device. - advamed...division of dockets management (hfa-305) docket no. fda-2016-d-2021 november 7,...

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Bringing innovation to patient care worldwide

November 7, 2016

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

Re: Docket No. FDA-2016-D-2021

Dear Sir/Madam:

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

a request regarding the Food and Drug Administration (FDA or “Agency”) Center for Devices and

Radiological Health draft guidance Deciding When to Submit a 510(k) for a Change to an Existing

Device. Notice of this draft guidance and request for comments was published in Fed. Reg. Vol.81,

No.152/Monday, August 8, 2016.

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. 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 appreciates the Agency’s significant efforts in updating the 1997 guidance document,

“Deciding When to Submit a 510(k) for a Change to an Existing 510(k)” (the K-97 Guidance). The

K-97 document has served industry well for nearly two decades, however, it is obvious that updates

and clarifications are needed. We also appreciate that FDA has maintained the basic format and

content of K-97. It is important to stress that the flowcharts should not be used in isolation. The

accompanying guidance text provides the actual guidance and valuable examples that aid in decision-

making.

We are very pleased that FDA has recognized and defined the role the Quality System Regulation

(QSR) can play in assuring there are processes in place to evaluate and document changes to a

marketed device. As noted by the Agency, a new 510(k) is not necessary for some type of changes

and reliance on existing quality system requirements may reasonably assure the safety and

effectiveness of the changed device. Manufacturers are required to comply with the provisions of

the Quality System Regulation and are routinely inspected by FDA to ensure compliance. This adds

to the wisdom and validity of the role of the QSR in determining when a new 510(k) is appropriate.

AdvaMed supports the use of risk management principles in interpreting the language in 21 CFR

807.81(3)(i) to determine the effect of a device change. The Agency’s acknowledgement of ISO

14971 as standard for risk management practices not only reinforces the use of internationally

http://www.advamed.org/

Division of Dockets Management (HFA-305) Docket No. FDA-2016-D-2021

November 7, 2016

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recognized standards but also supports the use of practices currently used by industry. However, we

are concerned that the concept of applying risk management in assessing the impact of a change to

the device is inconsistently applied throughout the document. At times, it is properly used; in many

other places, it is missing entirely, and the Agency reaches a conclusion that a 510(k) is likely

required, without much justification. We suggest that the Agency review the draft guidance to ensure

the risk management assessment is applied to all decision-making.

We are concerned about the Labeling Changes section where the “significantly affect safety or

effectiveness” test is applied to the question of change in intended use. The device modification

concept is embodied in the regulations and has been in force since 1977. Although the administrative

history is not terribly revealing of the thinking behind 21 CFR 807.81(a)(3), it makes clear that there

are two tests for determining whether a new 510(k) is necessary: a test for technology changes, i.e.,

“could [a device change] significantly affect safety or effectiveness” or a test for intended use

changes, i.e., “major change or modification in intended use.” 42 FR 42520, 42522 (1977) (stating,

“A change has been made in new [sec.] 807.81(a)(3) to indicate that premarket notification is

required only if the change or modification could significantly affect the safety or effectiveness of the

device or if there is a major change or modification in the intended use of the device.”). Id.

(emphasis added). This disjunctive statement makes clear that technology and intended use changes

are evaluated differently.

What is clear from this regulation, and the FD&C Act since 1990, is that classification of a new

device turned on two distinct characteristics: technology and intended use. Each device classification

regulation has an identification statement that defines the intended use of the type of device classified

under each such regulation. Accordingly, FDA in promulgating its regulation on device modification

clearly recognized that technology changes required a test to determine if such changes required a

new premarket notification and intended use changes likewise required a separate test to determine

whether a change in intended use may result in a new device classification, thus the need to submit a

new premarket notification for FDA’s consideration. In this draft guidance, it appears FDA is

conflating two distinct regulatory concepts by applying the test of one to both.

In conclusion, AdvaMed appreciates the extraordinary efforts taken by FDA personnel in preparing

this draft guidance and supports the goals of developing a guidance that serves the mission of FDA,

the needs of industry and the common goal of benefiting public health. We are generally pleased

with the draft guidance, particularly the recognition of the role of the Quality System Regulation.

We do, however, have some concerns that need to be remedied before issuing the final guidance.

Please see Attachment A for specific suggestions for improving the draft guidance.

Sincerely,

/s/

Ruey C. Dempsey, RAC

Vice President

Technology and Regulatory

ATTACHMENT A ADVAMED COMMENTS

Deciding When to Submit a 510(k) for a Change to an Existing Device

Draft Guidance for Industry and Food and Drug Administration Staff

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Line(s) No. – Line number of the guidance

Change – Proposed Change to the guidance.

Reason – Reason/Rationale for the proposed Change.

Line(s) No. Change Reason

General

We appreciate the stakeholder collaboration that FDA pursued in

developing this draft guidance and see a marked improvement in its

content. In particular, we appreciate FDA’s clear acknowledgement of

the role that Quality Systems and risk management play in modifying

and assessing modifications of medical devices.

General

The terms “Modifications” and “Changes” are used throughout this

guidance. Please define the two terms if they are different or note that

the terms are interchangeable.

Avoid confusion in interpretation.

General

Class I devices are exempt from complying with 510(k) premarket

notification requirements as long as they remain within the limitations

on the exemption. For instance, drainage catheters (paracentesis /

thoracentesis) are Class I devices which are exempt from complying

with premarket notification requirements, 510(k)s, as long as they

remain within the limitations on the exemption as spelled out in 21

CFR 878.9.

Add a section addressing when modifications to Class I devices would

trigger a 510(k) submission.

Manufacturers of Class I devices would benefit from a

discussion on how this guidance can help in evaluating if or

when potential modification to their devices (labeling,

materials, environmental specification, etc.) make the new

device go outside the limitation on the prescribed

exemption and a 510(k) submission would be required.




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Main Flow

Chart

The main flowchart (figure 1) should include software changes.

Materials Change

Software Change

Documentation

Go to Chart C, or D if IVD

Go to Guidance: Deciding When to Submit a

510(k) for a Software

Change to an Existing

Device

This guidance does not directly point to the new software

guidance. Some parallel changes made to the device that

may impact software and other criteria including labelling

or design, will require a parallel assessment. This comment

supports FDA’s recommendation for evaluation of

simultaneous changes (ref. line 200).

90-91

Add scope of wording to include an existing device, or family of

devices:

“….who intend to modify a 510(k) cleared (or family of devices) or a

preamendment device (or family of devices) subject to 510(k)….”

The current wording seems to be applied to a given device,

and although it may refer to a range of sizes for a given

device, clarity by adding family would also allow

alternative options within the product family.




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113

The recall guidance currently states that ODE will review the proposed

modification to determine whether the modification could significantly

affect safety or effectiveness. If this guidance is going to highlight

recalls as being a separate situation, then this section needs clarification

on whether it is the manufacturer's or FDA's responsibility to make this

assessment.

Reconcile the two guidances.

115

Replace “…is indicated.”

With “…is planned.”

More specific wording.

125-127

Change to: “This draft guidance does not apply to software changes or

modifications; however, this guidance does apply to non-software

changes to devices containing software or software that is a medical

device on its own.” to “This draft guidance does not apply to software

changes or modifications; however, this guidance does apply to non-

software changes to devices containing software and non-software

changes to or software that is a medical device on its own.”

Clarify that changes to software are out of scope of this

document. Grammatically, the sentence as written could be

interpreted that the guidance does apply to software that is a

medical device on its own.

130

Delete current wording and replace with:

“Refer to the FDA guidance “Deciding When to Submit a 510(k) for a

Software Change to an Existing Device.”

It is important to direct readers to the guidance; the

reference to a draft guidance being issued is unnecessary.




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133-137

Change to: “This draft guidance does not specifically address

combination products, such as drug/device or biologic/device

combinations, however, the principles and concepts described herein

should be used in determining…”

The guidance must clearly state that the guidance applies to

the device portion of combination products. The current

wording implies that the guidance may just be “helpful.”

137-142

Make sentences beginning with “Furthermore…” and ending with

“…or intended use…” into new paragraph.

Create a new section entitled, “Remanufacturers of Existing Devices or

Reprocessors of Single-Use Devices” and move lines 137-142 under

this new section and heading to read as follows:

Remanufacturers of Existing Devices or Reprocessors of Single-Use

Devices: Furthermore, this guidance, when finalized, is not intended to

address whether 510(k) submissions are required from remanufacturers

of existing devices who do not hold the 510(k) for the device, such as

reprocessors of single-use devices. This guidance does apply to

reprocessors and remanufacturers who have their own 510(k) and are

addressing changes. Remanufacturer is defined at 21 CFR 820.3(w) as

“any person who processes, conditions, renovates, repackages, restores,

or does any other act to a finished device that significantly changes the

finished device’s performance or safety specifications, or intended use.

”

Information regarding remanufactured and reprocessed

medical devices is provided under the heading of the

“Combination Products” subsection. Information regarding

remanufactured and reprocessed medical devices should be

moved to a separate subsection from combination products

for clarity and ease of use.




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144-248

The guiding principles described in Section 4 of the guidance need to

be referenced in Section 5, How to Use This Guidance and in Figure 1

– Main Flowchart. Add a statement at the end of Section 4. Guiding

Principles (Line 248) that these principles need to be considered and

utilized when using the flowcharts, especially Figure 1 – Main

Flowchart.

The guiding principles need to be considered before Figure

1 – Main Flowchart is used, especially the section

Modifications made with intent to significantly affect safety

or effectiveness of a device in Lines 152-158.

153 Please provide an example of a change related to "effectiveness" that

does not result in a 510(k). This example will provide further clarity.

153-155

Define “known risks”. The term needs to be clarified to avoid confusion. Further, a

risk that has been previously identified (“known risk) must

increase in severity or frequency to trigger a new 510(k).

The guiding principles need to distinguish between

continuous improvements that do not significantly affect

safety or effectiveness, even though they may address

known risk or adverse events, versus other improvements

that could significantly affect safety or effectiveness.

Changes that address “known risks” of the same risk level

and frequency as existing risk and could not significantly

affect safety and effectiveness would not require a new

510(k).




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165

Change “…role of testing…” to “…role of verification and

validation…” 21 CFR 820.30 does not limit verification and validation

activities to testing. Modification is proposed to avoid

unintended & overly prescriptive interpretation.

174

Insert from Line 928: “If successful application of appropriate

verification and validation activities confirms the initial assessment,

manufacturers should proceed with the design change and document

their assessment.”

Change “routine” to “appropriate”.

This brings clarity to the entire thought process by bringing

an end to documentation decision. The paragraph discusses

what happens when verification and validation does not

align with the decision made to document based on risk

assessment, there should be discussion on what happens

when it does align with the decision made at the risk

assessment.

204-214

Change wording to the following (changes in red type);

Appropriate comparative device and cumulative effect of changes – In

using this guidance to help determine whether a particular change

requires the submission of a new 510(k), manufacturers should make a

risk-based assessment that compares the changed device to their device

as previously found to be substantially equivalent in their most recently

cleared 510(k) (or to their preamendment device, if no 510(k) has been

cleared). Manufacturers may make a number of changes without having

to submit a new 510(k), but each time they make a change, the device,

with its cumulative changes, should be compared their most recently

cleared device. When the manufacturer compares the proposed

modified device to the device in its most recently cleared 510(k), the

manufacturer should evaluate the cumulative impact of all changes

since their most recently cleared 510(k). When the cumulative effect

Improve clarity and specify that cumulative changes are

considered when comparing to the previously cleared

device.




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of individual changes triggers the regulatory threshold the manufacturer

should file a 510(k). When it does not, the manufacture should

document the last change(s) to file.

222-234

Provide clarification on Agency’s expectations for submission of

510(k)s for modifications for which a 510(k) should have been filed in

the past, but was not. Some of the changes will be several years old,

what is the best way for the company to approach the situation?

Companies should be encouraged to come forth and do the right thing.

This situation arises when

- a company acquires another company and finds that

some modifications that may have required a 510(k)

were not covered by a 510(k)

- the agency’s regulatory thinking is clarified over

time through new guidance documents, creating the

potential for old modifications to become more

significant than they appeared to be in the past.




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224-227

Revise as follows:

That 510(k) should also describe other relevant modifications since the

last cleared 510(k). (i.e., those that did not require a new 510(k)) that

would have been documented as part of the original 510(k) for that

device. Relevant modifications are those that did not require a new

510(k), but are the type of information that is generally expected in a

new 510(k) for that device type.

While we agree with the circuit board and warning

examples that the FDA has provided in lines 228-234, the

current text is very broad and could be interpreted to mean

that manufacturers must communicate and describe an

exhaustive list of changes to the FDA when submitting a

new 510(k) for a modified device. For example, throughout

the life of a product, a manufacturer may have made many

inconsequential, editorial changes to a device’s user

manual. Since the device user manual is a part of the

submission, the manufacturer would be required to describe

each one of these changes in the new submission despite

the fact they were of little consequence. This would be

non-value added to the submission and could also be

extremely burdensome to the manufacturer. As such, we

recommend that only “significant” modifications that did

not require a new 510(k) be described within the new

510(k) for the modified device. The non-510(k) submitted

modifications that are deemed “significant” should be

determined at the discretion of the manufacturer.




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236-241

Delete bullet The premarket notification regulation requires submission

only of changes that could significantly affect safety or

effectiveness or are major changes or modifications to

intended use. See 21 CFR 807.81. The provision here

requires submission of all changes, which goes beyond the

regulation and establishes a new submission or reporting

requirement without foundation. In addition, manufacturers

are required, under the Quality System Regulation, to have

design controls, including procedures to identify, document,

validate or where appropriate verify, review and approve

design changes. See 21 CFR 820.30(i). Where these design

changes do not meet the criteria for submission to FDA, the

Agency still has access to the required documentation

during an inspection. Finally, the inclusion of a large

number of minor changes that would not otherwise require

submission unnecessarily burdens both FDA and industry.

We urge FDA to reconsider this approach.

272 (Main Flow

Chart)

Delete or reword the first question in the flowchart, “Change made with

intent to significantly improve the safety or effectiveness of the device,

e.g., in response to a known risk, adverse event, etc.?”

While we agree with the principle that modifications made

with intent to significantly affect device safety or

effectiveness will likely require a new 510(k), we believe

that incorporating this question as is into the flowchart will

lead to confusion.

One possible point of confusion is the manner in which this

question can conflict with the logic scheme associated with

Section A, Labeling Changes. For example, a manufacturer




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may determine that it needs to update a warning in its

device labeling in response to a significant safety issue with

the intent to significantly improve the device safety and

effectiveness. According to the first question in Figure 1

(Main Flowchart), the manufacturer should submit a new

510(k) to have this modification cleared by the FDA.

However, if the logic scheme provided in Section A is

followed, the manufacturer may implement this labeling

update immediately and submit a Change Being Effected

(CBE) 510(k). We believe the logic scheme presented in

Section A is much more appropriate in this situation, since,

as stated in the draft guidance, manufacturers should be

encouraged to notify existing users of their devices as

expeditiously as possible whenever a pressing public health

need arises. If a manufacturer strictly follows the logic

scheme outlined in the Main Flowchart, the option of

updating the labeling and submitting a CBE 510(k) is not

available. Following such an approach is not in the best

interest of patients.

We also recommend updating the wording in lines 333-337

and 587-589. The “Guiding Principles” section accurately

addresses modifications made with intent to significantly

affect device safety and effectiveness and can be relied

upon to communicate this principle.




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272 (Main Flow

Chart)

To the main flow chart add a question: “Is the change being made

solely to return the device into specification of the most recently

cleared device?”

This initial threshold question is missing from the

flowchart, although discussed in concept at lines 117-118.

276 - 346

Move this section to 269—prior to the main flowchart. This is very important information and should have a more

prominent location in the document. It is more appropriate

to understand this information prior to using the

Flowcharts.

293

Add information on when manufacturing processes are subject to this

guidance (ex., bioresorbables, biological fixation-type devices). It is important to provide information for devices that

require manufacturing information to be provided in a

510(k).

296-297

Delete:

“In cases with multiple changes, manufacturers should use all

applicable flowcharts and explanatory text.”

Replace with:

“In cases with multiple changes, manufacturers should use all

applicable flowcharts and explanatory text and the guiding principles in

Section 4 of this guidance.”

Emphasize that the user needs to include the information in

Section 4, Guiding Principles in the assessment of the

change(s).




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333-337,

Revise to read: “Note that a manufacturer should always consider the

first question is always whether the change is being made with the

intent to significantly improve the safety or effectiveness of the device,

for example, in response to a change in severity or frequency of a

known risk, adverse event, etc. (Figure 1 – Main Flowchart). If so, then

the change likely ‘could significantly affect safety or effectiveness’ and

a new 510(k) likely must be submitted.”

Consistent with recommended revision to Main Flow Chart.

See discussion above (line 272).

353 and

generally

Change “indications for use” to “intended use”. The premarket notification regulation requires submission

only of changes that could significantly affect safety or

effectiveness, or are major modifications to intended use.

See 21 CFR 807.81. See also lines 372-375. Not all

changes in indications for use are major modifications to

intended use, so the reference to indications for use is

confusing and could lead to submissions to the Agency of

changes that do not meet the regulatory trigger.

374

Change the sentence to: “…and a new 510(k) citing a different

predicate, a PMA or a de novo submission…” If the device is no longer substantially equivalent to the

original predicate, it is possible there may be a different

predicate to which the device is substantially equivalent.




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379-381

Delete sentence beginning, “FDA interprets…” FDA’s interpretation in this guidance and use of guidance

to broaden the types of changes that constitute a “major

change in intended use,” a term found in the regulation, is

inappropriate. The regulation sets out two standards: could

significantly affect safety or effectiveness and a major

change in intended use. To subsume the second standard

into the first obliterates the distinction in the regulation.

381 (Chart box

a5.2); 585,630

(Chart Box

B5.2), 894,1151

(Chart D3),

1189,1204

Add the word “significant” as follows: Does a risk assessment of the

changed device identify any significant new risks or significantly

modified existing risks?

Not all new risks require a new 510(k), but the existing

wording in the flowcharts makes it seem that way. Adding

the word "significant” re-introduces judgment into the

situation and makes the document more consistent with the

ideology described in lines 1362-1363: “If a device

modification creates a new risk…that did not exist for the

original device and the new risk cannot be determined to be

negligible, it is likely that the modification could

significantly affect the device’s safety’ or effectiveness, and

a new 510(k) is likely required.”

395

Remove “likely” from “…this change would not likely require

submission of a new 510(k).” Conflicts statement starting on line 39, “In addition, some

changes in the indications for use that limit use within the

currently cleared indication may occur without the

submission of a new 510(k).” -which affirms a 510(k) is not

required.




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398-406

Modify from:

Common changes to the indications for use that typically could

significantly affect safety or effectiveness and therefore usually require

submission of a new 510(k) are:

(1) Reuse of devices previously labeled as “single-use only”

(2) Changes form prescription to over the counter (OTC).

(3) Changes that introduce a new therapeutic or diagnostic claim.

(4) Changes to allow device use in a new patient population.

(5) Changes to the type of joint,, organ, bone vasculature, or tissue

applied to our interacted with.

To:

Changes to the indications for use that are major changes usually

require submission of a new 510(k). In considering whether a change is

a major change, areas to evaluate are changes from single use to reuse,

prescription to OTC, new therapeutic or diagnostic claims, new patient

populations, or new anatomical elements.




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404-406

Move these two items, designated as 4 and 5, to the section beginning

on line 415 that discusses the role of risk.

Add text:

“To assess labeling changes that have a major impact on the intended

use the manufacturer should ask whether the labeling change expands

the use to a new and distinguishable patient population, etc. If the

expansion is to a population with similar demographics, diagnosis,

prognosis, comorbidity, and potential for complications as the original,

then a new 510(k) is not ordinarily expected.”

Unlike items 1-3, which are substantive changes in

indication with longstanding identification as items with a

major change in intended use (see 1997 guidance), items 4-

5 may include more subtle changes, which do not alter the

device risk. An assessment of risk will determine whether

new risks or significantly modified risks exist. Changes to

closely related populations or tissue/vasculature may not

trigger the regulatory threshold.

Language from the 1997 guidance is especially useful in

this type of assessment and is recommended for inclusion in

the revised document.

410-414

Include examples that are more in the gray area. The examples included here are obvious and are not helpful

to industry. We recommend providing examples that might

provide direction in an area that is less clear cut.

419-421

Revise text as follows: “As discussed in Section E, a change that

introduces a significant new risk or significantly modifies an existing

risk likely requires a new 510(k).”

To be consistent with the descriptive text in Section E (lines

1362-1363), the word “significant” should be added here.




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425-439

Add a sentence that clarifies that the change in use environment should

be evaluated for the impact on the risk of use of the device. Not all changes in use environment will result in a change

in the risk of a device. The guidance document states that

changes from professional uses to ambulatory transport are

more likely to affect the device’s risk profile, which is not

the case for all devices. This is a gross generalization, and

a risk evaluation must be applied before reaching a

conclusion.

462 Clarify which guidance is meant. Is this a reference to a guidance

document? It is not clear what guidance is being referenced.

463-475

Revise to read: "Although the guidance is not intended to be used

as the sole justification for whether a new 510(k) may be

required, the factors discussed therein - particularly those

discussing the risk and public health impact of an indication

change -- may be helpful to consider in deciding whether to

submit a new 510(k) for a change to an existing device."

As currently drafted, it appears that FDA may be

qualifying or limiting the Guidance for Industry;

General/Specific Intended Use, which we understand is

not the Agency's intent. The change in order and

language here clarifies that the guidance should not be

used as sole justification, but that it can be helpful in the

analysis.

487-488 Insert language regarding the use and role of the risk assessment to

evaluate changes concerning compatibility or interoperability. Main document principle is missing from this section.

494-514

Delete lines Modification of the Replacement Reagent guidance

document should occur through notice and comment on that

document not through a general 510(k) modifications




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document.

526-531

Use of “change being effected (CBE)” for contraindications is

unfamiliar. Provide more instructions on the appropriate use of CBE.

Please consider the use of CBE for “warnings” as well as

contraindications.

The reference to CBE 510(k) originates from blue book

memo K95-1. This was originally intended to address

510(k) submissions made as a result of a change during a

recall.

540

Add the text provided below: From the K-97 guidance : "Because we

recognize that device labeling often includes contraindications that

would more appropriately be warnings or precautions, labeling changes

that delete contraindications under such circumstances can be made

without the need for a 510(k).”

This language is helpful for applicable devices still in

distribution.




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575-579

Move discussion of items 2-4 to section A5.2 that discusses the role of

risk assessment. Unlike items 1 and 5, which are substantive changes in

indication, items 2-4 may include more subtle changes,

which do not alter the risk assessment. As described in the

principles, use of the risk assessment will determine

whether new risks or significantly modified risks exist.

Changes to closely related populations or tissue/vasculature

may not trigger the regulatory threshold.

The following language from the 1997 guidance is

especially useful in this type assessment and is recommend

for inclusion in the revised document:

“In determining whether a change to the indications for use

raises issues of safety or effectiveness, the manufacturer

should ask whether the changes pose any additional risks,

expands the use to a new and distinguishable patient

population, etc. If the expansion is to a population with

similar demographics, diagnosis, prognosis, comorbidity,

and potential for complications as the original, then a new

510(k) is not ordinarily expected.”

582

Delete sentence beginning, “If the change affects the indication for

use…” The standard has strayed significantly from that set forth in

the regulation from a “…major change or modification in

intended to use…” to “…change affects the indications for

use.”

585 Change the question to: “Does a risk assessment of the device with the The impact of the labeling change is being assessed.




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labeling change identify any new risks or significantly modified

existing risks?”

585-598

Provide an example of the type of change covered by this section. Per EN 14971, most labeling cannot be used to reduce risk

and therefore, cannot affect a devices risk profile. It may

be helpful to have an example here to help give some

context to what FDA would expect to see. One is

inclusion/revision of MR Instructions, which is critical to

ensuring that the device is used in the appropriate MR

conditions.

587-590

Revise text as follows: “As discussed in Question 1 of the Main

Flowchart, if a change to labeling is intended to significantly affect

safety or effectiveness by mitigating a new, significant risk or an

increased probability or severity of a known risk, that change likely

requires a new 510(k)…”

To be consistent with the descriptive text in Section E (lines

1362-1363), the word “significant” should be added here.

591-592

Strike “…particularly if the new risk or increased risk has resulted in a

recall, adverse events…” This language is not needed, and adds confusion. The

analysis will be the same regardless of whether a recall or

adverse event has occurred.

626

Revise to state:

“These changes should be….”

21 CFR 820.30(i) specifically relates to design changes –

should be reflected in the guidance language. The sentence

should specifically refer to the changes discussed in this

section.




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Flowchart B

Include a question asking if the change is a software or firmware

change and a reference to the software change guidance. Device software changes often affect the platform -

particularly as it relates to the use of device accessories

(page 24, Line 820) and changes in human factors (page 24,

Line 830). Because of the overlap, the two guidance

documents should be used in concert. The software

guidance does not address these topics. One still needs to

go back through the relevant questions in Flowchart B

when assessing some software related design changes.

646-647 Delete “This is also true for changes in operating principle as well as

for changes in energy type (discussed below).” Irrelevant as energy type is discussed in a separate section.

714-716 Provide examples of changed in reprocessing instructions when a

510(k) is not necessary. Provide clarity.

770

Change the question to: “Is the same method or validated equivalent

methodology/protocol, as described in a previously cleared 510(k), used

to support the change?”

Change to flowchart as well.

Restricting to “same method” is too narrow, as equipment

becomes obsolete and may need to be upgraded, and

standards for testing may be updated without significant

impact on safety or effectiveness. Therefore the question

needs to be more flexible and allow for an equivalent

method that does not introduce a significant departure from

the original method.

Protocol updates related to changes to test methodology are

subject to the QMS [quality management system] controls

(21 CFR, Part 820) and should not drive the need for a new




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510(k) in and of themselves, if they have been adequately

validated by the manufacturer as equivalent to the original

test methodology that was included in a prior 510(k)

clearance and the test methodology change is not driven by

the change in design as noted in lines 951-954.

777

Add “…in a previously cleared 510(k) and are not equivalent…” Minor, insignificant changes in protocol would trigger the

regulatory threshold.

778

Add:

“Note that modifications or changes to international and recognized

standards that are being used for package integrity or shelf-life claims

would not require a 510(k) when the methods or protocols are updated

as a result of changes to international and recognized standards. Also, a

new 510(k) would not be required when a test method or protocol is

substantially equivalent to the original and has been validated per QSR

[quality system regulation] requirements.”

Packaging validation and testing as well as shelf-life

evaluations for the most part are based on internationally

recognized standards/methods. A 510(k) submission for a

packaging or shelf-life change triggered solely because

there was a change in a method or protocol as a result of

changes to international and recognized standards seems

excessive and unnecessary assuming no other changes have

been made to any other device design specifications.

Internal documentation demonstrating the integrity of the

new packaging or product tested at new expiration dating

continues to meet the intended specifications according to

recognized standards and methods should suffice.

790

Revise to state:

“….magnitude of the dimension….”

Wording is more appropriate. The relative magnitude of

the dimension change compared to the current dimension

should be considered.




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820

Clarify use of the term “component” as used in the statutory definition

of medical device from the use of “component” in the quality system

regulation.

Reduce industry confusion. In QSR, components are parts

or subassemblies. This differs from the meaning of

component in the statutory use.

894

Change from: “Does a risk assessment of the changed device identify

any new risks or significantly modified existing risks?”

To: “Does a risk assessment of the changed device identify any new

risks or significantly modified existing risks that impact the safety/risk

profile of the device?”

Add clarity that risks that impact the safety of the device

are what necessitate a new 510(K). A newly identified risk

might be minor in nature and not warrant a new 510(k).

911-914

Please provide justification for why clinical testing is treated differently

than bench or animal testing. Provide more discussion of the decision-

making relating to clinical testing,

It is unclear why the need for clinical testing automatically

likely requires a new 510(k). An explanation and

understanding will help compliance.

914

Revise to state:

“For the purposes of this question, clinical data does not include data

used for design validation, such as user or patient preference testing.”

Use of a double negative is confusing and I’m not sure if

the intent of the original wording is accurate.

920-921 Add examples of unexpected issues of safety and effectiveness and the

subsequent decision-making. To clarify the intention of when a 510(k) is necessary and

when a 510(k) is not necessary.

922 Provide a definition and examples of “evaluations”. “Evaluation” is a somewhat vague term so a definition and




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examples would clarify the FDA expectations.

925-928

Revise text as follows: “If the manufacturer determines after an initial

assessment that a new 510(k) is not required, the manufacturer should

conduct routine appropriate verification and validation activities to

ensure that no new issues of safety or effectiveness are raised.”

We believe “appropriate” is a more suitable word choice

here, as a manufacturer’s routine quality processes should

be used to identify the appropriate verification and

validation activities required when assessing a product

change. These verification and validation activities are not

necessarily “routine” and will be dependent upon the

modification.

959

Insert: “…or equivalent…” after “…the same…” Changes in the protocol (better test equipment, more robust

acceptance criteria, increased number of test samples, etc.)

that do not minimize the robustness of the testing should

not trigger the regulatory threshold.

After 993 in

Figure 4 –

Flowchart C

See comment about Lines 1025-1042 regarding interchangeability of

the terms “body tissues or fluids” and “tissue or bodily substance”. In

the Diamond C3 of the Figure 4, Flowchart C, uses the term “body

tissues or fluids”. Need to make consistent with verbiage used in Lines

1025-1042.

Provide consistency in terms for “body tissues or fluids”

and “tissue or bodily substance”.




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1003-1004

Sentence should be changed to “C2. Is this a change in supplier,

material type, material formulation, chemical composition, materials

processing or finishing steps?”

Line 1006 calls out additional considerations “…change in

supplier…” and “…finishing steps…”, and for

manufacturers to consider those additional factors in

answering the flowchart question. Without these additional

factors, manufacturers may not be considering these in their

regulatory assessment based on the flowchart question,

although it is understood that the flowchart is NOT a

standalone document for the purposes of performing a

regulatory assessment.

1065-1070

We recommend that FDA provide a specific example in this section to

better inform users on the types and level of information necessary for

toxicological assessment of chemical formulation changes.

Chemical formulation changes can be a challenging area for

manufacturers to assess, particularly related to the level of

testing and detail expected by FDA. Examples with further

detail, particularly for permanent implants such as

orthopedic implants and cardiovascular implants with

differing tissue contacting challenges, would be helpful in

this area to assure that both industry and FDA reviewers are

applying these principles consistently.

1081

Add examples of similar devices: If the manufacturer has used the same

material in a similar device that has been cleared or approved by the

FDA (this would typically involve a biocompatibility evaluation).

Providing examples will allow additional clarity of FDA’s

definition of “similar.”




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1116

Revise question C5 to the following: “Could the change significantly

affect the device’s performance specifications?” Consistent with the rest of the document, the focus should

be on whether or not the change has a significant effect on

the device performance specification. Insignificant effects

should not result in a “Yes” to this question.

1147

Clarify what FDA means by “protocol”. It is not clear whether “protocol” here refers a laboratory

test protocol, which typically is the design of a laboratory

developed test, or another type of protocol. Please clarify

or delete the term.

1151

Move the example “…changes from liquid to solid reagent…” from

“Examples of changes in technology, engineering, performance, or

materials that likely alter the operating principle of the IVD and for

which a new 510(k) is likely required…” in lines 1149-1151 to

“Examples of changes in technology, engineering, performance, or

materials that might alter the operating principle of the IVD…” in lines

1153-1155.

Changes from liquid to solid reagent might require a 510(k)

but are not necessarily likely to require a 510(k). This is

supported by Example 29 (beginning on line 2140). In this

example, a modification takes place in which a reagent is

changed from a liquid form to a lyophilized (solid) form,

and the change is documented internally without

submission of a 510(k).

1157

Insert language to describe the role of the risk assessment in evaluating

the changes described in lines 1149-1157. As described in the principles, use of the risk assessment

will determine whether new risks or significantly modified

risks exist.




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1160

Add words “statistically significant” before word “…impact…” It would be difficult to prove that any change made would

have no impact; these words are in the K97 document and

should be maintained.

1175

Insert:

“Existing definitive guidance for modifications to specific IVDs…” to

this section.

Use language from cover letter to 1997 language to clarify

that the existence of a device-specific guidance, does not in

and of itself preclude use of the 510(k) modifications

guidance. It is only when device-specific modifications are

identified. Reduce industry confusion due to recent

approach to interpreting the Replacement Reagent

guidance.

1177 Add: “…in the Federal Register final…” between “…published…” and

“…device-specific guidance…” Consistent with requirement

1194 Change “can” to “might”. Reduce industry confusion.

1201-1205

Revise text as follows: “For IVDs, a manufacturer’s risk assessment

identifies significant new risks or significantly modified risks when the

risk assessment (1) indicates that the performance of the modified test

could significantly change from the previously cleared performance

claims or (2) identifies new significant risks or significantly modified

existing risks, apart from performance.”

Adding the word "significant” makes the text more

consistent with the ideology described in lines 1362-1363:

“If a device modification creates a new risk…that did not

exist for the original device and the new risk cannot be

determined to be negligible, it is likely that the modification

could significantly affect the device’s safety’ or

effectiveness, and a new 510(k) is likely required.”




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1208-1210

Revise text as follows: “When new significant risks or significantly

modified existing risks have been identified, in general, the change to

the IVD could significantly affect safety or effectiveness of the device

and a new 510(k) is likely required.”

Adding the word "significant” makes the text more

consistent with the ideology described in lines 1362-1363:

“If a device modification creates a new risk…that did not

exist for the original device and the new risk cannot be

determined to be negligible, it is likely that the modification

could significantly affect the device’s safety’ or

effectiveness, and a new 510(k) is likely required.”

1213-1221 Would be helpful to have IVD examples related to this section. Clarity

1259-1261

Revise text as follows: “…if the initial decision following the risk

assessment is that a new 510(k) is not required, the manufacturer should

conduct, as appropriate, design verification and/or validation activities

to confirm the decision.”

The appropriate design verification and/or validation

activities should be identified by a manufacturer’s routine

quality processes.




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1291-1294

Delete lines 1291-1294. This statement is not specific to modifications and should

be deleted. Because the criteria described in lines 1266-

1278 for likely not needing a new 510(k) include the

requirement that the performance of the modified IVD must

not significantly change from previously cleared

performance claims, the only way the performance

specifications of such a modified IVD would deviate from

the performance values of widely accepted voluntary

standards is if the FDA accepted this with the initial 510(k)

clearance. In other words, even without the modification, a

device’s performance specifications may deviate from the

performance of widely accepted voluntary standards if

accepted by the FDA in a 510(k). Furthermore, not all

widely accepted voluntary standards are FDA-recognized,

so it is unclear why manufacturers should necessarily refer

to such standards in their labeling.

1213

Clarify use of the term “component” as used in the statutory definition

of medical device from the use of component in the quality system

regulation.

Reduce industry confusion.

1311

Change: "...all possible risks…”

To: “…all risks related to the device change…”

Risk assessments are large, comprehensive documents that

may contain sections unrelated to the device change. The

risk assessment should focus on the relative portions of the

assessment.




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1335

Change From: Likelihood or probability of harm

To: Likelihood or probability of occurrence of harm

Clarity

1370

Remove words “tolerable” and “insignificant” in parenthesis.

Add the word “unacceptable” within parenthesis.

Qualitative severity level tables in ISO 14971 Annex D

provide acceptable or unacceptable risk acceptability

criteria and do not utilize the terms tolerable or

insignificant.

1371

Remove: “…either before or…” As long as a risk can be mitigated to a pre-defined

acceptability level, there is no change in risk acceptability

so only changes that affect the risk acceptability after

mitigation should be included.

1385-1387

Add in line 1386 after “effectiveness of device,” the phrase “unless

mitigated by existing risk controls,” and add on line 1387 after “can be

mitigated” the phrase “by new risk controls.”

21CFR 807.81(a)(3)(i) reads:

“(i) A change or modification in the device that could

significantly affect the safety or effectiveness of the device,

e.g., a significant change or modification in design,

material, chemical composition, energy source, or

manufacturing process.” It does not specify that the

decision is made prior to mitigating or controlling the risk.

If the mitigation returns the risk to acceptable levels, a new

510(k) may not be required.




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1403

Change the sentence to read:

“Note that labeling modifications, which affect…”

The paragraph is discussing modifications so it should be

discussing labeling modifications.

1415-1418

Consider moving this last sentence into the body of the Draft Guidance,

perhaps in the Guiding Principles, rather than in an Appendix. This is a critical aspect of the law, and should be

prominently stated for those companies that are not as

familiar with the requirements.

1814 - 1823

…“remote” - <10-5 and ≥10-6…..“improbable” - <10-6

“However, the probability of occurrence increased from “remote” to

“improbable” “

Needs clarification as the probability of occurrence appears

to decrease.

1966-1987

Revise the responses to d. The responses are confusing. They appear to relate to a

catheter but the question is related to a device with limited

skin contact.

2124

Add the following modifications scenarios to the IVD technology,

engineering, performance, and materials change examples provided in

lines 2124-2214 in Appendix A:

Change: An IVD depends on a light source for the excitation of

fluorescent signals to achieve its operating principle. Because of

supply issues, a change is made to the light source associated with the

IVD instrument. This change to the light source does not impact the

We believe this section could benefit from a few more

examples and have provided recommendations.




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excitation wavelength.

Relevant questions:

D1 – Does the change alter the operating principle of the IVD? No.

Although the light source is modified, the instrument excitation

wavelength remains the same, and therefore the operating principle of

the system is unaffected.

D3 – Does a risk assessment of the changed device identify any new

risks or significantly modified existing risks? No. The manufacturer’s

risk assessment indicates that the new light source is equivalent to the

previous light source and that the performance of the modified IVD

could not significantly change from the previously cleared performance

claims. The risk assessment also indicates that the modified IVD

presents no significantly new risks or significantly modifies any

existing risks.

D4 – Do design verification and validation activities produce any

unexpected issues of safety or effectiveness? No. Standard methods

and established and justified criteria are used to verify and validate the

modification, and results of the verification and validation studies do

not indicate new issues of safety and effectiveness. The testing also

confirms that the excitation wavelength of the system remains

unchanged despite the change in light source.

Decision: Document the change to file.

Change: The material of an immediate container for an IVD reagent is

modified such that shelf-life of the reagent is improved.




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Relevant questions:

D1 – Does the change alter the operating principle of the IVD? No.

The change in the immediate container does not alter the operating

principle.



risk assessment indicates that the change to the immediate container

does not present any significant new risks or significantly modified

existing risks.





not indicate new issues of safety and effectiveness. Specifically, in

assessing the impact of the modified immediate container on the

reagent shelf-life, the manufacturer uses the same method for

evaluation as was described in the previously cleared 510(k) and

determines that the reagent shelf-life is extended by 3 months.


Note: This change should also be evaluated as a labeling change.

Change: An IVD depends on a thermal cycling system to achieve its

operating principle. A modification is made where the thermal cycler

mechanism changes from liquid to air-based heating while maintaining

the same thermal cycling parameters.




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Relevant questions:

D1 – Does the change alter the operating principle of the

IVD? No. Although the thermal cycler mechanism is modified from

liquid to air-based heating, the thermal cycling parameters did not

change, and therefore the operating principle of the system is

unaffected.



risk assessment indicates that the new heating mechanism (liquid) is

equivalent to the previous heating mechanism (air) and that the

performance of the modified IVD could not significantly change from

the previously cleared performance claims. The risk assessment also

indicates that the modified IVD presents no significantly new risks or

significantly modifies any existing risks.





not indicate new issues of safety and effectiveness. The testing also

confirms that the thermal cycling performance is unchanged despite the

change in heating mechanism change.


2159 - 2168 Expand to have two versions or two decision points. One where V&V

documentation found no significant change and a second where there Under the guiding principles section of this guidance it

talks to modifications that “could significantly affect” and




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was a significant chance. The V&V studies that determined there were

no unexpected issues would result in “Document the change to file” and

the other would be “Submit the change in a new 510(k).”

allows for “…this decision should be confirmed by

successful, routine verification and validation activities. If

routine verification and validation activities produce any

unexpected issues, any prior decision that a new 510(k) is

not required should be reconsidered...” This would seem to

suggest that if no unexpected issues were produced during

V&V performance that the change would not require a new

510(k).

2234

Move lines 2265-2279 to line 2234. We believe that lines 2265-2279 would be more effective if

inserted after line 2234. In doing this, the flow of the

discussion would move from less complex documentation

to more complex documentation, which seems reasonable.

2235

Replace the text in line 2235 with: “When making the decision to not

submit a 510(k), the documentation for a complex change should

include the following:…”

We believe it’s important to clarify that the documentation

elements described in lines 2237-2252 only apply to

complex changes. As described in lines 2265-2279,

simpler changes require less documentation. We also

believe it’s important to clarify that such documentation is

only required for decisions to not submit a 510(k). When

there is a decision to submit a 510(k), such documentation

is not necessary.




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2743

Propose the addition of the term “risk assessment”, taken from

ISO14971:2012 to the Definitions section of the guidance.

Risk Assessment: overall process comprising a risk analysis and a risk

evaluation

Align Risk assessment definitions to ISO 14971:2012

Appendix A

Please provide more examples related to orthopedics and wound

dressings, particularly related to changes in colorants and process

changes that may impact the materials within the design.

These are significant industry sectors and would benefit

from having more relevant examples in applying the

principles defined in this proposed guidance. In particular,

colorants utilized in orthopedic implants have proven

particularly challenging with regards to FDA’s expectation

for testing and 510(k) submission requirements for these

types of changes. Further, colorants are identified in the

definition of “material formulation” but not discussed in the

proposed guidance.

EDITORIAL CHANGES

General

Use one term to express the documentation when a 510(k) is not

filed.

“Documentation” and “letter for file” are used

interchangeably throughout the document and may cause

confusion. We suggest using “documentation” and

providing a definition of what it can comprise.




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General Each flowchart should be on its own page with clear text (largest

font possible) in each flow diagram.

Ease of use.

125 Underline “Software Changes”. For consistency within the document, “Software Changes”

should be underlined.

211

“…compare it to is their…”

Remove ‘is’.

273 Insert page numbers on main flowchart for each chart (A-D) in their

respective circle.

This will help the reader locate the applicable sections more

quickly.

383 Modify from “Figure 2 - Flowchart A” to “Figure 2 - Flowchart A –

Labeling Changes”.

Provide clarification that Figure 2, Flowchart A is for

labeling changes.

564 Renumber A5.1 and A5.2, so that is clear there isn’t an A5. Clarity

632 Modify from “Figure 3 – Flowchart B” to “Figure 3 – Flowchart B –

Technology, Engineering, and Performance Changes”.

Provide clarification that Figure 3, Flowchart B is for

technology, engineering, and performance changes.




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Figure 3 The diamond from B1 needs a “Yes” on the arrow to the right. Minor illustrative correction.

995 Modify from “Figure 4 – Flowchart C” to “Figure 4 – Flowchart C –

Materials Changes”.

Provide clarification that Figure 4, Flowchart C is for

materials changes.

1139

Modify “Figure 5 – Flowchart D” to “Figure 5 – Flowchart D –

Technology, Engineering, Performance, and Materials Changes for

IVD Devices”.

Provide clarification that Figure 5, Flowchart D is for

Technology, Engineering, Performance, and Materials

Changes for IVD Devices changes.

1420 Consider using the format used in the Draft Guidance on software

modifications.

The software modifications document is easier to read.

1569 Reference Example 33, as Example 34 does not exist. The text incorrectly references Example 34 (which does not

exist). We believe the intent was to reference Example 33.

1769 Add: “Relevant Questions:…” Match format of other examples.

1794 Add: “Relevant Questions:…” Match format of other examples.

1809 Superscript -5 and -6 to read: “…of occurrence of <10-5 and ≥ 10-

6…”.




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1836 Remove: “a” due to being the only example for item 20.

1881

Change “Example 27” to “Example 26.” Alternatively, make

Example 26 into Example 22 (and change the preceding note to

match).

It currently points to an incorrect example number. The

alternative of moving from 26 to 22 creates a natural

transition (for the change discussed as a technology change

to immediately discussing it as part of the material

changes).

2071 “.., so the manufacturer is directed to B5.” B4 should be changed to B5.

2107 The note should reference Example 21, not 22. Correction

2224 Fix punctuation of CFR references. It should be part of the preceding sentence.

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