(k) – not whether it complies with FDA’s substantive

expectations. In addition, although this allows for an

“alternative approach”, it risks the reviewer determining

whether that approach is acceptable, and issuing an RTA on that

basis.

Pg 9 #22 Remove. This item would require a substantive review to determine if

labeling complies with 21CFR 809.10.

Pg 10 #23

Modify to read: “Full test report is provided for

each completed test.”

The statement: “..to explain how the data generated from the

test supports a finding of substantial equivalence” implies that

the reviewer will make a qualitative assessment of the

information provided. This would not be appropriate for the

RTA review.

Pg 10 #24

Remove. This should be part of the substantive review. The wording is

too specific for merely a check-in process; it implies adequate

documentation, which may only be determined during the

substantive review.

Pg 10 #25 Add the underlined word, “submission includes Ensure the person doing the substantive review has legible

ATTACHMENT A

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reprints (legible)”

information.

The RTA review should simply confirm the presence of a

discussion, not that the discussion is correct.

Pg 10 #26a

Delete:

“…to explain how the data generated…” to the

end of the sentence.

Delete the sentence in the parenthesis (“A final

study report…pathology, etc.”)

Review of the content of the report is part of the substantive

review.

What is a “contributing scientist report”? This is overly

prescriptive as to what should be in a final animal study report.

Pg 13 #30 Delete the end of the sentence from “…and

storage conditions…” to the end of the sentence.

Determining if the storage conditions could impact safety and

effectiveness requires a substantive review.

Pg 14 #30b

Delete the end of the sentence beginning with “as

applicable…”

The end of the sentence is unclear; appears to be part of

substantive review and determination of substantial

equivalence.

Pg 15 #34

Restate as:

“Software verification and validation

documentation is provided.”

Current wording requires the reviewer to evaluate the content of

the submission to determine if the level of concern is

appropriate. This should be done during the substantive review.

Page 16 #35

Restate as “Submission includes evaluation of

electrical safety.”

Current wording requires the reviewer to evaluate the

information in conjunction with the reference standards or

assess the use of other methods or standards. This should be

done during the substantive review.

Page 16 #36

Restate as “Submission includes evaluation of

electromagnetic compatibility.”

Current wording requires the reviewer to evaluate the

information in conjunction with the reference standards or

assess the use of other methods or standards. This should be

done during the substantive review.

Pg 17 #37a Delete “(at least 3 sites generally necessary)” Not relevant to the RTA review process. Substantive review.

ATTACHMENT A

ADVAMED COMMENTS



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Pg 17 #37b Delete the information within the parenthesis. The information in parenthesis is not relevant to the RTA

review. Should be part of substantive review.

Pg 17 #37c Delete “(detection …LoQ)” The information in parenthesis is not relevant to the RTA

review. Should be part of substantive review.

ATTACHMENT A

ADVAMED COMMENTS



of 15

Refuse to Accept Checklist for Abbreviated 510(k)s Question


ALL

SEE Traditional comments for items that are

identical (Elements of a Complete Submission

sections).

Where applicable, the Traditional comments apply to the

Abbreviated sections.

Pg 1 #3 Remove item #3 See comments on lines 341-346

Pg 7 #9

Add checklist item for user fee form &

confirmation of payment

Why is the user fee referenced with respect to bundling of

submissions but the user fee form is not a separate entry on the

checklist? It would be more useful to sponsors to have the user

fee item in the checklist as well.

Pg 11 #18 Delete “advertisements” or add “if available” after


Advertisements are often developed at the time of 510(k)

submission.

Pg 13 #26a

Delete:

“…to explain how the data generated…” to the

end of the sentence.

Delete the sentence in the parenthesis (“A final

study report…pathology, etc.”)

Review of the content of the report is part of the substantive

review.

What is a “contributing scientist report”? This seems overly

prescriptive as to what should be in a final animal study report.

ATTACHMENT A

ADVAMED COMMENTS



of 15

Refuse to Accept Checklist for Special 510(k)s

Question


ALL SEE Traditional comments. Where applicable, the Traditional comments apply to the

Special sections, even though there are fewer repeating sections.

Pg 1 #3 Remove. While we recognize this is a requirement for a special 510(k),

this should be determined in the substantive review.

Pg 4 #8

Add checklist item for user fee form &

confirmation of payment.

Why is the user fee referenced with respect to bundling of

submissions but the user fee form is not a separate entry on the

checklist? It would be more useful to sponsors to have the user

fee item in the checklist as well.

Pg 5 #13

Modify to read (add underlined wording):

“Identification of history of changes requiring

letter-to-file made since the previous 510(k)

submission.”

Limit the history to those changes that require letter-to-file

documentation.

Pg 8, #20 Delete “advertisements” or add “if available” after


Advertisements are often developed at the time of 510(k)

submission

Draft Guidance for Industry and Food and 1

Drug Administration Staff 2

3

Refuse to Accept Policy for 510(k)s 4

5

This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) 6

current thinking on this topic. It does not create or confer any rights for or on any person and 7

does not operate to bind FDA or the public. You can use an alternative approach if the approach 8

satisfies the requirements of the applicable statutes and regulations. If you want to discuss an 9

alternative approach, contact the FDA staff responsible for implementing this guidance. If you 10

cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of 11

this guidance. 12

13

Purpose 14

The purpose of this document is to explain the procedures and criteria FDA intends to use in 15

assessing whether a 510(k) submission meets a minimum threshold of acceptability and should be 16

accepted for substantive review. 17

18

This guidance document updates two existing guidance documents entitled “Center for Devices and 19

Radiological Health’s Premarket Notification (510(k)) Refuse to Accept Policy” issued on June 30, 20

1993 and “510(k) Refuse to Accept Procedures, 510(k) Memorandum K94-1” issued on May 20, 21

1994. Upon issuance as a final guidance document, this guidance will replace those documents. 22

23

Focusing FDA’s review resources on complete submissions will provide a more efficient approach to 24

ensuring that safe and effective medical devices reach patients as quickly as possible. Moreover, with 25

the enactment of the Medical Device User Fee and Modernization Act of 2002 (MDUFMA), the 26

Medical Device User Fee Amendments of 2007 (MDUFA II) and the Medical Device User Fee 27

Amendments of 2012 (MDUFA III),1 FDA agreed to performance goals based on the timeliness of 28

reviews. Acceptance review therefore takes on additional importance in both encouraging quality 29

submissions from sponsors of 510(k) notifications and allowing FDA to appropriately concentrate 30

resources on complete submissions. 31

32

Therefore, we have modified our 510(k) Refuse to Accept (RTA) policy to include an early review 33

against specific acceptance criteria and to inform the submitter within the first 15 34

35

36

1 See Title II of the Food and Drug Administration Safety and Innovation Act (FDASIA) (P.L. 112-144), amending 37 sections 737, 738, and 738A of the Federal Food, Drug, and Cosmetic Act (FD&C Act). 38

calendar days after receipt of the submission if the submission is administratively complete, or if not, 39

to identify the missing element(s). In order to enhance the consistency of our acceptance decisions 40

and to help submitters better understand the types of information FDA needs to conduct a substantive 41

review, this guidance, including the checklists included in the appendices, clarify the necessary 42

elements and contents of a complete 510(k) submission. The process we outline is applicable to all 43

devices reviewed through the 510(k) notification process and has been compiled into checklists for 44

use by FDA review staff. 45

46

It is critical to distinguish between the completeness of the regulatory submission, and the quality of 47

the data provided and any studies conducted in support of the submission. The assessment of the 48

completeness of the 510(k) occurs during the acceptance review, while the assessment of the quality 49

of the submitted information occurs during the substantive review. FDA will base acceptance on the 50

objective criteria outlined in the associated Acceptance Checklist and not on the quality of the data. 51

52

FDA encourages all submitters to provide an electronic copy (eCopy) in place of one of the two hard 53

copies of the 510(k) submission.2 For additional information regarding formatting eCopies for 54

submissions sent to the Center for Devices and Radiological Health (CDRH), please refer to our 55

website for guidelines for submitting: 56

· General information 57

(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDev58

ice/PremarketSubmissions/ucm134508.htm) and 59

· Clinical data 60

(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDev61

ice/PremarketSubmissions/ucm136377.htm). 62

· 63

For additional information regarding formatting eCopies and submitting hard copies for submissions 64

sent to CBER, please refer to: 65

· “Draft Guidance for Industry: Providing Regulatory Submissions in Electronic Format-66

General Considerations” 67

(http://www.fda.gov/RegulatoryInformation/Guidances/ucm124737.htm) and 68

· “CBER SOPP8110: Submission of Paper Regulatory Applications to CBER” 69

(http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/P70

roceduresSOPPs/ucm079467.htm). 71

· 72

FDA's guidance documents, including this guidance, do not establish legally enforceable 73

responsibilities. Instead, guidance documents describe the Agency's current thinking on a topic and 74

should be viewed only as recommendations, unless specific regulatory or statutory requirements are 75

cited. The use of the word should in Agency guidance documents means that something is suggested 76

or recommended, but not required. 77

78

79

80

81

82

83

2 FDA has issued draft guidance (“eCopy Program for Medical Device Submissions,” available at 84 http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM313794.85 pdf) to implement section 1136 of the FDASIA, which added Section 745A(b) of the FD&C Act, and provides 86 statutory authority to require eCopy. When final, this guidance will represent the Agency’s thinking on this topic. 87

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/ucm136377.htm

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/ucm136377.htm

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm079467.htm

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm079467.htm

Background 88

89

The purpose of the 510(k) acceptance review is to assess whether a submission is administratively 90

complete, in that it includes all of the information necessary for FDA to conduct a substantive review 91

and to reach a determination regarding substantial equivalence under section 513(i) of the FD&C 92

Act, 21 U.S.C. § 360c(i). To find a device substantially equivalent under section 513(i) of the FD&C 93

Act, FDA must find that it has the same intended use as the predicate device, and either (1) has the 94

same technological characteristics as the predicate device, or (2) has different technological 95

characteristics, as defined at section 513(i)(1)(B), and the submission contains information, including 96

appropriate clinical or scientific data if necessary, that demonstrates the device is as safe and 97

effective as the predicate and does not raise different questions of safety and effectiveness than the 98

predicate. 99

100

The 510(k) regulations at 21 CFR 807.87 to 807.100 provide greater detail regarding the specific 101

information that each premarket notification submission must contain. For example, the submission 102

must include proposed labeling (807.87(e)), a statement regarding the similarities and differences 103

between the device and others of comparable type (807.87(f)), supporting data (807.87(f) and 104

807.100(b)(2)(ii)(B)), and FDA may request any additional information necessary to determine 105

whether the device is substantially equivalent when the information provided is insufficient to enable 106

such a determination (807.87(l)). Please also refer to our guidance document entitled, “Format for 107

Traditional and Abbreviated 510(k)s” 108

(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm0843109

65.htm). 110

111

The previous guidances relating to 510(k) RTA policy and the checklist currently used for 112

acceptance review have focused on defining broad issues or principles. Additionally, the previous 113

checklist deals largely with administrative elements but it does not address specific content that is 114

essential for 510(k) review. As a result, FDA accepts many inadequate submissions for review and 115

FDA staff invests significant time in constructing extensive letters requesting all of the additional 116

information needed to conduct a substantive review. This approach is an inefficient use of resources 117

and frequently lengthens review times. For additional information see CDRH’s “Analysis Of 118

Premarket Review Times Under The 119

510(k)Program”(http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProduct120

sandTobacco/CDRH/CDRHReports/UCM263386.pdf). The goal of this guidance document is to 121

clarify the content needed in traditional, special, and abbreviated 510(k) submissions to allow FDA 122

to conduct a substantive review, thereby enhancing the quality of received 510(k) submissions and 123

improving overall review time. The review process presented in this document is captured in the 124

Acceptance Checklists for traditional, special, and abbreviated 510(k) submissions, which FDA staff 125

will use during the acceptance review process. 126

Scope 127

128

The information presented in this document is intended to provide FDA staff with a clear, consistent 129

approach for acceptance review for traditional, special, and abbreviated 510(k) notifications and to 130

outline the RTA policy on 510(k)s. 131

132

The acceptance policy does not alter the substantial equivalence decision-making process once the 133

submission has been accepted for review; however, it does alter the start of the FDA review clock for 134

purposes of MDUFA performance goals for those submissions that are not accepted for review. 135

136

This document does not address the monetary aspects or the MDUFA goals associated with 510(k)s. 137

Information pertaining to the fees and payment procedures for submission of a 510(k) notification 138

can be found online; see “Premarket Notification [510(k)] Review Fees” 139

(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/Pre140

marketSubmissions/PremarketNotification510k/ucm134566.htm). 141

142

Pre-submission Interaction 143

144

Prior to interacting with review staff, submitters should consult CDRH’s Division of Small 145

Manufacturers, International and Consumer Assistance (DSMICA) or CBER’s Manufacturers 146

Assistance and Technical Training Branch for general information regarding the 510(k) regulations. 147

Before submitting a 510(k) notification, we encourage submitters, especially those who are less 148

familiar with the 510(k) review program or who have novel issues to address, to interact with FDA 149

review staff. Such pre-submission interaction is an important way of improving the quality and 150

completeness of a 510(k). For additional information regarding the Pre-Submission process, please 151

refer to the Draft Guidance “Medical Devices: The Pre-Submission Program and Meetings with FDA 152

Staff.” 3 153

(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm3103154

75.htm). 155

156

In addition, other FDA guidance documents and resources provide valuable information for 157

preparing 510(k)s, including: 158

· “Guidance for Industry and FDA Staff: Format for Traditional and Abbreviated 510(k)s” 159

(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/u160

cm084365.htm?utm_campaign=Google2&utm_source=fdaSearch&utm), 161

162

· Other applicable CDRH device-specific and cross-cutting guidance documents, 163

(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/d164

efault.htm), and 165

· CDRH’s Device Advice 166

(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/default.htm) 167

168

169

170

171

172

3 Once finalized, this guidance will represent the Agency’s current thinking on this topic. 173

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/default.htm

510(k) Refuse to Accept Policies and Procedures 174

175

FDA staff will conduct an acceptance review of all traditional, special, or abbreviated 510(k)s based 176

on objective criteria using the applicable Acceptance Checklist (see Appendices A - C) to ensure that 177

the 510(k) is administratively complete. In order for the submission to be accepted, all administrative 178

elements identified as RTA items should be present or a rationale should be provided for those 179

elements determined by the submitter to be not applicable. The acceptance review should be 180

conducted and completed within 15 calendar days of FDA receiving the 510(k) notification. 181

182

The staff will select the applicable checklist based on the 510(k) type (i.e., traditional, special, or 183

abbreviated). The acceptance review will be conducted on original 510(k) submissions and responses 184

to RTA letters, but not supplements or amendments submitted in response to requests for additional 185

information after a submission has been accepted. The staff should assess whether the submission 186

should be accepted by first answering the preliminary questions below, and then verifying that the 187

submission contains all of the information identified as RTA items in the checklist. The submission 188

should not be accepted and should receive an RTA designation if one or more of the items noted as 189

RTA items in the checklist are not present and no explanation is provided for the omission(s). 190

191

If one or more items noted as RTA items on the Acceptance Checklist are not present, staff 192

conducting the acceptance review should obtain management concurrence and notify the designated 193

510(k) contact person in writing that the submission has not been accepted.4 FDA staff should also 194

provide the submitter with a copy of the completed checklist indicating which item(s) are the basis 195

for the RTA designation. 196

197

The 510(k) submitter may respond to the RTA notification by providing the missing information 198

identified in the checklist. The submitter should submit this information to be included in the file 199

under the originally assigned 510(k) number. A new submission and new user fee are not necessary. 200

Nor should the submitter re-send the entire 510(k) submission, unless FDA notes otherwise (e.g., 201

because the majority of the submission is not in English, or the submission is missing the majority of 202

the items on the checklist). It is sufficient to submit and address only the information requested per 203

the Acceptance Checklist. 204

205

Upon receipt of the newly submitted information, FDA staff should conduct the acceptance screening 206

again following the same procedure within 15 calendar days of receipt of the new information. If the 207

submission is still found to be incomplete, FDA staff should notify the contact person and provide 208

the new checklist indicating the missing item(s). 209

210

211

212

213

214

215

216

4 As outlined in the commitment letter for MDUFA III [FDA, "MDUFA Performance Goals and Procedures" (April 217 18, 2012), available at 218 http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM295454.pdf) (attachment 219 to letter dated July 16, 2012 from Secretary of Health and Human Services Kathleen Sebelius to The Honorable Fred 220 Upton, Chairman, U.S. House of Representatives Committee on Energy & Commerce)], the review clock will not 221 start until the 510(k) submission is accepted for review. 222

When a submission is found acceptable, FDA staff should notify the submission contact person in 223

writing that the 510(k) has been accepted and begin a substantive review of the submission to 224

determine substantial equivalence. Should FDA fail to complete the acceptance review within 15 225

calendar days, the submission should be considered accepted, the submitter should be notified in 226

writing, and FDA should commence with substantive review.5 Once a submission has been accepted, 227

FDA may ask for any information during the substantive review that may have been unintentionally 228

overlooked during the acceptance review. 229

230

FDA Review Clock 231

232

As explained in the commitment letter for MDUFA III referenced in Title II of FDASIA, Public Law 233

112-114, “FDA days begin on the date of receipt of the submission or of the amendment to the 234

submission that enables the submission to be accepted (510(k)) or filed (PMA).”6 Thus, the FDA 235

review clock does not start when a submission is designated RTA. The FDA review clock also would 236

not start if we receive unsolicited amendments during the acceptance review period. Once an 237

application is “Accepted,” the FDA review clock begins as of the date of receipt of the most recent 238

submission or amendment that made the 510(k) complete (even if FDA later requests information 239

that should have been requested during acceptance review). 240

241

242

Refuse to Accept Principles 243

244

In order to use this guidance appropriately, FDA staff should review the following basic principles 245

regarding FDA’s review policies and procedures. 246

247

Acceptance should not be based on a substantive review of the information provided in the 248

510(k) notification. 249

250

It is important to make the distinction between the acceptance review and the substantive review. The 251

acceptance review is conducted to assess whether the submission contains all of the appropriate 252

elements, as identified in the applicable checklist, in order to begin a substantive review. In assessing 253

whether a 510(k) notification should be accepted, submitted information is not evaluated for 254

adequacy to support a finding of substantial equivalence. The checklist is a tool to ensure that the 255

submission contains the necessary information in order to conduct a substantive review (i.e., FDA 256

should not refuse to accept a submission if information is present but inadequate to support a finding 257

of substantial equivalence). The evaluation of the quality of the content and the substantial 258

equivalence decision making process occur within the substantive review once the file has been 259

accepted. 260

261

262

5 In the case of extenuating circumstances such as a government closure during the 15-day review period, the 263 review period may be extended by a comparable number of business days that the FDA buildings are closed. If the 264 submitter receives an automated notice that the acceptance review was not completed because the screening period 265 has exceeded 15 days, FDA may send a correction notice to the submitter. 266 6 FDA, "MDUFA Performance Goals and Procedures" (April 18, 2012), available at 267 http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM295454.pdf) (attachment 268 to letter dated July 16, 2012 from Secretary of Health and Human Services Kathleen Sebelius to The Honorable Fred 269 Upton, Chairman, U.S. House of Representatives Committee on Energy & Commerce)],). 270

Staff should consider the submitter’s justifications for any alternative approaches 271

272

The submitter may provide a rationale for why any criteria in the checklist are not applicable to the 273

device. Likewise, the submitter may provide a rationale for any deviation from a device-specific or 274

cross-cutting guidance document or FDA-recognized standard. It is FDA’s expectation that each item 275

in the checklist will be addressed either by including the requested information or providing a 276

rationale for why is it not applicable or why there is a deviation.7 FDA will not consider a given 277

criterion in the checklist to be “Present” if the submission fails to include either the information 278

requested or a rationale for omission or deviation. See Acceptance Review section below for 279

examples and further explanation. 280

281

The submitter should review device-specific and cross-cutting guidance documents, applicable 282

recognized standards, and applicable regulations. 283

284

Before submitting a 510(k), the submitter should consider the currently available guidance 285

documents and standards, as well as applicable regulations for the proposed device in the preparation 286

of the submission. Staff and industry are encouraged to refer to the product classification database 287

(http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm) to assist in identifying 288

any applicable recognized consensus standards and product specific guidance document(s). 289

290

The Checklist – Preliminary Questions 291

292

Within 15 calendar days of receipt of the 510(k), FDA staff should answer the preliminary questions 293

below, which are included on the first page of the Acceptance Checklists. Depending upon the 294

answers to these preliminary questions, the remainder of the acceptance review may or may not be 295

necessary. If the responses to the preliminary questions and subsequent consultation with the Center 296

personnel identified below indicate that the 510(k) acceptance review should not continue,8 FDA 297

staff should promptly notify the submitter using proper administrative procedures. 298

The preliminary questions are: 299

300

301

302

303

304

305

306

307

308

309

7 The presence of a justification is particularly relevant in the acceptance review stage while the adequacy of such 310 justifications to justify the omission of certain information falls within the scope of the substantive review phase. 311 8 FDA will not process a 510(k) unless it meets the following requirements: i) the submission must be sent with the 312 user fee required by section 738 of the FD&C Act, and ii) the firm must submit the correct number of copies per 21 313 CFR 807.90(c). FDA has issued draft guidance to implement section 1136 of FDASIA, which added Section 314 745A(b) of the FDA&C Act (“eCopy Program for Medical Device Submissions,” available at 315 http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM313794.316 pdf). Once this guidance is final, at least one copy of the submission will be required to be an eCopy. Since any 317 510(k) not meeting these two requirements will not be processed by the CDRH Document Mail Center or the CBER 318 RPM, they are not included in the checklist. 319

1. Is the product a device (per section 201(h) of the FD&C Act) or a combination product (per 320

21 CFR 3.2(e)) with a device constituent part? 321

322

If the product does not appear to meet the definition of a device under section 201(h) of the FD&C 323

Act, or does not appear to be a combination product with a device constituent part, then the 510(k) 324

lead reviewer should consult with the CDRH Jurisdictional Officer or the CBER Office Jurisdiction 325

Liaison to determine the appropriate action, and inform division management. If FDA staff 326

determines that the product is not a device and is not a combination product with a device constituent 327

part, the 510(k) review team should stop the review and notify the submitter. 328

329

2. Is the application with the appropriate Center? 330

331

If the application is for a single-entity device and appears to be subject to review in a Center different 332

from the one to which it was submitted, or if it is for a combination product with a device constituent 333

part and it appears that a Center different from the one to which it was submitted has the lead, the 334

510(k) team leader should consult with the CDRH Jurisdictional Officer or the CBER Office 335

Jurisdiction Liaison to determine the appropriate action and inform division management. If the 336

510(k) is submitted to CDRH and CDRH staff determines that the application is not subject to 337

CDRH review, or the 510(k) is submitted to CBER and CBER staff determines that the application is 338

not subject to CBER review, the 510(k) review team should stop the review and notify the applicant. 339

340

3. Is a 510(k) the appropriate regulatory submission? 341

342

Staff should determine whether a 510(k) is the appropriate regulatory submission. If a 510(k) is not 343

appropriate (e.g., Class III type and PMA required, or Class I or II type and 510(k)-exempt), staff 344

should make this determination during the acceptance review and notify the submitter of the 345

determination. 346

347

4. Is there a pending PMA for the same device with the same indications for use? 348

349

If there is a pending PMA for the same device, the submitter should withdraw either the 510(k) or the 350

PMA. The review team should consult division management and other Center resources to determine 351

the appropriate action. 352

353

5. If clinical studies have been submitted, is the submitter the subject of the Application 354

Integrity Policy (AIP)?9 355

356

The lead reviewer should refer to the AIP list 357

(http://www.fda.gov/ICECI/EnforcementActions/ApplicationIntegrityPolicy/ucm134453.htm 358

359

360

361

362

363

9 When data in a pending application have been called into question by certain wrongful acts (fraud, untrue 364 statements of material facts, bribery, or illegal gratuities), FDA intends to defer substantive scientific review of such 365 data until completion of a validity assessment and questions regarding reliability of the data are resolved. (See FDA 366 Guide 7150.09 Compliance Policy Guide, Chapter 50 – General Policy – Subject: Fraud, Untrue Statements of 367 Material Facts, Bribery, and Illegal Gratuities, 56 FR 46191.) 368

). If the applicant is on the list, the reviewer should consult the CDRH Office of 369

Compliance/Division of Bioresearch Monitoring (OC/DBM - BIMO) or CBER Office of Compliance 370

and Biologics Quality/Division of Inspections and Surveillance/Bioresearch Monitoring Branch 371

(OCBQ/DIS/BMB) to determine the appropriate action. 372

373

The Checklist – Acceptance Review 374

375

Organizational Elements 376

Although missing one or more of the items in the table of Organizational Elements in the Acceptance 377

Checklists, such as a Table of Contents or page numbers, generally will not lead to an RTA decision, 378

we strongly encourage submitters to incorporate these elements in their submissions to streamline 379

FDA review and decision-making. If, however, the submission is so disorganized that FDA cannot 380

locate the information needed to assess substantial equivalence, or if the submission is so poorly 381

written (e.g., in broken English) that the information submitted to support substantial equivalence 382

cannot be understood, the submission should receive an RTA decision. 383

384

Elements of a Complete Submission (RTA Items) 385

The objective criteria in this checklist outline those elements that are explicitly required by regulation 386

or that are essential to FDA’s substantive review of the submission and determination of substantial 387

equivalence under section 513(i) of the FD&C Act. For example, proposed labels, labeling, and 388

instructions are required by 21 CFR 807.87(e)), while a description of the materials, design, and 389

other features of the device is essential to determining whether its technological characteristics are 390

the same as those of the predicate and whether any differences raise new questions of safety and 391

effectiveness under section 513(i) of the FD&C Act. 392

393

We have also identified several categories and subcategories of data and information that, when 394

applicable, are critical to supporting a statement indicating the device is similar to and/or different 395

from other products of comparable type under 21 CFR 807.87(f) and the substantial equivalence 396

determination. For example, if the new device has direct or indirect patient-contacting components, a 397

biocompatibility assessment will be essential to evaluating whether the new device is as safe as the 398

predicate with respect to the risk of toxicity it poses to the patient. While testing and data would 399

usually be necessary to such an assessment, this is not always the case (for example if the device 400

under review and the predicate are identical in all relevant respects), and acceptance should be based 401

only on the presence of an item or an explanation why the item is not applicable, not the adequacy of 402

such explanation. If the device has no direct or indirect patient-contacting components, no 403

biocompatibility assessment would be necessary and the biocompatibility items on the checklist 404

would be inapplicable. 405

406

Because the applicability of these categories is also critical to the substantial equivalence 407

determination, in order to be accepted, all submissions should include a statement indicating whether 408

these categories apply, as outlined in the Acceptance Checklist (e.g., materials, presence of software, 409

whether the device is intended to be used sterile). When performance data are 410

provided, the submission of full test reports describing how the testing was conducted is crucial to 411

FDA’s assessment of whether the data support a finding of substantial equivalence. 412

413

Where a device-specific guidance document exists for the subject device, the sponsor should follow 414

the recommendations included in that document, or the sponsor should provide a rationale for 415

addressing the scientific issues discussed in the guidance document using an alternative approach in 416

order to meet the applicable statutory and regulatory criteria. In the absence of the recommended 417

information and without a supporting rationale for an alternative approach, the submission should be 418

considered incomplete and not accepted. If special controls have been identified for the device, those 419

controls should be addressed in order for the submission to be accepted. Note, however, that the 420

special controls must be followed in order for the device to be considered in Class II and therefore to 421

support a finding of substantial equivalence. 422

423

Applying the Checklist of RTA Items 424

Using the Acceptance Checklist appropriate to the submission type (Traditional, Abbreviated, or 425

Special), within 15 calendar days of receipt of the 510(k), FDA staff should answer each question for 426

the elements identified as RTA items. For those items that have an option of “yes,” “no,” or “not 427

applicable (N/A)” as an answer, the item should receive an answer of “yes” or “N/A” for the 510(k) 428

submission to be accepted for substantive review. 429

For the first question in each section related to the need for certain performance data (such as 430

biocompatibility, sterilization, software, etc.), staff should indicate whether the submission has 431

addressed one of the options for the 510(k) submission to be accepted for substantive review. For 432

example, the submission should state that either there are or are not direct or indirect (e.g., through 433

fluid infusion) patient-contacting components in order for the submission to be considered complete 434

and accepted for substantive review. 435

436

Elements marked “Not applicable” 437

In developing the checklists, the Agency has considered the general categories and respective 438

subcategories of information that are necessary to conduct a substantive review for the wide range of 439

medical devices that are appropriate for review under 510(k) premarket notification. All such criteria 440

may not be pertinent to a particular device. Staff should select “N/A” for those elements that do not 441

apply to the subject device. For example, the requirements for financial certification and disclosure 442

statements (21 CFR 807.87(i)) only apply to submissions with clinical data. If the submission 443

contains no clinical data, staff should select “N/A.” 444

445

Adequacy of information 446

In order to make the checklist criteria objective, for each RTA item, FDA should consider only the 447

presence or omission of the element or a rationale for the omission of the element or use of an 448

alternative approach during acceptance review. It is likely that FDA staff will encounter scenarios 449

where information is provided, but is incomplete or inadequate. In such instances, FDA staff should 450

answer the question for the respective item as “Yes,” but may communicate the inadequacy or 451

request additional information in the course of the substantive review. For example, the submitter 452

may have provided full test reports for all performance testing; however, FDA may determine that 453

the results of a particular test are not sufficient to support a finding of substantial equivalence and 454

additional justification would be needed. The performance testing 455

criterion would be marked “Yes” in the checklist and the need for additional justification should be 456

communicated to the submitter during the substantive review. 457

458

Elements marked “No” 459

For any acceptance criterion designated as “No,” FDA intends to provide an explanation to describe 460

the missing element(s), if needed. This explanation is particularly important for a criterion in which it 461

may not be immediately apparent to the submitter what necessary information, specifically, is not 462

present. For example, the Device Description section includes an element that states “submission 463

contains all descriptive information recommended in the device-specific guidance document” and a 464

notation of “No” alone may not be sufficient to inform the submitter of what specific piece(s) of 465

information is missing. FDA staff should include a list or statement of the additional information that 466

is necessary to meet the acceptance criteria. This list or statement can be communicated in the 467

comment section on the checklist beside each specific criterion. 468

469

Conversion of Special 510(k) to Traditional 510(k) 470

FDA has developed separate checklists to address the differences in content for special and 471

traditional 510(k) submissions. FDA staff will utilize the appropriate checklist based on the file type 472

as designated by the submitter. In the event that the submitter has submitted a special 510(k), but 473

FDA determines that the file should be converted to a traditional 510(k), FDA will notify the contact 474

person designated in the 510(k) submission of the conversion and the rationale for the conversion. 475

Additionally, FDA staff should provide the completed Acceptance Checklist for traditional 476

submissions indicating which elements are missing. The submitter may respond by providing the 477

identified information and the acceptance review will proceed with the traditional checklist. 478

479

If a 510(k) designated as a special 510(k) qualifies as a special 510(k), but the submission includes 480

performance data, FDA should offer the submitter two options: (1) the data can be removed from the 481

510(k) and staff will proceed with the special 510(k) checklist, or (2) the 510(k) can be converted to 482

a traditional 510(k) and the submitter will provide any other missing information needed for a 483

traditional 510(k) in order to be accepted for substantive review. 484