Docket No, FDA-2013-D-0350 Comments on 'Use of ......characterization, (2) toxicological risk assessment, and (3) biological testing. This updated paradigm for the appraisal of medical

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July 22, 2013

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Re: Docket No. FDA-2013-D-0350, Comments on “Use of International Standard ISO-

10993, ‘Biological Evaluation of Medical Devices Part 1: Evaluation and Testing,’

Draft Guidance for Industry and Food and Drug Administration Staff.”

Dear Sir or Madam:

The Advanced Medical Technology Association (“AdvaMed”) is pleased to provide

comments on FDA’s draft guidance “Use of International Standard ISO-10993, ‘Biological

Evaluation of Medical Devices Part 1: Evaluation and Testing,’ Draft Guidance for Industry

and Food and Drug Administration Staff.”

AdvaMed represents 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 treatment. Our members range from the smallest to

the largest medical technology innovators and companies. Nearly 70 percent of our members

have less than $30 million in annual sales.

The FDA’s mission is to protect and advance public health by helping to speed innovations

that provide safe and effective medical devices. In general, FDA has been consistent in

conveying its acceptance of ISO 10993-1:2009 by listing it as a recognized consensus

standard and by issuing the subject draft guidance document. We applaud the agency for

endorsing this international standard on the evaluation and testing of medical devices. We

also are pleased to have available a draft FDA guidance that allows manufacturers to

consider the agency’s current thinking on this topic. We have a number of

comments/suggestions for improving the guidance document; however, which are discussed

below and in Attachment 1.

Docket No. FDA-2013-D-0147

July 22, 2013

Page 2 of 78

FDA’s Draft Guidance Document is Inconsistent with ISO 10993-1:2009

The extent of FDA’s acceptance of the principles established by ISO 10993-1:2009 is not

consistent and not completely clear. For example, as written, the draft guidance document

places a very strong emphasis on biological test selection with minimal guidance dedicated to

the Part 1 standard’s three-step process for biological evaluation, which is: (1) material

characterization, (2) toxicological risk assessment, and (3) biological testing.

This updated paradigm for the appraisal of medical devices is clearly explained in the 2009

standard; however, the agency’s newly issued draft guidance document only mentions

chemical characterization and risk assessment three times (e.g., Pg. 8; lines 374-377

describes that carcinogenicity testing can be waived when chemical characterization testing

and data from literature are provided for justification; Pg. 25; line 986 describes Contents of

Test Report for actual testing or chemical characterization) and toxicology four times. The

guidance does not discuss Material (chemical) Characterization as a first step, as described in

the standard. Additionally, the guidance does not define material characterization.

This guidance document implies FDA favors biological testing rather than utilizing the

principles established in ISO 10993-1:2009 to prompt necessary testing using a risk-based

approach for the evaluation of biological safety of medical devices (e.g., see lines 11, 23, 34-

36, 40-42 in the draft guidance document). Ignoring such a fundamental change to a key

international standard is a major oversight that needs to be addressed.

In the interest of innovation and least burdensome provisions, this guidance document should

be revised to acknowledge throughout that ISO 10993-1:2009 is intended to be applied in the

context of a risk management system, and that the principles of risk management be

considered in determining the level of chemical testing and toxicological assessment

appropriate to demonstrate the biological safety of medical devices. This can be

accomplished by revising the document to accept ISO 10993-1:2009 with a limited list of

exceptions to the standard. For each exception FDA should provide an evidence-based,

literature-cited, patient-safety focused rationale demonstrating the need for the exception. In

this manner, the guidance document will: (1) take advantage of the considerable knowledge

and experience FDA has reviewing a wide variety of medical devices in a large population;

(2) be an objective improvement to FDA’s current interpretation of the ISO 10993-1

guidance; and (3) contribute to a unified and not a fragmented vision for biocompatibility

evaluation. The rationale for each exception will serve to educate industry and allow

qualification plans to specifically address the types of questions FDA has surrounding each

exception.

Extent of Biocompatibility Testing Needed

We appreciate the importance of demonstrating the biological safety of medical devices, but

urge FDA to avoid requiring testing to address speculative considerations, which can have a

chilling effect on innovation because of the inefficient use of FDA’s time (i.e., multiple

review cycles, etc.) and extension of the product development time to rule out theoretical


July 22, 2013

Page 3 of 78

concerns. Rather, FDA’s guidance should recommend testing of those materials that have

unknown or inadequately characterized toxicological risk (e.g., a new implant material). The

guidance also should allow for the possibility that some issues may be better addressed by

material characterization and toxicity risk assessment, or later in the development life cycle

(e.g., after a clinical feasibility study), as well as to consider the level of experience and

expertise required to interpret the relevant information and make well-informed judgments of

the evaluation so that an assessment of the biological safety of medical devices can be made.

Throughout the guidance, FDA utilizes the term “omission” [e.g., pg. 4, line 217, “If

literature is used to support omission of certain biocompatibility tests. . .”]. However, the

term “omission” is not appropriate to describe the use of biological evaluation data from

other sources (e.g., literature reference, other devices’ materials experience, commercial

device use, etc.). The term “omission” is defined as “leaving out something” but is also

defined as “neglect or negligence.” Alternative terminology could include “waived,”

“referenced,” or “in place of.”

Not All Devices are Toxic

The guidance document appears to assume that all devices or materials are toxic. For

example:

“The device materials should not, either directly or through the release of their material

constituents: (i) produce adverse local or systemic effects. . .” (pg. 3, lines 181-184). This

does not take into account the purpose of the material or device, or the risk-benefit

profile, e.g., a device which treats cancer may release chemotherapeutic-like actions

which by their nature intentionally produce “local or systemic” adverse effects and thus

‘non-compliant’ with the FDA guidance requirement. (ii) This same concept is currently

stated within the guidance’s Reproductive and Developmental Toxicity discussion, i.e.,

“for materials with known reproductive toxicity risks, testing and/ or labeling to mitigate

these risks may be necessary” (pg. 21; lines 820-822), i.e., the device has known adverse

event potential and remains acceptable by incorporating mitigation factors, but remains

‘non-compliant’ with the FDA guidance requirement.

These examples illustrate that the draft guidance document does not appear to acknowledge

that a material or device’s tissue interaction is “only one of a number of characteristics to be

considered when making” a material choice, as ISO 10993-1 standard states, “in designing a

device, the choice of the best material with respect to tissue interaction might result in a less

functional device, tissue interaction being only one of a number of characteristics to be

considered when making that choice.”

Inclusion of Real Examples to Illustrate Biocompatibility Issues or Concerns

As FDA has done in other guidance documents, the Agency should include actual rather than

theoretical examples whenever possible. For each of the examples below, it is not possible to


July 22, 2013

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determine whether the examples are “real” or “theoretical.”

The FDA discussion regarding a mucosal membrane contact devices, longer than 24

hours (pg. 7, lines 338-340) for which “certain toxicities that would not be detected with

short term could exist and lead to adverse events.”

The FDA discussion of devices with indirect contact with the blood could introduce

chemical leachants from the device infusion channel that could be irritants” (pg. 7, lines

343-345).

The FDA discussion of device mechanical failure, “if coating particles are released from

a coated device, those particles could lead to a biological response because their materials

properties, such as geometric and/ or physicochemical properties. In addition, coating

delamination could expose the biological system to leaching of different chemicals or to

an increased level of chemicals from the substrate materials. Another consideration is

whether the surface topography could change with mechanical loading is such a way that

the biological response changes.” (pg. 10; lines 437-442):

The term of “animal safety study” is utilized in several locations [e.g., pg 16; lines 643-

653; pg. 18; lines 712-716). This term is not utilized within the ISO standard and is not

explained or defined within the guidance.

The statement that “for certain chemicals, elution from the device may not be necessary

for the chemical to induce toxicity” (Pg. 23; lines 887-891).

Chemical and Biological Evaluation of Biological Materials

The guidance document needs to address chemical and biological evaluation of biological

materials more comprehensively. Chemical characterization of biologics such as collagen is

difficult to perform. What are the special considerations for testing biological materials?

Guidance Implementation

Once this guidance document is finalized, AdvaMed recommends that there be an

implementation period granted to applicants. Companies will need to implement the changes

into their procedures, and some of the required tests are lengthy.

Additionally, in multiple instances, the draft guidance document advises sponsors to contact

the review division prior to initiation of biocompatibility testing (e.g., pg. 2, line 153-154).

As it takes a minimum of 60 days to obtain an FDA in-person meeting, we are concerned that

this recommendation will result in even slower development and review times.


July 22, 2013

Page 5 of 78

Other Comments

A review of recent pre-market applications/submissions by AdvaMed’s member companies

reveals inconsistencies with Agency historical precedent and policies regarding

biocompatibility testing requirements and data interpretation/presentation. While we hope

that the draft guidance will mitigate some of this uncertainty, the inconsistencies our

companies have encountered are extremely impactful as the Agency’s current approach often

is not transparent, nor predictable, and in fact, at times have been in conflict with other such

initiatives. A few examples of these concerns are provided below.

Lack of reviewer experience in interpretation/use of the ISO 10993 standard: This area

encompasses several different issues. ISO requires biocompatibility to be interpreted by

qualified, trained, experienced personnel.1 It appears that many reviewers are unfamiliar with

common materials and processes that have been used by industry for many years and have

ample history of safety. Many reviewers are also unfamiliar with the tests and how to

interpret the results (e.g., hemocompatibility tests, such as complement and coagulation,

which actually are screening tests with no pass/fail criteria).

History of safe use: Many FDA reviewers have not accepted the ISO 10993-1 allowance for

reference to commercial experience of a material. AdvaMed has learned of many instances

where FDA reviewers have required animal biocompatibility testing on a component

identical to that used in a legally marketed device. FDA should define the

threshold/expectation with regard to materials having a “sufficient history of use in medical

devices” including identifying any limitations manufacturing process differences with the use

of prior history (e.g., sufficient history but require on one or two of the basic biocompatibility

tests or surface analysis studies). Industry needs FDA’s clarification on what is acceptable

with regard to comparison of design and materials to legally marketed devices.2

Inconsistencies in FDA’s interpretation of the characterization of a device’s body contact:

Companies are experiencing data requests for incorrect/overly conservative duration/type of

body contact characterizations without understanding the rationale for these requests. For

example, device types that are unchanged in terms of body contact and have for many years

been cleared through the 510(k) process with the same body contact categorization

(consistent with ISO 10993-1 and #G95-1) are now being viewed by the FDA to have a

different body contact classification to that previously accepted (e.g., reclassification of some

devices from skin contacting to externally communicating, tissue contacting).

1 “This part of the ISO 10993 is intended for use by professionals, appropriately qualified by training

and experience, who are able to interpret its requirements and judge the outcome of the evaluation for

each medical device, taking into consideration all the factors relevant to the device, its intended use,

and the current knowledge of the medical device provided by review of the scientific literature and

previous clinical experience.” (ISO 10993-1)

2 See Appendix 1 of Draft Guidance for Industry and Food and Drug Administration Staff –

Investigational Device Exemptions (IDE) for Early Feasibility Medical Device Clinical Studies,

Including Certain First in Human (FIH) Studies, Nov. 10, 2011


July 22, 2013

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FDA refuses to accept alternative test data despite being provided adequate data supporting

the use of the test: For example, we have been told of cases where FDA has refused to accept

alternatives to animal testing (such as leachable and extractable testing) despite this approach

being consistent with recognized standards.

Thank you for the opportunity to submit comments on this important document.

Respectfully submitted,

Sharon A. Segal, Ph.D.

Vice President

Technology and Regulatory Affairs

Attachments

Attachment 1

“Use of International Standard ISO-10993, ‘Biological Evaluation of Medical Devices Part 1:

Evaluation and Testing’”

Page 7 of 78

Comment

No. Line No. Comment/Proposed Revised Text Rationale

1

1-4, 91-94, 113-114, 131-132, 239-240

Use the correct title of the ISO 10993-1 standard throughout the document: “ISO 10993-1:2009, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.” Further, the correct use of the standard name is “ISO 10993” not “ISO 10993” (no hyphen).

The title of the ISO 10093-1 standard was changed in 2009. This guidance document should use the current title of the ISO standard. Given this guidance document discusses an international standard it should be explicitly stated somewhere in the introduction section (e.g., line item 106) of this document that this applies only to US submissions to avoid confusion.

2 26-28

In addition to having this guidance, when final, replace the 1995 Blue Book Memo (G95-1), the guidance should be modified so that it can also supersede the 1987 Tripartite Biocompatibility Guidance (G87-1).

Clarification.

3 58

Revise to read: “In Situ Polymerizing and Bioabsorbable Absorbable Materials” to “In Situ Polymerizing and Materials”

Also, include a footnote that states that “ the term absorbable includes products that fall under the bioresorbable and bioabsorable category.”

ABSORBABLE - referring to an implant’s ability to eventually be absorbed by the body - provides terminology that is consistent with historical and current USP and Eu. Pharm. monographs for both absorbable and nonabsorbable sutures, a designation that dates back at least to the early 1970s when the first glycolide-lactide based implantable devices were commercialized (see nomenclature discussion in Appendix X4 of ASTM F2902-12, Standard Guide for the Assessment of Absorbable Polymeric Implants).

Additionally, the term ABSORBABLE is consistent with the language of numerous 21 CFR Parts 862-892 regulations and the accompanying FDA-CDRH product codes (e.g. HMO, GAK, GAL, GAM, GAM, LMF, LMG, MNU, NEW). Conversely, there are NO current FDA product classifications that utilize the term BIOABSORBABLE. (Source; FDA - Medical Devices - Product Classification Database)

ISO TC194 is currently in the process of converting to utilization of the term ABSORBABLE.

However, a number of companies have started using the term “bioresorbable” and would like the terms to be acknowledged in FDA guidance.

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Page 8 of 78

Comment No.

Line No. Comment/Proposed Revised Text Rationale

4 107-111

Please clarify FDA’s expectation with respect to requirements and thresholds for biocompatibility for IDE studies, including granularity for feasibility, traditional, pivotal, etc. as compared to marketing applications.

The biocompatibility expectations for IDE applications are not specifically outlined in the guidance. The requirements outlined in the guidance appear to be unnecessarily burdensome for an IDE application and in conflict with other FDA initiatives. For example, Draft Guidance for Industry and Food and Drug Administration Staff - Investigational Device Exemptions (IDE) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies Issued for comment on November 10, 2011 states that “FDA recognizes the value of encouraging medical device innovation to address clinical needs and improve patient care, particularly when alternative treatments or assessments are unavailable, ineffective, or associated with substantial risks to patient safety. This guidance has been developed to facilitate the early clinical evaluation of medical devices in the United States under the IDE regulations, using risk mitigation strategies that appropriately protect human subjects in early feasibility studies.”

5 116-120

Revise as follows:

“This guidance document also incorporates several new considerations, including assessment of known or potentially toxic chemicals (e.g., color additives), and sample preparation for submicron or nanotechnology components, in situ polymerizing and bioabsorabable materials, which were not previously discussed in #G95-1.”

In the context of introducing new considerations being incorporated in this document, the use of color additives as the example of known or potentially toxic chemicals may imply color additives are always considered known toxic chemicals or are the only potentially toxic chemicals of concern.

It there something specific about color additives that industry should be aware of?

Suggest removing the color additive example because it may cause confusion at this stage in the document.

6 119 Revise to read: “ . . . in situ polymerizing and bioresorbable absorbable materials, . . .”

See rationale in comment 3.

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Comment No.


7 128-163

Consider reorganizing the document or revise language throughout to reflect:

ISO 10993 1 is intended to be applied in the context of a risk management system, and the principles of risk management are to be considered to form the evaluation appropriate to demonstrate the biological safety of the medical device.

The list of items included in the scope of this document implies the focus of this document is on the selection of biological tests and general and specific considerations for testing and places little credence on the framework established in ISO 10993-1. Since there are many facets associated with an assessment of biological safety, more emphasis on the considerations and thresholds with respect to the ISO 10993-1 framework are essential to interpretation of relevant information and judgment of the outcome of the evaluation in order to make an assessment of biological safety.

As the history of use and mechanisms of tissue responses become better understood, preference can be given to chemical constituent testing and in vitro models in situations where these methods yield equally relevant information to that obtained from in vivo models. For example, a properly designed chemical extraction study with a toxicological risk assessment to rule out patient risks from leachables and extractables can help to reduce further testing and minimize animal usage. The framework established in ISO 10993-1 uses a risk-based approach, and where necessary, the selection and application of additional tests. This approach aligns more closely with the least burdensome provisions of the FDA Modernization Act of 1997.

8 130-132 Please include the specific ASTM standard method titles. Please clarify which ASTM standards (standard methods) are relevant to this this guidance.

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Comment No.


9 130 “ . . . medical devices that come into direct or indirect contact with the human patient’s body.”

Differences in scope between ISO 10993-1 and the FDA guidance document will contribute to user confusion. Focusing on the patient/device interaction rather than “contact with the human body” would focus the guidance on patients and medical devices without creating a distraction about whether the packaging is: (1) considered a medical device, (2) is covered by this medical device standard, (3) handled with gloves, and (4) what testing is indicated packaging, etc. Suggest retaining the ISO 10993-1 language.

10 134 There should be a space after line 134. “This document discusses the following issues:

test selection…”

11 134-142

Revise as follows:

“This document discusses the following issues:

test selection determining an evaluation strategy through assessment of biological effects;

general testing considerations, including sample preparation general evaluation considerations, including comparison to current products, chemical characterization data, and use of safety assessments to justify not conducting of specific biological effects testing;

specific considerations for the following testing: cytotoxicity, sensitization, hemocompatibility, pyrogenicity, implantation, genotoxicity, carcinogenicity; reproductive and developmental toxicity, and biodegradation;

use of animal safety studies to justify omission not conducting of specific biocompatibility tests (e.g., __________); and; . . .”

Please revise as indicated (for clarification) and add an example.

The order implies test selection (cytotoxicity, sensitization, etc.) prior to assessment of risk associated with the product.

Additionally, it is unclear what is meant by “use of animal safety studies to justify omission of specific biocompatibility tests.”

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Page 11 of 78

Comment No.


12 141 Clarify the statement that the document discusses issues with “assessment of known or potentially toxic chemical entities.”

It is not clear whether FDA’s intent is to: (1) combine “known toxic entities” and “potentially toxic entities” or, alternatively, state “known entities” and “potentially toxic entities.”

13 149-151

Include additional guidance with respect to contacting the Agency.

This guidance document advises sponsors to contact the appropriate review division in ODE, CDRH prior to the initiation of long-term testing of any new device material to ensure that the proper testing will be conducted. However no guidance is provided with respect to the Agency’s expectation for this interaction.

Should a pre-IDE meeting be requested? What type of information would be helpful in meeting briefing document? Estimated timeframe from meeting request to meeting? Should documentation of the meeting minutes be included/incorporated into the final submission or biological evaluation plan?

14 150 Define “long-term.” It is unclear how FDA defines “long-term.”

15 157 to 161

Revise as follows: “FDA recommends that full test reports be made available upon request, provided for all tests performed because ISO 10993 includes general methods with multiple options and in some cases does not include acceptance criteria or address assessment of results. It is therefore not appropriate to submit a declaration of simple conformity with respect to ISO 10993. Revise as follows: “Therefore, it may not be appropriate to submit a declaration of simple conformity with respect to ISO 10993.The declaration of conformity with respect to ISO 10993 shall include sufficient detail to provide this information to the scientific reviewer. In addition, the statements contained in Section 10 shall be included on the Declaration.”

Alternatively: Revise: “FDA recommends that full test reports be provided for all tests performed unless testing is conducted according to a recognized standard that does not require data submission. Note that some ISO 10993 standards include general test methods with multiple options and in some cases

The text as written is overly burdensome to the preparer of the 510(k) in that the inclusion of all biocompatibility reports would result in a massive submission for every 510(k). The statement as written defeats the purpose of the Declaration of Conformity.

This revision will also ensure consistency with Guidance for Industry and FDA Staff: Recognition and Use of Consensus Standards, issued Sept. 17, 2007 and Section 3.B.5 (lines 294 – 296) of this proposed guidance.

All records relating to the declaration of conformity with the standard test methods are subject to inspection.

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Comment No.


does not include acceptance criteria or address assessment of results. Additional follow up from FDA may be required.”

16 158 Data transmittal reports should be acceptable for historical compendial testing.

Historically, compendial tests were not within the scope of the GLP regulations, based on the Federal Register, Vol. 43, No. 247 (12/22/1978). Therefore, data transmittal rather than full reports were generated.

17 166 and

through-out document

Revise title of section to read: “Biological Effect Test Selection: ISO 10993 Part 1 and the FDA-Modified Matrix.”

Also throughout this document, as appropriate, language should reflect biological effects to consider, rather than biological tests to perform.

Section 3 Test Selection. The intent of ISO 10993-1 is an evaluation of risks to consider for biological effects and toxicological endpoints as indicated by the device or materials’ patient contact and duration. Continued reference to biological tests may lead to proscriptive interpretation of biological testing identified as being necessary (e.g., checklist). This also leads to confusion in thinking there is one cytotoxicity test, one irritation test, one genotoxicity test, etc. This is the old paradigm reflected in ISO 10993-1 documents prior to 2009. The new paradigm allows for using chemical characterization and toxicological risk assessment prior to biological testing to satisfy the patient safety risk for many of the biological effects to consider. Even though ISO 10993-1 refers to the biological effects as tests FDA should use the correct terminology.

18 171- 172

Revise to read: “The Agency does not clear or approve individual materials that are used in the fabrication of medical devices. The Agency recommends testing medical devices in their final product form and condition whenever possible, except for selected tests (e.g., implantation) that may require that individual materials be evaluated separately. If finished devices will not be available for testing, the evaluation of representative subcomponents of the device should be acceptable, as long as the representative component(s) has been through all intended manufacturing and sterilization processes.”

AdvaMed understands that to ensure patient safety, the biological evaluation of medical devices must go beyond the testing of constituent materials. It is imperative to confirm that manufacturing steps will not compromise the biocompatibility of the device. Processing aids, mold release agents, lubricants, and other additives, as well as cleaning agents and sterilants, can have adverse effects if they contact the body; therefore, the samples used for testing must be selected to take these factors into account. The standard recommends testing medical devices in their final product form and condition whenever possible, except for selected tests (e.g., implantation) that may require that individual materials be evaluated separately. If finished devices will not be available for testing, the evaluation of representative subcomponents of the device should be acceptable, as long as the representative component(s) has been

Attachment 1



Page 13 of 78

Comment No.


through all intended manufacturing and sterilization processes.

19

175 -176, 181-182; 188-189

Please define “material”, “material constituents”, “medical device” “finished medical device,” and “medical device materials” to align with ISO 10993-1 for consistency.

There is inconsistency and confusion within the document in the definitions of several terms: material; material constituents; medical device; medical device materials; final finished device. Each term is defined or their definition is inferred differently throughout the document and is not consistent with their use in ISO 10993-1. Clarification of definitions and consistency is their use is needed throughout this document.

Material. The document states that the use of the term “material” in this document refers to the final finished medical device and not the individual material constituents. However, on page 5 and line 238, the document states the scope of this multi-part standard is to evaluate the effects of medical device materials. The use of the term “material” in this document refers to any synthetic or natural polymer, metal, alloy, ceramic or other non-viable substance, including tissue rendered non-viable, used as a medical device or part thereof.

The FDA should be consistent with the definition provided by the referenced standards (ISO 10993-1 and ISO 10993-12) when using the term “material.” Both standards keep a distinction between material and medical device. Also use of the word “material” to mean “final finished medical device” is confusing and not consistent throughout the document. To interpret the term “material” to refer to the final finished medical device captures one, and not the entire, definition of material. To be completely consistent with ISO, which states “ISO 10993-1 appreciates that the term ‘medical device’ is wide ranging and at one extreme consists of a single material.”

The use of the term “material” does in fact go beyond the final finished medical device.

Material constituents. It is unclear if “individual material constituents” refers to the raw material, or individual materials representative of the final finished device (e.g., same processing of the materials, same manufacturing methods, same sterilization, and same manufacturing

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Comment No.


residuals) or the chemical components of each device material.

Medical Device. In the introduction to ISO 10993-1, the term “medical device” is defined as ranging from a single material to a complex instrument made of more than one material. Also, ISO 10993-1 later defines the term “material” as any substance used as a medical device or any part thereof which is different than how FDA defines the term. A clarification and consistency in defining terms” is essential and required.

Final Finished Device/Form. The term “final finished medical device” refers to a medical device in its “as used” state, as defined by the manufacturer’s specification or labeling. The definition of “final finished form” is slightly misleading and could lead to different interpretations. It could refer to when the device is used in surgery after end-user manipulation, when the device is sterilized as intended but not packaged, when the device is packaged and sterilized (for sterile packaged products), or when a non-sterile device is sent. The handling during shipment or additional end-user sterilization is often outside the control of device maker.

20 177

(footnote)

Revise to read: “ISO 10993-12:20072012 “Biological evaluation of medical devices – Part 12: Sample preparation and reference materials”

Correct the typographical error (part 1 v part 12) and to reflect the most current edition of ISO 10993-12.

21 180-184

Revise to read: “To ensure fitness for use, consideration should be given to device materials and material constituents that may become available to the patient when the device is in the use environment. In general, consideration should include evaluation of the potential for The device materials should not, either directly or through the release of their material constituents: (i) produce adverse local or systemic effects; (ii) be carcinogenic unacceptable carcinogenic risk; or (iii) produce adverse reproductive and developmental effects.”

Additionally, in the interest of innovation and least burdensome approach, the agency should consider taking the risk-based

This language needs to be modified since it states that if any extractant is found to have positive carcinogenicity data, the material would not be allowed in a device. This has not been FDA practice. This statement also contrasts with the language on page 20 (second bullet line item 788), where it describes a cancer risk assessment should be provided to demonstrate that a carcinogenic chemical does not pose an unacceptable carcinogenic risk.

The agency’s current thinking does not seem to allow for scaling of biological evaluation based on patient risk, a key theme of ISO 10993-1:2009, or acceptance of reasonable risks when potential benefits are determined to outweigh risk for a particular patient

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Page 15 of 78

Comment No.


position similar to ISO10993-1:2009 with regard to the need for systemic testing.

population.

Both scalability and acceptance of risk with benefit to the patient population are essential principles to ensuring that manufacturers invest in research and design of innovative medical devices.

Additionally, the guidance seems to indicate that if the first tiers of evaluation indicate that occurrence of biological hazards are low then the manufacturer should proceed to more testing rather than concluding that the risk to the patient from biocompatibility hazards is as low as reasonably possible.

Examples reference line items 21-23 of the table.

Further, It is unclear why the biological effects associated with devices that have prolonged or chronic tissue contact is specifically called out. This may lead the reader to believe these effects are relevant to all devices.

Additionally, it is possible that a device may produce minor local or systemic effects may be an identified hazard for a device but in consideration of benefit of the device this may be acceptable.

Additionally the use of a device in a certain patient population may negate potential adverse effects.

22 181-184

Revise to read: “To ensure fitness for use, consideration should be given to device materials and material constituents that may become available to the patient when the device is in the use environment. In general, consideration should include evaluation of the potential risk of adverse local or systemic, carcinogenic, reproductive and developmental effects with attention to the device use environment, intended patient population and device overall benefit.”

23 184 Define “new device.” Clarity is needed on how FDA defines a “new device.”

24 184-185 Revise to read: “Therefore, evaluation of any new device intended for human use requires data from systematic testing

Unclear what is meant by the term “risks.” “Toxicological risk” is

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Comment No.


to ensure that the benefits provided by the final product will exceed any potential toxicological risks produced by device materials.”

preferred.

25 184-186

Revise as follows: “Therefore, evaluation of any new device intended for human use requires data from should include consideration of system effects and may require data from systemic testing to ensure that the benefits provided by the final product will exceed any potential risks produced by device materials

Duration of use and mobility of chemical constituents may negate the need for systemic testing.

Further, this statement is not consistent with the ISO standard. To require “all” new devices to undergo systemic testing does not allow the use of referenced data as allowed by the ISO standard, forcing animal testing when it may not be necessary, in conflict with the ISO standard’s stated objective to reduce animal use.

26 188-195

Revise to read: “When selecting the appropriate tests for biological evaluation of a medical device, one should consider the chemical characteristics of device materials and the nature, degree, frequency and duration of exposure to the body in order to determine the probable biological effect risks. Depending on probable biological effect risks associated with the intended use of the device, target population, and/or nature of contact with the body the safety evaluation may include some or all of the following: comparison to marketed product and/or clinical history of use, chemical characterization and safety assessments, or biological effects testing including: in vitro cytotoxicity; acute, sub-chronic and chronic toxicity; irritation; sensitization; hemocompatibility; implantation; genotoxicity; carcinogenicity; and effects on reproduction, including developmental effects as appropriate. Additional testing may be required if methods described above are not capable of generating evidence regarding probability of occurrence required for demonstrating safety with regard to an identified potential biological effect.”

The option of chemical characterization/comparison is presented after biological testing in Section 3. Due to order/organization of this guidance document it is not clear if FDA expects biological testing on all products or accepts chemical characterization/comparison.

Suggest presenting the chemical characterization information prior to biological testing information for consistency and alignment with ISO 10993-1.

Also including a statement that these tests may not be sufficient to demonstrate safety (with example) as well as a statement that not all testing is required for every device (with example).

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Comment No.


27 190-195 Clarify that all of tests listed are not required for all devices.

Reference to the battery of extensive testing as general may be inappropriately interpreted as a requirement of completing all the ‘general tests’ for all devices or materials that seem to conflict with other statements in the guidance:

‘selecting the appropriate tests for biological evaluation of a medical device, one should consider the chemical characteristics of device materials, and the nature, degree, frequency and duration of exposure to the body’

‘The specific clinical application and the materials used in the manufacture of the new device will guide selection of the appropriate tests.’

28 193-194 Please clarify between device and material characteristics. What is the difference between “device” and “material” characteristics in this context? Are they both referring to the material of the device?

29 195-196 “Additional tests for specific target organs . . .” should be provided in device-specific guidance documents and not in a general device guidance.

Specific target organ tests are more appropriately discussed in device-specific guidance documents.

30 196-200

Revise to read: “For example, a neurological device with direct contact with brain parenchyma and cerebrospinal fluid (CSF) may require an animal implant test to evaluate its effects on the brain parenchyma, susceptibility to seizure, and effects on the functional mechanism of choroid plexus and arachnoid villi to secrete and absorb CSF pathological and neural behavior effects.”

There is no reason to elevate susceptibility to seizure, which is just one potential manifestation of neurotoxicity, over other potential neuronal effects

It is hypothetical to consider devices with CSF contact could “affect functional mechanism of choroid plexus and anrachnoid villi to secrete and absorb CSF”, unless data from well-controlled studies could be provided to support this statement.

31 197-200

Revise to read: “…an implantable neurological device with direct contact with brain parenchyma and cerebrospinal fluid (CSF) may require an animal implant test to evaluate its effects on the brain parenchyma…”

Surgical instruments and other non-implant devices with limited or transient contact with CSF or brain parenchyma may not need the brain implantation study to estimate the risk. Make allowance for contact duration instances.

32 203 “…that have been well-characterized chemically and…” The term “well-characterized” should be hyphenated.

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Comment No.


33 204 Revise to read: “Some devices are made of materials that have been well characterized chemically and physically in the published literature and/or have a long history of safe use.”

Statement indicates materials have been well-characterized in the literature and have a long history of use. It is possible a material has not been characterized in the literature yet does have a long history of clinical use in predicate devices. Also possible is a material has been well characterized in the literature yet does not have a history of clinical use.

34 203-208

Revise to read: “Some devices are made of materials that have been well characterized chemically and physically in the published literature and have a long history of safe use. For the purposes of demonstrating the substantial equivalence of such devices to other marketed products, it may not be necessary to conduct all of the tests suggested in the FDA matrix of this guidance. FDA reviewers are advised to use their scientific judgment in determining which tests are needed for demonstration of substantial equivalence in a 510(k) submission.”

Guidance suggests that amount of data required for determining biological safety is dependent on submission path way, i.e., stating that demonstrating chemical equivalence through chemical characterization is only acceptable for 510(k) products. Section 10 discusses chemical equivalency evidence for PMA products. This separation implies demonstration of chemical equivalency is more rigorous for a PMA than a 510(k). Required evidence for chemical equivalency should depend on risk (potential harms) regardless of approval pathway.

Example: Hypodermic Needles are considered 510(k) products, however, when kitted with a PMA product they are part of the PMA submission for the same intended use. A change to the manufacturing facility of a hypodermic needle evaluation to demonstrate safety would require the same information since the products have the same intended use and therefore are equally capable of causing the same harm.

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Page 19 of 78

Comment No.


35 204-206

For the purposes of demonstrating the substantial equivalence of such devices to other marketed products, it may not be necessary to conduct all of the tests suggested in the FDA matrix of this guidance.

We agree with this guidance statement; however industry has noted that reviewers appear to be interpreting the tests identified in Table A.1 in ISO 10993-1as a checklist for mandatory testing, rather than as tests for consideration within a biocompatibility risk assessment. Please see recommendation below.

36 206-208

Revise to read: “FDA reviewers are advised to consult a toxicologist to determine whether certification to a material standard is sufficient or if additional tests are necessary in determining which tests are needed for the demonstration of biological safety in an IDE, PMA, or 510(k).”

New text is consistent with FlowChart C and line 393.

It appears this statement was taken directly from the Blue Book Memorandum #G95-1 and incorporated in the revised draft guidance.

AdvaMed has noted inconsistencies across FDA reviewers with regard to interpretation/use of ISO 10993 standard. We recommend that as part of implementation of this guidance, appropriate training of ODE reviewers be incorporated in such a way to mitigate the interpretation/use inconsistencies that are currently encountered.

Note: A memo was distributed with Blue Book Memorandum #G95-1, entitled Use of International Standard ISO 10993, "Biological Evaluation of Medical Devices Part 1: Evaluation and Testing" and related to implementation of #G95-1 requiring training for all ODE reviewers in the proper use of ISO 10993.

We recommend that if training to this standard has not occurred recently that the Agency mandate updated training (once this guidance has been finalized) and ensure there is periodic (annual) retraining to support guidance and standard intent.

Further, for clarity and in accordance with ISO 10993-1, a reviewer of a submission may not have the training or expertise to determine which biocompatibility tests would still be needed if the material already has long history of safe use.

The draft states that FDA Reviewers are to use their “scientific judgment” in determining which tests are needed….” This statement provides no practical means for a device manufacturer to assure

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Page 20 of 78

Comment No.


compliance with the standard. This is a kin to “trying to hit a moving target.” This approach provides no evidence of objectivity and certainly will lead to situational interpretation by Reviewers. None of which provides a least burdensome approach for industry.

37 208 It is unclear what submission requirements are appropriate for demonstrating substantial equivalence.

Add explanations, expectations, and/or examples of submission requirements for demonstrating substantial equivalence.

38 208-209 How does FDA define “particular material?”

How specific must the comparison material description be? For example, stainless steel material is a somewhat general category; does comparison have to be stainless steel 316 vs 316L? Or can it remain simply “stainless steel,” which has a long, successful human exposure clinical record.

39 211-214

Revise to read: “For the purposes of demonstrating a reasonable assurance of safety and effectiveness in a PMA application, an independent assessment of the biocompatibility of the device is necessary; however, sponsors may leverage information from existing approvals and clearances. Refer to Section 10, Component and Device Documentation Examples for additional information on comparisons to legally marketed devices.”

The purpose of biological evaluation is to demonstrate safety and not effectiveness.

Please clarify what would constitute “an independent assessment of the biocompatibility of the device.” Is the sponsor responsible for obtaining this assessment? How does the sponsor ensure that the assessor is acceptable to FDA?

40 211-225 Clarify the use of information from existing approvals or clearances.

The guidance seems to:

Limit the data sources available to the sponsor, i.e., the ISO standard allows the consideration of “other information, other non-clinical tests, clinical studies and post-market experience for an overall assessment”(10993-1; section 4.8).

Allow the sponsor to reference (for biocompatibility purposes) a cleared 510(k) device within a PMA application. However, it is not stated directly that a 510(k) application may reference a “legally marketed device” may include PMA approved device’s materials’ experience.

Specify that an “independent assessment” is necessary. Who provides this assessment? Can the assessment be performed

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Comment No.


by experts outside of FDA and the sponsor? (such as notified body or similar test laboratory with known toxicological expertise).

41 219-221 Revise to read; “In addition, while literature may be appropriate to support the omission of certain toxicity tests, it may not be appropriate to justify omission of all biocompatibility studies.

NOAELs are usually established based on most sensitive toxicity endpoints in toxicity studies. In those studies, both general systemic toxic effects and specific toxicity effects are monitored. If a NOAEL is established in a toxicity study based on reproductive or carcinogenic toxicity endpoints, we should be able to use this NOAEL to support not conducting a carcinogenicity or reproductive toxicity study.

42 221-225

Revise to read: “For example, No Observed (or Observable) Adverse Event Effect Level (NOAEL) and Low Lowest Observed (or Observable) Adverse Event Effect Level (LOAEL) data should be derived from studies relevant to the endpoint under consideration. Existing (literature) data and/or toxicological risk and/or safety assessments based on the literature may be used to meet ISO 10993-1 requirements without unnecessary animal testing.” could be used to justify omission of acute, subchronic, or chronic system toxicity assessments, but would not be relevant for genotoxicity, local and systemic carcinogenicity, sensitization, or reproductive toxicity assessments.”

NOAEL is an acronym for No Observed (or Observable) Adverse Effect level, not "no observed adverse event level." LOAEL is an acronym for Lowest Observed (or Observable) Adverse Effect Level, not "low observed adverse event level."

The guidance document is inconsistent in the applicability of literature references and no observed effect levels. In lines 376 and 787-796 literature is indicated as an appropriate method for omitting carcinogenicity testing. In lines 912-917 “One approach to this assessment is to consider whether, if all of the chemical were to become bioavailable, how this amount compares to the amount at which toxicities are known or thought to exist. If available toxicity information suggests that even if all of the chemical were to become bioavailable, no toxicity concern would exist (i.e., the amount is well below the amount at which toxicity concerns are present), no further information is needed.” [emphasis added]

With respect to carcinogenicity:

For example, FDA is considering a proposed change to ICH S1 guidance on rodent carcinogenicity where “knowledge of pharmacologic targets and pathways together with toxicological and other data can, in certain cases, provide sufficient information to anticipate the outcome of 2-year rodent studies and their potential value in predicting the risk of human carcinogenicity of a given pharmaceutical. It is hypothesized that consideration of this

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Page 22 of 78

Comment No.


information can provide sufficient information to conclude that a given pharmaceutical in certain cases presents a negligible risk or, conversely, a likely risk of human carcinogenicity without conducting a 2-year rodent study.” 78 Fed Reg 16681-4, March 18, 2013. Nevertheless we understand that carcinogenicity NOAELs have not typically been accepted by the regulatory community because of the theoretical mechanistic argument with genotoxins (i.e. the one-hit theory). Therefore carcinogens need to be evaluated on an acceptable risk or de minimis risk basis.

With respect to genotoxicity:

To address this, a toxicologist should be able to use a threshold of toxicological concern as suggested in “FDA Draft Guidance for Industry: Genotoxic and Carcinogenic Impurities in Drug Substance and Products: Recommended Approaches” or in “ICH DRAFT CONSENSUS GUIDELINE – Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk M7” (if appropriate based on dose, duration and route of effect) to determine if the product has a reasonable safety profile over all toxicity end points. This type of safety assessment may support not conducting genotoxicity tests.

43 227-304 (Section

3.B) Move history section to the beginning of the Introduction.

The history section seems a better fit at the beginning of the introduction to the guidance document, where it would align the guidance more with the ISO standard and frame test selection and testing details more in the context of addressing data gaps to assess device risks.

44 229-231 Clarify this statement to fully describe the intent of the Tripartite Agreement.

The Tripartite Agreement was intended for use only for “polymers” and that FDA should use their judgment in “adapting the present table to other materials (e.g., metals, ceramics, biological).”

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Page 23 of 78

Comment No.


45 253-255

Revise to read: “For FDA submissions, substantially equivalent product comparison evaluations, material/chemical characterization data and toxicological risk assessments should be reflective of the final product. If toxicological risk assessments are inconclusive regarding the potential occurrence of a particular biological effect, then targeted biocompatibility testing (using validated in vitro and/or in vivo models) should also be done with consideration to the final product. final product biocompatibility testing (using both in vitro and in vivo models), and/or adequate chemical characterization in conjunction with supplementary biocompatibility testing may be acceptable and/or Acceptable justification as identified in attachment C.”

The listing of biocompatibility testing before chemical characterization implies the agencies preference is different from ISO 10993-1:2009. Also, the text, as written, seems to imply that any chemical characterization testing must be supplemented with biocompatibility testing.

Further, the document indicates two options:

1) “final product biocompatibility testing (using both in vitro and in vivo models),”

and/or

2) “adequate chemical characterization in conjunction with supplementary biocompatibility testing may be acceptable.”

Attachment C provides a third option “Acceptable justification or test data.” Please revise lines 254-255 to be consistent with attachment C

46 257-258

The Tripartite seven principles should be kept separate (e.g., separate paragraph, section, or heading) from the FDA’s 2013 “expansion” as follows:

Principle 1(pg. 5, line 264): The text starting with “In situations where materials. . .” is not contained within the Tripartite or ISO document and should be separate from the previous text.

Principle 4 (pg. 6, lines 286-292): The text starting with “If information on non-clinical. . .” is not contained within the Tripartite or ISO document and should be separate from the previous text.

Principle 5 (pg. 6, lines 295-296): The text starting with “unless testing is conducted. . .” is not contained within the Tripartite or ISO document and should be separate from the previous text.

The FDA’s described “same seven principles” are not the “same, but have been expanded upon with additional information and scope.

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Page 24 of 78

Comment No.


47 260-263

Revise to read: “The selection of material(s) to be used in device manufacture and its toxicological evaluation should initially take into account full chemical characterization of all patient contacting manufacturing materials of manufacture, for example, chemical formulation for each component material, including adhesives, known and suspected impurities, and constituents associated with processing.”

Biocompatibility testing assesses chemicals present on or extract from device patient contacting materials.

The phrase “…of all materials…” conflicts with lines 110-111 “…determine the potential toxicity resulting from contact of the component materials of the device with the body.” Including materials known to be non-patient contacting is beyond the scope of biocompatibility.

“Manufacturing material” is the preferred term because it is defined in 21 C.F.R. §820.1.

48 267-268

Revise to read: “However, this may not be sufficient or represent the full characterization of the final device patient contacting materials and additional chemical analysis may be needed.”

This statement is not applicable to the entire device -- only to patient contacting materials.

The term “analysis” is vague and will be confused with other types of device testing. “Chemical analysis” is more accurate than just “analysis.”

49 271-273 Please provide additional explanations and/or examples of how literature data can be used to support not conducting studies of certain biological effects.

It is unclear how literature data is suitable in place of certain biological effects but not others.

50 279-282 For clarity and alignment with this principle, as well as consistency with the flow chart from ISO 10993-1, Section 10 should precede Section 4.

This principle from G-95 is consistent with the revision to ISO 10993-1 in 2009. However, it does not appear to be consistent with much of the language in Section 3A and the location within the document with respect to Section 10: “Component and Device Documentation Examples”

51 284

Revise to read: “Any in vitro or in vivo experiments or tests should be conducted in accordance with recognized Good Laboratory Practice (GLP) including, but not limited to, the assignment of competent trained staff in the conduct of biocompatibility testing.. Non-GLP studies are permitted for historical data.”

There is no guidance on the use of previous study data with no GLP/full report. Add a grandfather clause to allow for acceptance of this historical testing. GLP clearly specifies staff training and records, so there is no need to reiterate

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Page 25 of 78

Comment No.


52 294-296

This language states is not consistent with Lines 157-160, which states that FDA wants full test reports for all tests performed, while this language states that full data should be submitted unless the test is done per recognized standards that do not require data submission.

Please clarify when data submission is not required. Please include an example. The statement is unclear and appears contradictory. Either all test reports need to be submitted or they do not all need to be submitted. Perhaps executive summaries would be a good mid-point between requiring full test reports and only claiming compliance to recognized standards in some cases. Executive summaries should include specific test methods and acceptance criteria.

53 298-300

Revise to read: “Any change in chemical composition, manufacturing process, physical configuration or intended use of the device should be evaluated with respect to possible changes in the toxicological effects and the need for additional toxicity testing. Physical configuration is defined as dimensional changes or geometric changes in the device design that based on risk require new biocompatibility testing or analysis. Additional toxicity testing may or may not be required.”

Clarify whether it is FDA’s expectation that the evaluation referred to in this section is required to be performed by a toxicologist.

If the term - “physical configuration” is to be used in this clause, then an example and/or definition should be provided.

There may be situations where changes in composition or process or physical configuration may involve less material or chemical of interest. Thus a smaller size or lessened chemical risk may be used as appropriate justification for not performing additional testing.

It is understandable what FDA is trying to address with changes in physical configuration, but there are situations where less material is present in a next-generation device than in the predicate and used this smaller size argument as justification for no additional testing. Smaller size = less extractants.

54 302-304

To ensure clarity with respect to FDA intention, please include the following:

“ISO 10993-1 is intended to be applied in the context of a risk management system, and the principles of risk management and “least burdensome” should be considered in determining the level of toxicological evaluation appropriate to a safety assessment of a device.

There should be a reasonable possibility of a toxicological risk to prompt testing, based on a risk analysis, and that the least burdensome approach to address the risk should be acceptable.”

Clarification.

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Page 26 of 78

Comment No.


55 307-311

“Previous revisions of Like ISO Part 1, and Tripartite, this guidance also used a tabular format (matrix) to outline the recommendations for biological effects evaluation based on the various factors discussed above for testing to be submitted in support of an IDE or marketing application. However, biological effects for evaluation should be selected based on risk assessments with consideration to device intended use. The matrix should be used to provide general guidance of potential biological effects for consideration not as a checklist for testing. The This matrix in this guidance consists of two tables.”

ISO 10993 Part 1: 2009 has removed the matrix to an informative appendix signifying less weight on the matrix and more reliance on risk evaluation.

56 322-323

If your device has multiple types of exposure, you should consider testing from both categories for your sponsors need to establish a biocompatibility strategy, test plan with justifications and a toxicological risk assessment to determine which tests from the categories are appropriate for the device.

This suggested revision employs stronger language than “consider” testing both categories. There may be cases where testing one category is worst case and covers both contact classifications appropriately with a justification.

57 322-325 AdvaMed disagrees with FDA’s characterization of devices that contact the patient gas pathway (masks, tubing) as both externally communicating and mucosal communicating.

This statement is taken directly from the 1995 Ventilator Reviewers Guidance. However, the mask and tubing (patient circuit) do not contact the gas pathway. They are not-invasive and should be at a minimum classified as skin contacting devices. The ventilator blows air from the device, thru the tube to the mask which is strapped to the patient. The tube has no direct contact with the mucosal membranes, nor does the mask as it only contacts a patient’s intact skin. An Endotracheal tube as stated on line 326 and 327 does contact the gas path and mucosal membranes directly and should fall in this category.

It is AdvaMed’s understanding is that the 1995 reviewer’s guidance for ventilators is being re-written to reflect today’s current use scenarios. We suggest that in light of this, this statement be removed.

The clinical definition that is applied by FDA is inconsistent with the human anatomy, as depicted below.

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Page 27 of 78

Comment No.


58 322-330

Revise to read: “If your device has multiple types of exposure, you should consider testing assessment of biological effects that may result from both categories of your device. For example, devices that contact the patient gas pathway (i.e. masks, tubing) are externally communicating due to the potential for chemical leachants from the device to enter the patient airway. Some gas pathway contacting devices may also fall into an additional category such as skin or mucosal membrane contact. However, these devices are an extension of the gas pathway acting as a conduit to the patient airway and lungs. Therefore, we have considered these devices to be classified as both mucosal contact and externally communicating for evaluation of biocompatibility.”

Revision switches the emphasis to assessment of potential biological effects rather than testing, that latter of which is inconsistent with ISO 10993-1:2009 themes. Suggested text is provided to maintain consistency.

59 336-340

Clarify: As the ISO standard states to consider all described tests for all devices, there is confusion as to how the guidance can state that the tests be considered for “a broader set of devices.”

The guidance itself also acknowledges in lines 385-387 by stating “all tests included in the matrix may not be relevant for all devices.”

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Page 28 of 78

Comment No.


60 335-345,

1133 Delete additional test suggestions, or strengthen rationale with literature references or specific examples.

The broadening of Table 1 Initial Evaluation of Testing for Consideration is arbitrary. Addition of literature references or FDA experience on this topic would contribute to an evidence-based, literature-supported, patient-safety focused rationale that would justify this additional testing.

61 338-340

Revise to read: “For example, for devices in contact with mucosal membranes for longer than 24 hours (e.g., neonatal feeding tubes), certain toxicities that would not be detected with short term assessments could exist and lead to adverse events, and should be considered for additional testing. In this instance, evaluation of local tolerance at a mucosal surface would be more appropriate than an intramuscular or subcutaneous implantation test.”

Lines 338-340 indicate that implantation testing is appropriate for testing of neonatal feeding tubes. This is confusing and requires clarification. It is AdvaMed understands that FDA is interested in local tolerance rather than a bone, IM or SC implantation study as defined in ISO 10993-6; therefore, this should be indicated more clearly.

62 343-345

Clarify how the leachants from a device with indirect blood contact can be tested.

From a physiological viewpoint, what potential adverse events would occur in humans when an irritant is introduced into the blood path?

Considering that the ISO standard describes Irritation/ Intracutaneous reactivity tests to evaluate a localized tissue reaction of tissue, skin or eye, how could the described example be tested?

What are the possible tests which could be utilized as “additional tests?”

These same concerns apply to the statements described in other sections (e.g., Pg. 8; Lines 347-351 and Lines 353-356; i.e., genotoxicity and pyrogenicity testing to be considered for a broader set of devices and/or exposures than outlined in 10993-1.

63 347-348

Revise to read: “…than outlined in ISO 10993-1:2009, unless existing data can be used to meet the requirements of the standard without unnecessary testing.”

Please add clarification and supporting literature references.

It is unclear why FDA suggests that genotoxicity tests are required to be considered for a broader set of devices/patient exposure. Please reference scientific data demonstrating why high surface area devices, such as extracorporeal circuits, require genotoxicity biological effect evaluation when this biological effect is not currently required per ISO10993-1 for devices with less than 24 hours contact?

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Page 29 of 78

Comment No.


64 347-351

Revise to read: “FDA has also suggested that genotoxicity tests be considered for a broader set of devices/patient exposures than outlined in ISO 10993-1:2009. For example, for all devices used in extracorporeal circuits, even if the contact is less than 24 hours, genotoxicity testing is recommended because of the high surface area, increased potential for chemical leaching, and introduction of any leachables into the systemic circulation. For limited duration devices assess the risk of patient exposure to leachables with an unknown genotoxicity profile. If the risk cannot be managed adequately, then perform genotoxicity testing.”

The original paragraph is inconsistent with Attachment A, Table 1 for Type A device.

Genotoxicity testing for devices that have limited exposure duration is generally not warranted (except if cumulative contact is greater than 30 days) and is inconsistent with the practice of toxicology in other areas. Genotoxicity testing may be warranted for devices with limited exposure duration if the materials are new and uncharacterized and/or if the potential for patient exposure is high and if the leachables have an unknown genotoxicity profile.

Genotoxicity testing for short-term contact devices is suggested with an example of a device with a large surface area. Please consider that devices with such abbreviated duration of contact have minimal risk of genotoxicity, especially if the materials used are well known. Please more clearly define conditions under which genotoxicity testing for short-term contact devices is required and provide a unique example.

65 350 Provide guidance or definitions for a low and high surface area device.

It is unclear what is considered a high surface area device? What is the cut off between a low and high surface area device?

66 372 Include that FDA accepts ISO 10993 definition of chronic toxicity or include FDA’s definition.

Chronic toxicity is defined in ISO 10993. Clarify FDA’s definition of chronic toxicity.

67 371-377

Revise to read: “For permanent devices in contact with the mucosal membrane, persistent breached or compromised surfaces, the blood path, or tissue/bone/dentin, FDA recommends that chronic toxicity be considered, since there could be toxicities associated with long-term contact that might not be detected with short-term assessments. In addition, FDA recommends that carcinogenicity testing be considered for all permanent externally-communicating and implanted devices. As appropriate, chemical characterization testing, data from the literature, and a toxicological risk assessment may be provided to justify omission not conducting chronic toxicity and/or carcinogenicity testing.”

The above indicates that chemical characterization testing and data from literature may be provided to justify not conducting carcinogenicity testing. The same chemical characterization and literature data approach is applicable to the chronic toxicity evaluation and should be included as well.

“Breached or compromised surfaces” alone may imply any lesion or wound from an invasive surgery. While FDA defines “breached or compromised surfaces” as being from devices of permanent contact duration, not acute as from a lesion or wound from invasive surgery, a qualifier with respect to ‘breached or compromised surfaces’ may

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Comment No.


be warranted in this section to help provide clarity. Such as ‘prolonged or persistent’— may provide some clarity.

68 374-377

Revise to read: “In addition, FDA recommends that carcinogenicity testing be considered for permanent externally-communicating and implanted devices if there is no information from other sources regarding the potential carcinogenicity of the material or the risk of carcinogenicity cannot be adequately assessed or managed without generating new carcinogenicity test data.”

The current text is too strongly worded in favor of carcinogenicity testing.

69 375-377 Expand “other types of information” beyond chemical characterization and literature.

The FDA guidance restricts the type of “information” to only chemical characterization and literature and does not accept valid data from other sources. The ISO standard allows the consideration of “other information, other non-clinical tests, clinical studies and post-market experience for an overall assessment”(10993-1; section 4.8). All data sources should be acceptable to provide justification for waiving any test.

70 379-382

Revise to read: “Attachment C includes a flow chart which outlines how FDA reviewers historically have assessed whether any biocompatibility testing is needed, and how information provided by the sponsor may support the biocompatibility of the final, sterilized device.”

The use of a historical review is not consistent, nor does it provide reference-able guidance.

71 379-382

Please clarify if FDA reviewers will continue to use this flow chart in Attachment C for current and future submissions. Also, outline how FDA reviewers assess whether any biocompatibility testing is needed (e.g., process and thresholds).

The guidance document states that the Biocompatibility Flow Chart in Attachment C outlines how FDA reviewers have historically assessed whether any biocompatibility testing is needed.

Will reviewers continue to follow this flow chart to assess whether testing is required?

It is unclear what process and thresholds FDA will use to interpret the relevant information guiding the biological test selection. There seems to be potential for using the Biocompatibility Matrix for test selection independent of interpreting the other relevant information.

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Comment No.


72 379-382 Clarify the process of “consulting toxicologist.”

Are FDA reviewer’s knowledgeable as to where, or who, to contact as an FDA toxicologist?

Can a sponsor request a toxicology review when an FDA reviewer does not consult a toxicologist?

Will FDA accept a decision or justification by a non-FDA toxicologist?

73 380-382

Add “…This flow chart may be a starting point for sponsors to develop a biocompatibility strategy, test plan, justifications and the toxicological risk assessment to determine which tests need to be conducted.”

Provide additional guidance.

74 384-388

Revise to read: “Sponsors should consider all existing information and compare to the data necessary to assess the biocompatibility of the device. Then, sponsors should evaluate the need for chemical characterization and/or biocompatibility testing. If biocompatibility testing is necessary, then consult the modified matrix (Attachments A and B) for guidance on test selection. All tests included in the matrix may not be relevant for all devices. Thus, the modified matrix is only a framework for the selection of tests and not a checklist of required tests. As described in Attachments A, B, and C, sponsors should evaluate the need for each of the recommended tests to assess biocompatibility. All tests included in the matrix may not be relevant for all devices. Thus, the modified matrix is only a framework for the selection of tests and not a checklist of required tests.”

Current wording implies that all recommended tests for a given device be considered without prior evaluation of existing information. Suggested rewording reiterates that existing information be considered first prior to testing, which is more aligned with the current ISO 10993-1, and consideration of chemical characterization, which is discussed in the FDA guidance lines 252-255. Only Attachments A and B guide selection of which tests to perform.

75 385-388

Revise to read: “All tests biological effects included in the matrix may not be relevant for all devices. Thus, the modified matrix is only a framework for selection of tests and not a checklist of required tests.”

This text discusses testing rather than assessment of potential biological effects and is inconsistent with ISO 10993-1:2009 themes.

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Page 32 of 78

Comment No.


76 389-390

For consistency, align material/chemical formulation and manufacturing processing requirements throughout the guidance document.

Also please provide clarity for the kind and level of evidence the agency is expecting for physical form, material formulation, processing information, component interactions, and storage conditions.

“Material formulation and processing information may not always be needed for medical device submissions…”

This statement conflicts with page 5, sub-bullet 1, lines 260-273.

Also note line 398 “In order to conclude that no additional testing is needed, the sponsor should provide evidence that for each material, the intended use, physical form, formulation, processing, component interactions, and storage conditions are the same as for the comparator product(s).”

It is unclear from the guidance document how much material formulation and processing information is necessary per FDA requirements for a device submission.

Also why would material formulation information be required in the submission when biocompatibility testing of the final finished device materials is provided? What information on the raw materials is needed to support biocompatibility?

77 393

Clarify what is meant by “senior toxicologist” vs. “toxicologist.” Clarify how the FDA addresses whether the lead reviewer is competent to select the appropriate biocompatibility tests for a device under review, or whether the reviewer should consult a toxicologist.

In line 393 users are directed to consult a “Senior Toxicologist,” and in Attachment C users are directed to consult or seek concurrence with a “toxicologist.” Clarify the distinction between a “Toxicologist” and a “Senior Toxicologist,” if there is one, and when a reviewer is to consult with a toxicologist/senior toxicologist.

78 398-401 Consider employing ISO 10993-18 “Chemical Characterization of Materials” to address support for concluding that no additional testing is needed.

The ISO 10993-18 Chemical Characterization of Materials guidance provides requirements for leveraging biocompatibility test data that may match some of those listed here: material equivalence, manufacturing process equivalence, sterilization equivalence and clinical exposure equivalence. AdvaMed suggests rewording this section to more clearly show which parts of the ISO 10993-18 meet expectations of FDA, and to provide rationale for expectations that are not met by the ISO method. In this way industry can potentially develop a more systematic methodology for leveraging previous test data.

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79 399-401

Revise to read: “In order to conclude that no additional testing is needed, the sponsor should provide evidence that for each material, the intended use, physical form, formulation, processing, component interactions, and storage conditions are the same as for the comparator product(s) or the comparator product is “worst case” compared to the proposed product.”

A comparator product may contain a material formulated, processed, stored and used in the same way as a proposed product in a greater material quantity or in a higher biocompatibility risk classification, which still may be appropriate to leverage for a proposed device which will use less material in a lower-risk application.

80 401-402

Revise to read: “In cases where there are differences, these need to be explained and justified, particularly if the comparator device is the “worst-case” due to process treatment or material surface treatment or lack thereof.”

A “worst-case” comparator device may contain an identical material as the proposed device used in a larger quantity (processed identically) and could be used to justify omitting testing.

81 401-403 Delete this text or revise to read: “All clinical data are relevant and should be taken into consideration before implementing any biological test plan.”

All clinical data should be relevant regardless of whether or not “specific toxicology endpoints are included in the monitoring plan.” If a clinical study utilizes a particular material and there are no untoward responses, then that study should be used as a favorable reference for that material regardless of whether “specific toxicology endpoints are included in the monitoring plan.”

82 411 Provide verbiage to allow for use of representative sets of final devices.

To allow for evaluation of “worst case” to cover an entire product family.

83 417 Exhaustive extraction is defined in ISO10993-12 Annex D. Does FDA accept ISO’s definition for exhaustive extraction?

Please clarify and/ or define “exhaustive extraction.” e.g., extracted to non-detect or <10%.

84 417 Revise to read: “exhaustive exaggerated extractions”

The requirement to perform exhaustive extraction may be inappropriate for certain devices, for instance, for devices that contact the patient for less than 24 hours, exhaustive extraction does not properly represent the patient exposure, and constitute a unnecessary burden to users.

Sometimes exhaustive extraction adds no value, 10993-12 suggests extraction which is “an appropriate exaggeration of the product’s use”

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85 420, 820,

826 Revise title to read: “B. In Situ Polymerizing and Bioabsorbable Absorbable Materials”

Instead of BIOABSORBABLE, utilize the term ABSORBABLE (see prior discussion).

86 421 Revise to read: “For in situ polymerizing and bioabsorbable absorbable materials, …” to “For in situ polymerizing and materials, …”

Instead of BIOABSORBABLE, utilize the term ABSORBABLE (see prior discussion), but indicate that this term also applies to “bioabsorbable.”

87 422-425

Revise to read: “In addition, we recommend that toxicity be assessed for the finished product as well as at various time points over the course of polymerization and/or degradation to ensure that starting, intermediate and final degradation products are assessed. If the materials in the final product have a history of use in similar applications, a scientific justification shall be provided if toxicity is assessed only on the finished product. Should toxicity assessment of the materials during degradation be required, preparation of samples via accelerated in vitro degradation may be considered with appropriate technical justification. Samples degraded in vitro under accelerated conditions may be chemically analyzed to show that that the material breaks down into degradation products are known to be non-toxic.”

Many bioabsorbable materials used in implants have an extensive history of use in implants, and many of these are of a similar nature and location. A justification for not performing toxicity testing over the course of degradation should be feasible if the bioabsorbable material is well established, has a history of use in implants, and the history encompasses similar usages and anatomical locations as the filed device. If toxicity evaluation over the course of degradation is pursued, there is the question of how to prepare samples. Harvesting partially degraded samples from in vivo studies is very challenging for isolating the implanted material and justifying use of animals for such a study. Real time in vitro degradation can be time consuming and not representative of in vivo degradation due to differences in the in vitro and in vivo environments. Accelerated in vitro degradation can therefore be a viable pathway with appropriate justification.

For products made from materials with well-known degradation pathways, a chemical analysis of the intermediate and final degradation products by NMR or mass spectrometry can be used to show that the product degrades in a predictable manner, into species well known to be non-toxic.

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88 426-428 Clarify what is required for “until the biological tissue response is demonstrated to be stable.”

For products that begin being resorbed after 2+ years, it seems like stability could be demonstrated prior to the occurrence of any resorption. Clarify the statement to state that stability would have to be demonstrated after a significant portion of resorption has occurred or at a point where tissue responses are comparable.

For example:

Request for clarification on the duration at which FDA considered a biological tissue response to be “stable.” For example, two consecutive but sufficiently spaced (> 14 – 28 days) time points at which tissue responses were comparable would be an indication of a “stable” tissue response.

89 426-428

Revise to read: “We recommend that assessments continue until the polymer is no longer present in the tissue, or until the biological tissue response is demonstrated to be stable. For implantation testing of products with materials that intentionally degrade, assessments should occur at time intervals that demonstrate a pattern of progressive degradation. These assessments should include physicochemical measurements to characterize and quantify remaining material. Simultaneous histological analysis should also be performed at these time intervals to characterize the biological response to the product after it has experienced significant mass loss.”

The recommendation that in vivo assessments continue until the absorbable material is no longer present effectively sacrifices animals at time points that routinely yield unremarkable histology of device-free tissue. The alternative recommendation that assessment of absorbable materials continue until tissue response becomes stable is functionally ambiguous, since tissue response to absorbable materials could arguably be considered as not stable until the device is fully resolved. More relevant to device performance is to provide a clear profile of the characteristics of the degradation process as the device loses mass. Section 9.4 of ASTM F2902-12 attempts to address this concept with the following language:

“Retrievals should target time durations that will demonstrate a pattern of consistent continuing degradation leading to a final histological resolution of the device or absorbable polymeric component, if not already established through prior experimentation (direct or via reference) with a fundamentally similar polymer construct.”

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90 427-428 Revise to read: “. . . or until the biological tissue response is demonstrated to be stable at steady state.”

ISO 10993-6 uses the term “steady state” rather than “stable.” To be consistent with the ISO standard and to avoid confusion by using a second set of terminology, we suggest that the same terminology be used.

91 428-429 Revise to read: “For in vitro extraction degradation tests, chemical analytical testing of the extract may be useful to determine whether single or multiple tests are needed.

Reference to extraction studies in this context is confusing because extraction studies are not unique to bioabsorbable materials. Clarify whether FDA is referring to in vitro degradation studies of bioabsorbable materials.

92 428-429 Clarify whether “single or multiple tests” are referring to “in vitro extraction tests” or “chemical analytical testing” (or are these tests supposed to be one in the same?

Clarification.

93 428-429

Option 1: Revise to read:

“For in vitro extraction tests, chemical analytical testing of the extract may be useful to determine whether single or multiple tests (per flowchart in Figure A1 of 10993-18:2009) are needed.”

Option 2: Add a new sentence that independently resolves the described ambiguity and provides the needed clarity.

The 4th sentence in this paragraph reads rather ambiguously, in that it

is unclear as to what “single or multiple test” needs may be generated as a result of chemical analytical testing. Dependent on interpretation, the sentence could refer to single or multiple in vivo tests, in vitro tests, mechanical tests, additional chemical tests, or any combination of the above. More detail is needed toward explaining the nature of these potentially needed tests (for example, insert additional language such as “…in accordance with the flowchart in Figure A1 of 10993-18:2009”).

94 428-430 Clarify how “chemical analytical testing may be useful to determine whether single or multiple tests are needed?”

It is not clear how testing can be useful in determining whether single or multiple tests are needed.

95 432-446

General Comment on Section: Consider adding a section on “Biological Response Resulting from Device Process Failure” and provide examples on how process failure can impact biocompatibility and how to rationalize it (such as provide process validation results).

In addition to mechanical failure, process failure (e.g., failure to clean) may lead to biological hazards.

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96 432-446

General Comment on Section: Mechanical failure should not be included in biocompatibility testing.

Biocompatibility testing from potential mechanical failures should be limited to hazards/risks that could not be otherwise mitigated as a part of risk management, where residual risk prompts testing. This would provide more predictability and consistency in the review process across submissions. Identification of potential hazards from mechanical failure can vary widely between reviewers.

There is no provided guidance as to the cause of the mechanical failure that would require biocompatibility assessment or the risk of mechanical failure, i.e.,

Are only devices with coatings or multiple components required to consider such testing?

Is the failure a single fault event (only one component must fail to result in the mechanical failure), a double fault event (requires two (2) components to fail to result in the mechanical failure) or three (3) or more components to fail to result in the mechanical failure?

Does this requirement include outside forces to cause the mechanical failure, e.g., during traumatic injury (car accident) the device is harmed to cause the mechanical failure?

97 433-446

General Comment on Section: If not deleted, this section requires clarification. Provide additional guidance on how to scope potential toxicological hazards arising from mechanical failure on a risk basis. Clarify what types of mechanical failure need to be evaluated. Provide additional clarity around the failure modes that should be considered.

This section describes biological response from mechanical failure. The section is vague, references constituent materials (in contrast to other parts of the document), and may be hard to demonstrate.

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98 433

Revise to read: “Although the scope of ISO 10993-1 specifically excludes biological hazards arising from any mechanical failure, FDA believes this potential risk is important to consider when designing biocompatibility studies. Critical or significant technical failure modes need to part of the biocompatibility risk assessment. If risk assessment of mechanical failure indicates that the risk cannot be managed adequately and the hazard posed may affect device biocompatibility, then consider the impact of mechanical failure on the biocompatibility evaluation plan.” This comment applies to all of Section C.:

Add to beginning of section: “For certain devices, such as those incorporating a coating or multiple material components, if chemical characterization or resulting toxicological risk assessment demonstrate a reasonable possibility that mechanical failure could alter the biological response to the device…”

Biological response resulting from device mechanical failure. The risks posed by a biological response due to device failure should addressed first by risk assessment and management. Only if the risk of mechanical failure cannot be managed should biological testing be necessary to address the biological response. Testing to address biological responses from mechanical failures should only be considered when there is a reasonable possibility of a particular mechanical failure resulting in a deleterious biological effect.

99 443-446

“If your assessment does not include testing to evaluate for potential biological hazards due to mechanical failure, your rationale for why such testing is not needed should be included. The least burdensome approach to provide such a rationale should be used. For example, appropriate rationale may be provided by bench data showing the robustness of the design to mechanical failure, or an extraction study and toxicological risk assessment that shows delamination would not release materials at levels that would present a toxicological concern. may include the results of other nonclinical tests such as bench testing or animal safety studies.”

Testing to address biological responses from device mechanical testing should only be considered when there is a reasonable possibility of a particular mechanical failure and a resultant deleterious biological effect.

100 433-446

If it is possible that “particles” are implanted, would the full gamut of implant level testing be necessary?

Define the limit to the level or particle size that needs to be considered for mechanical failures.

This requirements and considerations need clarification and further detail.

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101 451-452

Section D concerns nanotechnology: Reference upcoming ISO technical specification document after line 476.

We acknowledge that there is no universal definition of “sub-micron.” Clarify what FDA considers to be “sub-micron.”

Currently ISO TC 194 Working Group 17 is preparing a guidance document on this topic. It will be called “ISO/TS 10993-22, Biological evaluation of medical devices – Part 22: Guidance on nanomaterials.” This new technical specification should be mentioned after line 476 because it addresses many of the issues discussed in Section D.

It is unclear how FDA defines sub-micron.

102 469

Provide examples of tests that should be considered for evaluating submicron particles, including information about size ranges, extraction conditions, and any FDA preferences with respect to specific protocols.

Additional information on the Agency’s testing expectations is needed (e.g; size, extraction).

103 481 Determine the appropriate amount of test sample as outlined in ISO 10993-12

12 or …..

Replace “material” with “sample” to be clear that a medical device, component, or material (or representative sample thereof, manufactured and processed by equivalent manufacturing methods) can be used. This also keeps the terminology consistent with part 10993-12.

104 481- 488

Revise to read: “Mass to extractant volume ratios should only be used if surface area cannot be calculated or if use of mass will result in a larger sample” Surface area should be used whenever possible. The mass-to-volume ratio should only be used for irregularly shaped samples or representative device components. In some cases it may be necessary to deviate from these ratios and doing so is considered acceptable as long as the ratio of test material to extractant simulates or exaggerates the conditions that will be encountered during clinical use and the ratios used are documented in the test results. A rationale for using ratios other than the surface area should be documented.”

The statement that says “mass to extractant volume ratios should only be used if surface area cannot be calculated or if use of mass will result in a larger sample” is unclear. “…, or if use of mass will result in a larger sample” does not agree with ISO 10993-12. Further, certain devices, such as sutures or meshes, have very large surface areas in comparison to their equivalent weight. It would equate to highly exaggerated safety margins for extractions that may cause unnecessary failures.

The “larger sample” seems to indicate a worst-case scenario. This paragraph could be simplified by indicating that the surface area ratio should be used whenever possible, with a mass-to-volume ratio used only for the testing of irregularly-shaped devices or representative device components. It is not necessary to determine which ratio results in a larger sample or not. However, in some rare cases it may be necessary to deviate from these ratios and doing so is considered acceptable as long as the ratio of test material to extractant simulates or exaggerates the conditions that will be encountered during clinical

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use and the ratios used are documented in the test results. A rationale for using other ratios other than the surface area should be documented.

105 483

Provide guidance on the use of historical testing that was based on ISO10993-12 guidelines. This testing required different ratios based upon the thickness of the material (i.e., did not use mass).

For many final products, using a mass to extractant ratio will result in a larger sample size than previously used.

106 490-496

Revise to read: “Use both polar and non-polar solvents as defined or as examples provided in 10993-12. Other solvents or blends of solvents may be required in certain conditions or applications.”

DMSO is polar but is not included in the polar definition in 10993-12.

107 490-496 Provide guidance for subchronic testing where the route of administration is IV, a polar extract maybe sufficient.

Use of 2 solvents may not always be relevant based on product usage. Suggest polar solvent is default, with both solvents used if other biocompatibility testing suggests toxicities are relevant under non-polar solvent conditions.

108 491 Revise to read: “(e.g., ethanol/water 20:80)” with “(e.g., cell culture media).”

The use of a 20% ethanol solution in water is not standard. USP <88> refers to a 1 in 20 (5%) solution of alcohol in saline. Cell culture media may be a more appropriate example.

109 498-506, 544, 685,

690 Revise temperatures as, for example, 37 °C.

This guidance presents temperatures incorrectly. Temperatures are units and need to be separated by a space from the number value.

110 498 to 501

Suggest including reference to ISO 10993-16 and/or -17 for this section.

Also need clarity on acceptance criteria and testing process if leachables are acceptable for use

Clarification.

111 502-503 Is exhaustive extraction at 37 °C sufficient to remove leachable materials?

Clarification.

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112 503 Revise to read: “. . . represents the chemicals that may leach out over the use life of the device during the lifetime the device is used.”

Clarification.

113 504 Revise to read: “ . . . result in degradants degradation molecule or molecules of interest as well as degradation of the device components that may not occur in clinical use . . ."

Clarify text to ensure that the right extractant is being analyzed and to avoid testing a degradant of a device component.

114 508-510

Revise to read: “…and the source of these changes (e.g., test article degradation). Historical testing may not include test extract descriptions so information should be supplied as available.”

Description of extract conditions may not be possible for historical testing. Make this conditional - “as available.”

115 509 Revise to read: “…changes in the…test extract extraction solvent (pre- and post …”

Clarification, uniform/consistent language.

116 521-527

Revise to read: “For products that include components with different lengths of contact (e.g., limited, prolonged or permanent), we recommend that you conduct extraction tests on the components separately for the biocompatibility tests that are not common between the lengths of contact. For instance, if both components based on their length of contact require cytotoxicity testing, the components could be tested together.

If a certain test is required for all device components there should be no reason to test components separately for that test. This would not represent “diluting” the sample as FDA suggests if it is required for the multiple components. For the tests required for a longer duration of contact component, those may be tested separately for just the additional tests.

117 522-527

Add to clarify: “Extractions should be performed on all patient contact components for the shorter contact length. Individual components (e.g., implants) should be tested for the longer length of contact.”

Additionally, clarification is required in terms extraction for devices that have same lengths of contact. Can they be extracted together?

If component interactions are taken into account, all components that interact with each other that have the shortest length should be tested together.

Line 522 mentioned that components with different lengths of contact should be extracted separately. It is not clear if the agency will accept if components that have same lengths of contact are grouped together.

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118 529-532

Delete: “For devices or device components that contain multiple materials with differing surface areas or differing exposure to the body, if one or more materials is new, it may also be necessary to test the new material components separately as well”

Add to end of sentence on Line 532: “Testing new material/parts separately may be warranted if the chemical characterization, clinical use, and/or literature search indicates potentially toxic agents that may be underestimated if the components were tested together (diluted).

Provide rationale for testing in a combined configuration if the sample requirements for separate testing exceed the clinically relevant exposure or if body exposure is limited to specific surface areas during use (e.g., interior lumen, exposed surfaces). To address material interactions it may be necessary to test the device in a combined configuration.”

This conflicts with Line 411 of the guidance, which suggests testing the final product or a representative sample. If an extract was prepared with appropriate ratios of the materials and tested for the appropriate contact level there should be no reason to test them separately. Testing separately would not represent clinical use.

If the new material/component is tested alone, to maintain the 10993-12 sample requirements, the amount used will far exceed the clinically relevant amount of material: body contact ratio. Part 12 currently requires large amount of test article material.

Please clarify why testing of the new material on its own (separately) is requested when that is not reflective of the final device presented to the patient in clinical use. Based on the chemical characterization and/or literature search separate testing may be indicated.

Also, it is not clear if all selected testing is required to be performed on the material as well as the final finished device.

119 529-532 Also suggest using an extraction method that mimics the clinical use of the device so every components of the device are extracted in a ratio representative of its clinical use.

Clarification: with respect to using an extraction method that mimics the clinical use of the device so every component of the device is extracted in a ratio representative of its clinical use. For instance, if a device is filled with saline solution in normal use, use a fill to capacity extraction method so every patient-contacting component of the device is assessed. Hence, the need to test both, the finished device and the new material component as a stand-alone, is not necessary.

120 532-534 Testing the new balloon material alone as well as the entire catheter-based delivery system seems redundant; suggest deleting this example.

Either need to test the new balloon or should test the entire delivery system with the new balloon.

121 545-546 Revise to read: “…such as mammalian cell culture media (MEM) supplemented with 5% serum”.

The Agency states “…such as mammalian cell culture media (MEM) and 5% serum.” Clarify whether the Agency means “…such as mammalian cell culture media (MEM) supplemented with 5% serum”.

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122 548 Clarify that the most appropriate test should be performed based on the characteristics of the device.

Implies that both direct contact and elution tests may be appropriate. Typically elution tests are most appropriate. For materials that are homogenous and lay flat then a direct contact test would be appropriate. Performing both tests is redundant and provides no useful additional information.

123 548-550 Clarify the market being referred to (i.e., U.S. only? Global?).

Explanation of a novel material includes reference to “a marketed medical device.” Is it acceptable to consider a device not to be novel based on use in a marketed medical device outside of the United States? Modified language should consider whether or not ISO 10993 is a recognized standard in the country where it is marketed.

124 548-550

Revise to read: “…we recommend that both direct contact and the elution method, and if applicable the direct contact method, be considered.”

OR:

“…we recommend that both qualitative and quantitative methods be considered.”

Direct contact cytotoxicity is not a commonly used test and is only applicable for certain types of test articles, such as those that are heavy enough to rest on the cells but not too heavy to mechanically damage the cells. The reason for requiring this test for new materials is unclear.

Recommend that FDA incorporate actual medical device biocompatibility issues or concerns that have occurred where both direct contact and elution have been necessary to demonstrate a cytotoxic response of a novel material.

125 553-555 Add the Buehler method. Only two types of sensitization tests are listed in this section: GPMT and LLNA is listed. ISO 10993 also includes the Buehler method.

126 557-558

Revise to read: “. . . we recommend that test reports confirm that all female animals used in the testing are not pregnant, male and/or female healthy young adult animals can be used. If females are used they should be nulliparous and non-pregnant.”

AdvaMed recognizes and agrees with FDA’s recommendation to use non-pregnant guinea pigs in the Guinea Pig Maximization Test (GPMT), as outlined by the OECD Guideline for Testing of Chemicals. However, the request by FDA to recommend test reports to confirm the pregnancy status of the guinea pigs requires undue extra confirmation steps (radiographs, ultrasound, and/or exploratory necropsy), as no passive, non-invasive definitive pregnancy test is available for this species. Vendors, such as Charles River, make a standard practice of providing non-pregnant animals, but do not document the pregnancy status of their shipped animals.

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AdvaMed questions whether the request for test report confirmation of pregnancy status is empirically justified by specific incidents, or recurrent findings that GPMT results submitted to FDA were derived from pregnant animals. If not, the need for an appropriate test system may already be met by standard industry practice. Modify the FDA’s Draft Guidance recommendation to mirror that of OECD Guideline to simply state that “Male and/or female healthy young adult animals can be used. If females are used they should be nulliparous and non-pregnant.” The complexity of definitively proving and documenting in a test report that the animals are “nulliparous and non-pregnant” should be reserved for those cases in which a pregnancy is suspected, due to altered or suspicious test results.

127 562

Revise to read: “Assays with positive controls using the same source and strain of animals should be performed regularly (at least once every 6 months or, if longer, concurrent with test assays) in order to ensure the reproducibility and sensitivity of the test procedure.”

The parenthetical requirement to conduct positive control testing “at least every 6 months” effectively states that controls need to be evaluated at the described time interval regardless of whether a test sample has been received. This requirement could potentially create an undue burden on test labs that conduct such testing at infrequent intervals that may exceed 6 months. Thus, the language should be changed to alternatively allow positive controls to be evaluated concurrent with the test assay).

128 564 Revise to read: “ . . . or from positive control testing within 3 6 months (before or after) of the device testing using the same methods and source and strain of animal.”

AdvaMed agrees with FDA’s suggestion to regularly perform assays with positive controls and concur with ISO Guidance and FDA’s suggestion that every 6 months is an appropriate time interval. In practice, testing as suggested will require that positive controls actually be performed every 3 months. For example, if a sample is tested in month 4, the previous control study would be separated by greater than 3 months, which would require either waiting an additional two months to release results with the next scheduled 6 month positive control, or performing the positive control every 3 months. Performing the positive control every 3 months is inconsistent with both this FDA Draft Guidance document and with established ISO guidelines, and would double the amount of control animals currently used. Such an increase in animal usage is contrary

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to the FDA’s position on minimizing animal use.

129 565-569 Include a statement that the studies will be invalid, after root cause investigation confirms that there is a reason to do so.

Clarification.

130 567-570

Delete “If a periodic positive control fails, all GPMT data generated after the last positive GPMT response is considered invalid because there is no assurance that the test system is working. Therefore, repeating positive control testing to justify a failed positive control test is not acceptable.”

This requirement is scientifically unsound and unnecessarily restrictive. The consequences of these requirements on the positive control are: (1) a failed positive control would prevent the test facility from testing GPMT for 6 months at which time another positive control group would be allowed, (2) a failed positive control would automatically result in recalls and/or prevented release of products without ensuring that these steps are necessary and scientifically justified. These impacts have significant deleterious effects on patients and industry. The practical outcome is that concurrent positive controls will be run for all GPMT with resultant unnecessary animal use that is inconsistent with the 6 month positive control guidance in this draft document, ISO regulations and is contrary to the FDA’s position on minimizing animal use.

The purpose of the proposed guidance is unclear. Response to a failed positive control of this type is best addressed at the Quality Systems level and not the test method level. The Quality System provides guidance on investigations into root cause and proper response.

131 573

“If a primary irritation study is not included in the sensitization protocol, adverse findings at the end of the study may be due to irritation or sensitization, and additional studies to determine the causality may be needed.”

Please elaborate on what additional studies may be necessary.

Clarification.

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132 576-623

LLNA – entire section

With regard to testing “substances,” this draft guidance document requires that the final device, and not individual materials, be tested. Clarify to ensure wording consistency with the rest of the guidance. Clarify the term “chemical mixtures” or replace with one of the other terms already used (e.g., material or material constituents).

Clarification and consistent use of terms throughout the document.

133 581-584 Elaborate on “unique physicochemical properties” that may interfere with testing.

Clarification.

134 593-597

Reorganize this text to read as follows: “When testing substances that do not penetrate the skin but are used in devices that contact deep tissues or breached surfaces, instead of the LLNA test, we recommend the use of the GPMT test for devices made from novel materials.”

Grammatically more correct.

135 595-597

Revise to read:

“(1) Instead of the LLNA test, we recommend the use of the GPMT test for devices made from novel materials, or when testing substances that do not penetrate the skin but are used in devices that contact deep tissues or breached surfaces. we recommend the use of the GPMT test for devices made from novel materials, or

(2 ) when testing substances that do not penetrate the skin but are used in devices that contact deep tissues or breached surfaces.”

The sentence is confusing, and could be re-written to be clearer by separating into two bullet points and stating the second point more directly.

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136 627 Revise to read: “. . . in vitro thrombogenicity testing.”

The requirement to conduct thrombogenicity testing routinely for short-term devices would result in a significant increase in the use of animals (usually dogs or goats), which is contrary to US Animal Welfare Act, USDA requirements, and ISO 10993 part 2. It is not clear why this test is needed in all cases.

Complement activation testing should be reserved for testing of devices with a large blood contacting surface area, such as hemodialyzers (ref ISO 10993-4). Small devices made with PVA will cause complement activation in vitro but are clinically biocompatible. The reason for this is that a small surface area cannot activate complement rapidly enough in vivo to overwhelm the homeostatic mechanisms that control the complement cascade.

137 626-630

AdvaMed member companies have recent experience with FDA asking for hemocompatibility testing for non-blood-contacting devices or components. Clarify that devices and materials that do not contact circulating blood will not be considered for hemocompatibility evaluation.

NOTE: ISO10993-4 applies only to devices, device materials, or device components that directly or indirectly contact blood. Devices, device materials, or device components that do not directly or indirectly contact blood do not require any ISO10993-4 testing.

138 632-633

Revise to read: “For hemolysis testing, we the FDA recommends that the ASTM F756 direct and/or indirect (extract) methods be used, as appropriate for the application.” Devices, device materials, or device components that do not directly contact blood do not require direct hemolysis testing, both direct and indirect (extract) methods be conducted per ASTM F756,16 or an equivalent method (e.g., NIH Autian method).”

The sentence reads as if a direct and an indirect test is recommended in all cases. However, this intention is not clear and does not make sense. For example, the insulin drug reservoir in an external drug pump never sees direct contact with blood. Thus, in this case only an indirect test should be necessary.

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139 632-633 Add text to this document that informs users that ASTM 756 methods conducted to maintain the recommended ASTM F619 or ISO 10993-12 SA/volume ratios will be considered valid.

ASTM indirect method F756 calls for the use of 7.0 mL extract per ASTM F619 or ISO 10993-12 and 7mL blood exposure in the direct contact method. Per these standards, for example, a test material of less than 0.5 mm thickness calls for 6.0 cm

2/ml of sample or 7 x 6 =

42 cm2. This amount of surface area can become extremely cost

prohibitive and wasteful.

(For example, the recommended testing in triplicate would require 3 x 42 = 126 clinical-quality stents when testing a stent of 1.0 cm

2.)

The logical alternative is to adjust the assay to use a lower surface area with the appropriately adjusted volume e.g., 12.0 cm

2/2.0 mL.

There have been instances where the FDA considers this not valid, yet pure scientific reasoning dictates this to be equivalent.

140 632-633

It is suggested that further recommendation of NIH/Autian method be dropped, or be based upon the outcome of the hemolysis round robin study, which will gauge its equivalence to ASTM.

TC194/WG9 is in the midst executing an international round robin study on ASTM, NIH, and MHLW hemolysis methods.

Line 633 states “….or an equivalent method (e.g., NIH Autian method).”

The round robin protocol attempts to reproduce the NIH method as written. However, it should be noted that this is a direct method only and there is no NIH indirect method. Further, the level of detail published for this method is very low, and, it describes a mass/volume ratio that is suspicious and does not offer a SA/volume recommendation. Thus, the method seems old and outdated, not standardized to today’s norm for a test methodology, and not in line with F619 and ISO10993-12.

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141 635-641

Reconsider requirement for complement testing of all devices and/or reference scientific data (peer-reviewed medical or scientific references) demonstrating why limited duration devices in direct blood stream need C3a/SC5b9 testing.

FDA should take factors such as those listed in Table 1 into serious consideration in their reviews and recommend that qualified test labs and SMEs work to establish and validate a unified method.

The utility and need for complement testing came from certain clinical observations linked with large surface area blood-contacting devices e.g., CPB components and hemodialysis filter membranes. Here, certain (no longer used) high surface area devices/ biomaterials can trigger an amplification response whose end result is a high level of cytokines, e.g., C5a, that can stimulate an array of inflammatory responses including WBC chemotaxis, reactive oxygen species production, and cytokine expression. This in turn leads to the clinical manifestation of activated leukocytes and leukocyte sequestration in patient lungs. To date, no clinical or scientific publications on smaller surface area devices have been identified by WG9 SMEs to be associated with such phenomena or any other complement related adverse events. Contrary to this evidence, FDA has required complement testing on all devices regardless of blood contacting surface area.

A review of complement test methods used by the major US test labs can be seen in Table 1 above. This table shows where test methods

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Comment No.


are consistent, and where there is inconsistency. Key parameters such as the type and amount of anticoagulants used, standardization of the surface area to blood (or e.g., blood plasma) applied, and the freshness and actual blood or blood fraction used is different between laboratories. In the field, it is also recognized that complement activation potential varies between donor blood. These observations, and the lack of any validation studies, bring complement testing as a standard into question.

142 643-673

Delete the recommendations for a specific animal model for thrombogenicity testing, specifically striking references to the 4-hour canine venous unheparinized model. Rephrase other sections to allow selection of an animal model that is justified to be the most appropriate for testing the safety concern at hand.

The FDA draft adds details that are not included in the ISO standard. Of particular concern is the unsubstantiated emphasis on the 4-hour canine venous unheparinized model for assessing thrombogenicity. This model, in which a test sample is placed in the venous system of an unheparinized dog to assess thrombus deposition, is not a suitable model for most types of device testing. Not only is the use of dogs in research discouraged by the general public and the USDA, but the literature does not support dogs as a particularly good model of blood material interactions. In addition, dogs may be too small to accommodate many human sized devices; a set duration of 4-hours has limited clinical relevance; and treatment with anti-coagulants or anti-platelet medication may be part of the clinical indications.

It is likely that laboratories will perform this test in an effort to be compliant with this guidance. They will find that the testing is uninformative because it may not model relevant clinical conditions. This will result in further testing being performed and will waste animal resources, which is contrary to the agency’s commitment to minimize animal use.

As recommended in ISO10993 part 4: Selection of tests for interactions with blood section 6.1 testing should simulate the “conditions of contact of the device with blood during clinical applications.” The ISO standard does not prescribe any particular species or state of anti-coagulation for testing materials.

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143 643-673

Stronger wording should be added that the best and most meaningful way to establish safety against device thrombogenicity is to include a test plan for measurement of indicators of thrombosis in the in vivo GLP preclinical study that tests the device in its intended implant configuration. And, that the later should be conducted using the anticoagulant regimen and levels (if any recommended) as recommended in the product IFU. Testing of devices in non-anticoagulation conditions when the device is intended for use with anticoagulants is irrational. This is akin to testing aircrafts and automobiles in conditions that guarantee failure.

The NAVI model is most useful when used to test the thrombogenicity and thromboadherence of material surfaces or surface modifications intended to impart nonthrombogenic properties e.g., heparin coatings.

There are no published studies on the non-anticoagulated venous implant (NAVI) model, or its alternative anticoagulated venous implant (AVI) model. In addition, a host of problems with the model are well recognized by device companies and the test labs that conduct the test.

1 Commonly used blood-contacting medical

materials and/or approved medical devices used as predicate controls get extremely mixed results in the NAVI model. And, all material tested in the AVI model receive passing scores of 0-1. The reasons for this are discussed in Reference 1. In the face of these strong criticisms by industry and test labs, the NAVI test continues to be recommended by FDA. The non-validated nature of the test and the frequent insistence on its use is in violation of ISO10993-2 regarding minimizing wasteful and improper use of animals in research.

1. Practical approach to blood compatibility assessments: general considerations and standards, Michael F. Wolf and James M. Anderson, in Biocompatibility and performance of medical devices, edited by Jean-Pierre Boutrand, Woodhead Publishing Ltd, 2012

144 643 - 644

Revise to read: “For devices that exclude contraindication for use in patients who cannot be heparinized, we recommend thrombogenicity be assessed as part of a safety study conducted in a relevant animal model, where such a study is planned for other reasons.

When device manufacturer includes contraindication in patients who cannot be heparinized, there is no need for the 4 hr in vivo canine unheparinized thrombogenicity study.

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145 644

Add: “Many direct blood contacting implantable devices will be tested in preclinical safety models that are accepted as being most relevant for a particular device. Data from these studies may be used to assess thrombogenicity with sound technical justification. These results should contain appropriate observations of thrombus formation and include relevant histology.”

The canine model was at one time popular due to the cost, availability, ease of handling, and size. However, significant problems exist in this model that makes it inappropriate for continued use in interventional vascular therapies. It has been noted that the canine has a limited inflammatory response, which reduces its sensitivity as a model.

3 Further, dogs have high fibrinolytic activity

and a coagulation system that is distinctly different from humans. These differences in fibrinolytic activity, combined with a low potential for acute thrombosis, make studies evaluating thrombogenicity in a canine model misleading or unrelated to the human experience.

While the 4-hour canine venous unheparinized model is known, it is not used extensively for all devices. For devices which are placed almost exclusively in the arterial vasculature, venous thrombosis mechanisms are different.

146 648-650

Revise to read: “If only a portion of the device is being utilized for thrombogenicity testing, the sponsor should confirm that the sample is representative of all materials that would be in direct contact with blood or provide a justification that all materials in direct contact with blood have been assessed for thrombogenicity.

Since coupons are not representative of the device geometry and only a small portion (~2 inches) of the device is inserted in the jugular for the canine model, not all device materials with direct blood contact can be assessed or confirmed using this model.

3 Schartz R.S., Edelman E.R., Carter A., Chronos N.A., Rogers C., Robinson K.A., Waksman R., Machan L., Weinberger J., Wilensky R.L., Goode J.L.,

Hottenstein O.D., Zuckerman B.D., Virmani R. “Preclinical evaluation of drug-eluting stents for peripheral applications: recommendations from an

expert consensus group.” Circulation 110, 2498-505 (2004).

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147 651-652;

671-673

Please incorporate ISO 10993-1 considerations and preferences for in vivo tests and that whenever possible in vitro screening shall be carried out before in vivo tests are commenced.

For blood-contacting devices, FDA recommends assessing in vivo thrombogenicity (such as 4-hr canine in vivo thrombogenicity test) and that color photographs of the device/vessel explants should be provided (lines 651-652).

For some devices for which a 4-hour canine venous thrombogenicity model is not appropriate, such as oxygenators, a series of in vitro blood damage assessments (both static and dynamic) can be used to support regulatory submissions if adequate rationales are provided (lines 671-673).

The 10993-1: 2009 standard states that validated and reliable in vitro tests shall be considered for use in preference to in vivo tests and that whenever possible in vitro screening shall be carried out before in vivo tests are commenced. In such cases, in vitro tests must be validated and use models that simulate actual in-use application conditions.

148 651-653

Revise to read: “In addition, we recommend that for all in vivo canine thrombogenicity assessments, regardless of whether evaluation was from the safety study or canine model, color photographs of the device/vessel explants should be provided.

Color photographs of device/vessel explants from animal safety studies would require sacrificing the animal. This may not be feasible if the animal study is planned for other reasons.

149 653

Add at the end of Line 653: “Alternatively, you may provide a rationale for omitting this testing, if all the materials used in the formulation and processing of the device with similar geometry have a history of previous use in blood-contacting devices with similar contact duration.

Clinical history of safety around thrombogenicity has been established for devices that use common materials to the industry, with established processing of devices and similar design (e.g., geometry) where additional animal testing would not be warranted.

150 653

Revise to read: “ . . . explants should be provided. The appropriate control article is a clinically equivalent predicate FDA cleared device. A 4-hour in vivo unheparinized canine thrombogenicity study may not be necessary provided that safety study supports the device to be non-thrombogenic and appropriate contraindications are included (e.g., not for use in patients who cannot be heparinized).

Need guidance on selection of appropriate control article for the in vivo canine thrombogenicity study.

Not all devices can be tested in the canine model.

Contraindication is an acceptable risk mitigation measure for thrombogenic potential under unheparinized conditions.

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151 655-668 Revise to allow the use of anticoagulants in the 4-hr canine in vivo thrombogenicity test, if such drugs are used with the device clinically.

The 4-hr canine in vivo thrombogenicity test has limited usefulness. In particular, for most devices, not using anticoagulants in the test is clinically irrelevant. There should be an allowance for the use of anticoagulants for the initial thrombogenicity test, if clinical practice routinely includes anticoagulants. The 4 hr canine in vivo thrombogenicity test should exclude anticoagulants only if clinical use excludes anticoagulants.

152 655-657 Provide a reference for “historical” usage of the 4-hour canine in vivo thrombogenicity test.

Clarification.

153 657

Add the following: “The 4-hour canine in vivo thrombogenicity study should be conducted if the study can appropriately evaluate the device for thromobogenicity to minimizing animal use.”

Due to the size limitation of the canine jugular, devices not appropriate for this model would yield inappropriate and inaccurate data that would contradict the position of minimizing animal use (ISO 10993-2 Animal Welfare).

154 675-698 Consider employing ISO 10993-11 Tests for Systemic Toxicity, Annex F Information on material-mediated pyrogens.

More appropriate testing.

155 676-678

Define the purpose of performing pyrogenicity testing if the device does not contact blood or cerebrospinal fluid, and if there is a very short duration of contact. Why are all implants included?

Unless there is potential for a pyrogen-causing substance to be distributed systemically via the cardiovascular, lymphatic, or central nervous system, pyrogenicity is not a concern. Performing pyrogenicity testing on all implants will likely lead to endotoxin testing and labeling the device as “Pyrogen-Free.”

Considering devices with a very short duration of contact (e.g., a novel material syringe needle), such as ten (10) seconds maximum, further clarification should be provided as to the rationale why material mediated pyrogenicity concern of a few seconds would be a pyrogen concern.

156 679-682 Clarify that bacterial endotoxin pyrogenicity is not included in the ISO standard.

As the ISO standard only describes the material-mediated pyrogenicity, the discussion of bacterial endotoxin pyrogenicity should be acknowledged as not included in the ISO standard and explained that FDA is including such discussion for ease of reference, i.e., bacterial endotoxin testing is most commonly associated with sterilization-related testing.

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157 683-689 Revise to include a statement that there is no rationale from existing literature or previous testing to suspect material pyrogenicity.

Testing as requested in this section should not be required or recommended. As it stands, a number of existing materials would be subject to this additional testing.

158 688-690

Should this apply to all studies, not just pyrogen testing?

Consider adding information in lines 688-690 to paragraph at line 498 as well.

Clarification.

159 696-698 Provide the reference for the stated “pyrogen limit specifications” in the guidance document.

Clarification.

160 699 Add at end: “Specific guidance has been previously published by FDA entitled “Guidance for Industry Pyrogen and Endotoxins Testing: Questions and Answers” in June 2012.”

The FDA has published “Guidance for Industry Pyrogen and Endotoxins Testing: Questions and Answers” in June 2012. Not including this critical reference is confusing.

161 701 Please add an explanation and/or examples of how intramuscular is more sensitive depending on the material.

It is unclear for what types of materials intramuscular implantation is more sensitive than subcutaneous.

162 703 Provide guidance for when devices are too big to implant (e.g., dialyzer).

Allow for testing of individual components vs. final device when the final device is too big.

163 702-704 It is unclear what appropriate justification would be for using coupons.

Add explanation and/or examples of appropriate justification for using coupons.

164 705-706 Provide example where subcutaneous implantation is appropriate (i.e., when the configuration of the device prevents intramuscular implantation).

Clarification needed -- add explanation and/or examples of cases in which subcutaneous implantation is appropriate.

165 709-712 Clarify “use in anatomical structures under clinical conditions” for implantable stimulators.

Does this testing need to be conducted in the anatomical structure (i.e., brain tissue, nerve tissue, heart, etc.) with the device actively stimulating? This would drastically increase the cost and complexity of any such testing.

166 709 Define/explain “clinically relevant” in this context. Clarification.

167 728-730 Clarify whether the intramuscular implant is necessary regardless of which tissue is targeted.

An intramuscular implant is not clinically relevant if another implant study in a relevant location is performed. It adds an unnecessary amount of time and cost.

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168 733-736

Revise to read: “For implantation testing of products with materials that intentionally degrade, assessments should occur at time intervals that demonstrate a pattern of progressive degradation. These assessments should include physicochemical measurements to characterize and quantify remaining material. Simultaneous histological analysis should also be performed at these time intervals to characterize the biological response to the product after it has experienced significant mass loss.”

The text as currently written provides a vague generalization of what can be considered early, middle, and late degradation and there should be a more specific definition to better establish what is considered early, middle, and late degradation (e.g., is early minimal degradation considered to be a time point where <10% degradation is observed based upon in vitro degradation testing?)

The recommendation that in vivo assessments continue until the absorbable material achieves a “steady state” is functionally ambiguous, since tissue response could be perceived as steady throughout the degradation process (especially with slowly absorbing materials). More relevant to device performance is to provide a clear profile of the characteristics of the degradation process as the device loses mass. Section 9.4 of ASTM F2902-12 attempts to address this concept with the following language:

“Retrievals should target time durations that will demonstrate a pattern of consistent continuing degradation leading to a final histological resolution of the device or absorbable polymeric component, if not already established through prior experimentation (direct or via reference) with a fundamentally similar polymer construct.”

169 740-742

Clarify and provide guidance on when genotoxicity testing will be necessary, especially since Attachment A clearly indicates when consideration of genotoxicity testing is unnecessary. For example, clarify and define an established genotoxicity profile vs. a genotoxicity profile that has not been adequately established.

Revise to read: “Genotoxicity testing is requested when the genotoxicity profile has not been adequately established. For type A or B devices, justification shall be provided if the test is not performed.

Clarification. The original paragraph is inconsistent with Attachment A, Table 1 for type A device and certain type B device.

170 744 Provide scientific rationale for why limited contact components need all 3 genotoxicity studies.

Clarification.

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171 744-763

Revise to read: Because no single test can detect all genotoxins, we recommend the following 3 2 tests be conducted:

Bacterial gene mutation assay

An in vitro mammalian genotoxicity assay

An in vivo cytogenetics assay. A choice of one of the following is recommended:

a) A bone marrow micronucleus (MN) assay (OECD 474):

b) A bone marrow chromosomal aberration (CA) assay (OECD 475); or

c) A peripheral blood MN assay.

The 3rd

test, In vivo Cytogenetics Assay, is not one of the initial recommended tests per ISO 10993-3 (Genotoxicity). Per 10993-3, If the results of all in vitro tests performed are negative, further genotoxicity testing in animals is not normally justified and should not be performed, in the interest of preventing undue use of animals.

ISO 10993-3 only recommends in vivo testing if one of the first two tests (Bacterial gene mutation assay or in vitro mammalian genotoxicity assay) results in a positive result,

We recommend FDA follow the standard or only recommend the cytogenetic assay for higher risk devices.

172 759-762

Revise this section to indicate that in vitro tests for gene mutations and clastogenicity should be the default approach followed by the appropriate in vivo correlate test if there was an in vitro failure. The exception to this default would be devices designed to have a biologically active component or a combination product. The genotoxicity of those devices should be addressed on a case by case basis, as appropriate

For example, revise to read: “In vivo cytogenetics assay genetic toxicity tests should be performed when either:

1. There is a mutagenic or inconclusive response in the in vitro tests or,

2. The results from chemical analysis, indicates the presence of a chemical whose genetic toxicity is unknown.

A choice of the following in vivo cytogenetics assay is recommended: . . .”

The performance of in vitro tests for gene mutations and clastogenicity should be the default for medical devices. If one of these in vitro tests fails, then testing in the appropriate in vivo correlate should be performed. In vivo only genotoxins are rare. (Refer to Tweats et al, 2007 Mutation Res 627, 92, and, Kirkland et al, 2011 Mutation Res 721, 27). These reviews indicate that in vitro tests for gene mutations and clastogenicity would be sufficient for medical device extracts, which are much less likely to be biologically potent. This in vitro first and then in vivo only if in vitro positive approach is consistent with other medical device regulatory bodies and with ISO 10993-3. Genotoxicity evaluation of devices designed to have a biologically active component should be addressed on a case by case basis, or as a combination product, as appropriate.

The requirement to do conduct an in vivo cytogenetics assay also is contrary to international consensus for medical devices and as such will lead to additional animal use which is in conflict with the US Animal Welfare Act, USDA regulations, and ISO 10993 part 2. The FDA is the only regulatory body that requires an in vivo genetic

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toxicity test as part of the initial test battery for medical devices (examples Japan and ISO 10993-3). The FDA has requested these tests on the bases that few chemicals, such as benzene and urethane, would be missed by in vitro test battery. However, these chemicals would easily be detected by chemical characterization. If these chemicals were present, the amounts would be very small and it is unlikely that an in vivo test would be sensitive enough to detect these chemicals if present in a medical device. Therefore the in vivo genetic toxicity test would be uninformative. A risk assessment using results from chemical characterization would provide a greater assurance for patient safety then a negative in vivo genetic toxicity test.

173 764-811

Consider accepting genotoxicity testing as an adequate screening method in cases where materials are known and commonly used in the medical device industry, or provide evidence and literature to support necessity of additional testing.

AdvaMed recognizes the need to assess potential risk of carcinogenicity of medical devices. Pre-IDE meetings with FDA would be needed to negotiate this well in advance (> 2 years in advance of a submission). The proposed guidelines require significant additional cost and time for industry that could negatively impact development of new products and moving helpful products to market, with consequent deleterious impact on patients who need these products. It is not clear that these costs will be outweighed by protections afforded by the proposed guidelines.

For instance, some devices contain circuit boards that are contained within the device, but shielded from patient contact. The current guideline specifies that complete chemical formulations and manufacturing residuals be provided for, “all components of the device.” It is not clear that the significant work indicated would result in a benefit for the patient.

AdvaMed suggests that genotoxicity data, together with a literature review (e.g., no materials from the NTP list of Carcinogens) is a reasonable strategy to ensure the safety of many medical devices that are made using standard materials and manufacturing processes. FDA has not provided literature or specific examples to indicate that this practice has failed to protect patients.

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174 765-767

Revise to read: “CDRH recommends that carcinogenicity potential be assessed to determine the necessity of the carcinogenicity testing for an implant device or a device with a novel material (regardless of the duration of contact)”

This statement is not consistent with the FDA Recognition position Number 2-156: AAMI / ANSI / ISO 10993-1:2009, Biological evaluation of medical devices -- Part 1: Evaluation and testing within a risk management process (Biocompatibility) and the FDA Blue Book Memorandum #G95-1. Indeed, carcinogenicity testing is recommended for permanent implantable and external communicating devices, only. Carcinogenicity testing is not required for surface devices with limited to permanent use and implantable and external communicating devices used for less than 30 days.

175 766-767 Provide rationale for requiring a carcinogenicity study for a device with a very short duration of contact.

Considering devices with a very short duration of contact (e.g., a novel material syringe needle), such as ten (10) seconds maximum, further clarification should be provided on the rationale for an extensive carcinogenicity study for a novel material with a few seconds exposure and what would be the carcinogenic mechanism of action?

176 767-770 Add discussion with references and examples to explain which materials or chemicals are carcinogenic without being mutagenic (genotoxic).

As stated within ISO 10993-3:2009, section 6.2.2.11, “It is rare for carcinogenicity tests to be considered appropriate for medical devices” and that “Carcinogenicity testing shall not be performed when risks can be adequately assessed or managed without generating new carcinogenicity test data.” In addition, the testing strategy in this standard also refers to the availability of significant and adequate human use history as evidence to rule out carcinogenic risks.

Additionally, the guidance states (Pg. 8; Lines 374-377) that in order to use clinical data or scientific literature, FDA requires chemical characterization data AND literature. This is overly burdensome when actual human clinical data are available.

177 765-793

Revise to read: “CDRH recommends that carcinogenicity potential be assessed to determine the necessity of carcinogenicity testing for an implant device or a device with novel materials (regardless of contact duration). Because there are carcinogens that are not genotoxins, FDA believes that the

Duration of contact should be a consideration per Table 2 of the Draft Guidance.

Since it may be difficult to obtain proprietary information or find suppliers with master files this process places excessive burden on the product development process. This will significantly slow or lead

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Comment No.


assessment of carcinogenicity cannot rely solely on the outcomes of genotoxicity testing and therefore the following elements should be considered in conjunction with genotoxicity testing on the final product.

Include chemical formulations and manufacturing residuals for the device. Device manufacturers should encourage third-party suppliers to set up FDA device master files for proprietary information.

Include the complete chemical formulations and manufacturing residuals for all components of the device. The sponsor should identify how much of each chemical would theoretically be present in an individual device (assume worst-case, e.g., the largest device) as well as in the worst-case patient exposure situations (e.g., assume a worst-case situation where a patient might receive multiple devices, if this scenario could reasonably occur in clinical use). For components that are provided by third-party suppliers where the chemical formula is proprietary, device manufacturers should encourage suppliers to use device master files to provide chemical formulation information to the FDA.

Identify potential leachants and breakdown products from Chemical Characterization (which may not be included as original materials or processing agents). Consideration should be given to effects of all processing agents (e.g., adhesives, mold cleaning agents, mold releasing agents, sterilization chemicals) that come into contact with the device. Consideration should be given to effects of all processing agents (e.g., adhesives, mold cleaning agents, mold releasing agents, sterilization chemicals) that come into contact with the device.

to the cancellation of programs to investigate new products which may require unique materials or processes to manufacture. This will be especially burdensome and impede innovation of devices to treat orphan conditions. Additionally, it is unnecessary since not all materials in the device leach into the biological environment, therefore, do not pose an exposure risk to the patient. However, Chemical Characterization may serve as a reasonable means of obtaining the data required for a cancer safety assessment since this data not only identifies available compounds but can be used to quantify the amount and duration of patient exposure to a particular leachant.

Additionally, carcinogenicity is determined by route as well as dose and duration. As an example per ICH S1A which lists several fundamental factors in assessing the need for carcinogenicity studies, duration of exposure of > 6 months is required and IARC classified nickel and nickel compounds as carcinogenic or potential carcinogens to humans (group 1) based on carcinogenic effects of insoluble nickel compounds, with no consideration of the lack of carcinogenic effects of soluble nickel compounds. IARC also concluded that cobalt and cobalt compounds were possibly carcinogenic to humans (Group 2B) based on findings that exposure to cobalt sulfate by inhalation of aerosols (a suspension of fine solid particles or liquid droplets in a gas) caused tumors in rodents. But both nickel and cobalt chloride are not carcinogen in animals when given their soluble forms orally. Therefore it is very important to consider the relevant clinical in-use condition when assessing any cancer risk.

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Provide a through literature review, identify the search terms, and conduct an analysis of toxicity of the chemicals. If potential carcinogens are found in the device, the sponsor should identify and quantify these chemicals and determine how much of the potential carcinogen and/or carcinogenic byproducts would be available in a single product in a worst-case scenario. A cancer risk assessment considering relevant clinical in-use application should also be provided with literature evidence to demonstrate that the amount of the potential carcinogen(s) available in a device does not pose an unacceptable carcinogenic risk. This analysis should also be provided assuming a maximum number of devices likely to be placed in a single patient in clinical use.”

178 772

Please add footnote to “manufacturing residuals” to state: “Please refer to ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL CARCINOGENIC RISK M7 for details on the level of sensitivity required”

The requirement to identify all manufacturing residuals is not possible unless a limit of sensitivity is provided. We suggest referencing ICH M7 entitled: “ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL CARCINOGENIC RISK M7”

179 772-773 Clarify what is considered a “complete chemical formulation.” Many of the formulations provided by the vendors are proprietary to some extent, especially when it comes to additives like colorants.

180 772-773 Revise to read: “Include the complete chemical formulations and manufacturing residuals for all patient-contacting components of the device”

Clarified that this requirement applies only to patient-contacting materials.

181 782-783

Add: “Identification of potential leachables and breakdown products (which may not be included as original materials or processing agents) should be performed using currently available analytical chemical methods. If full identification and quantification of the extractables and leachables is un-attainable, then TTC (Threshold of Toxicological Concern) concept can be used to assess the toxicity risk of the device.”

Full identification and quantification of the extractables and leachables can be difficult to impossible to achieve with current analytical techniques.

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182 782-785

Define the limit level for identification of leachants and breakdown products. Additional guidance on methods would assist industry in better understanding the Agency’s expectations for leachants and breakdown products.

There are unlimited numbers of potential leachants and breakdown products coming from any given component or device.

183 787-789 Make the second sentence the start of a new paragraph. This paragraph’s second sentence seems to be a separate “step” following the described analysis.

184 798-811 Note ICH suggesting moving away from 1-year rat carcinogenicity: 3/18/13 Fed Reg on ICH S1

Please incorporate an acknowledgement that the ICH has recommended that long-term rat studies no longer be considered the gold standard for carcinogenicity.

185 798-811

Revise to read (emphasis added): “If carcinogenicity testing is warranted (e.g., when data is not available to provide an adequate assessment or assessment indicates there is a potential risk), consideration of available test models should include:

Standard rodent long term carcinogenicity bioassays (OECD 451

30 or OECD 453

31) to evaluate the potential for

systemic carcinogenic effects. FDA recognizes that solid-state carcinogenicity occurs frequently in rodents. In the event that local tumors are present, FDA recommends that the sponsor provide a discussion of the potential for chemically induced as well as solid state carcinogenicity.

RasH2 transgenic mouse model, with confirmation of stability of transgene status. FDA recommends that prior to conducting carcinogenicity testing, the sponsor discuss proposed testing with CDRH to ensure that the study design is appropriate to assess the potential risk.

FDA recognizes that solid-state carcinogenicity occurs frequently in rodents. In the event that local tumors are present, FDA recommends that the sponsor provide a discussion of the potential for chemically induced as well as solid state carcinogenicity.

FDA recommends that prior to conducting carcinogenicity

Clarification.

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Comment No.


testing, the sponsor discuss proposed testing with CDRH to ensure that the study design is appropriate to assess the potential risk.”

186 813-824

Clarify that reproductive and developmental toxicity testing is only relevant if the toxicological assessment concludes that chemicals extracted out of devices pose reproductive and development toxicity to patients.

Clarification.

187 817-819

Revise to read: “We recommend that you consider this testing for novel implant materials if there is a potential for chemical leachants to contact reproductive organs, regardless of the type of contact, and the materials or devices in contact with the reproductive organs.”

Mobility of chemical leachants from implants should dictate if this testing is required.

188 818 Add a row: “For devices contacting reproductive tissues” to the Table in Attachment B.

The requirement to conduct reproductive toxicity testing for devices that contact reproductive tissues is not identified in Attachment B and should be. Attachment A uses a special nomenclature for testing extracorporeal circuits, and similar nomenclature could be used for reproductive tissues.

189 832-834

Revise to read: “FDA recommends that prior to conducting biodegradation testing, the sponsor discuss proposed testing with CDRH to ensure that the study design is appropriate to assess the potential toxicological risk.”

The term “risk” is unclear. The preferred term is “toxicological risk.”

190 848 Clarify the title of this section to indicate FDA’s intent.

Is FDA’s intent to:

Combine “known toxic entities” and “potentially toxic entities,” or

Alternatively, state “known entities” and “potentially toxic entities?”

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191 848-962 Comment/Question on Section 7

The requirements described in this section (“Assessment of Known or Potentially Toxic Chemical Entities”) is inconsistent with the requirement of testing the final finished product; if the final finished, sterilized product has passed all the required biocompatibility tests, based on duration of exposure and nature of contact and the device is determined to be non-toxic, why would it be necessary to assess the individual chemicals e.g., color additive present in that device?

192 850-860

Revise to read: “For chemicals used in a device for the first time, or for chemicals that are known potent toxicants with known or potential toxicities (e.g., color additives, or drugs used in combination products), additional information should be provided to determine whether toxicology information beyond standard biocompatibility testing is needed. if biocompatibility testing is needed to assess chemical safety manufacturers should consider whether additional toxicological data beyond the recommendations of the standard test is needed.

CDRH evaluates the safety of medical devices based on duration of exposure and nature of contact. Inherent in the review of medical devices is an understanding of the body’s entire exposure to the product, including all chemicals entities that may migrate from the product’s materials contained within the product. For devices containing these unknown or potential toxic chemicals, such as color additives, the evaluation of safety should be based on both the chemical risk of the chemical (i.e., the level of toxicological concern) and the duration of exposure (i.e., bioavailability and duration).”

All chemicals have potential toxicities and thousands have known toxicities. Also the term “color additives” includes many compounds with a broad range of toxicities. Specifying color additives here implies that these compounds are especially toxic and therefore require extra attention. However, these compounds as a group are not any more important toxicologically than any other chemicals. Calling particular attention to color additives here could distract from other chemicals that pose more of a patient risk. Thus, identifying color additives specifically is not warranted and may result in tunnel vision for the reader. All device materials including color additives should be assessed toxicities. Additionally, for drug/biologic delivery devices where the drug/biologic is the primary mode of action, the drug toxicity is evaluated by the primary reviewing division (CDER/CDRH) and this CDRH analysis is redundant and unnecessary.

For combination products where the device component has the primary mode of action (drug eluting stent, steroid tipped lead) the drug/biologic should still be subject to the drug/biologic regulations and this is still unnecessary.

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193 851, 858 Delete references to colorants or provide an example of a “known toxic color additive” that has been utilized in medical devices.

As there are numerous color additives considered “safe” as per 21 C.F.R. §§ 73 and 74, provide an example of toxic color additives used in medical devices. Further, color additives are provided as an example of a potentially toxic chemical when these chemicals, as a class, are no more important toxicologically that any other class of chemicals. What about solvents, metals, etc.?

194 857-860

Revise to read: “For devices containing these unknown or potentially toxic chemicals, such as known toxic color additives, the evaluation of safety should be based on both the toxicological risk of the chemical(s) (i.e., the level of toxicological concern), toxicological concern based on clinical use, and the duration of exposure (i.e., bioavailability).” Add to end of Line 860: “Note: this section is not relevant where the chemical is a drug or biologic as defined in FD&C Act. For medical devices that are indicated for the delivery of specific drugs or biological products, where the device also comprises the container closure system for the drug, the principles in FDA guidance Container Closure Systems for Packaging Human Drugs and Biologics: Chemistry, Manufacturing and Controls Documentation (May 1999) should be consulted for the safety evaluation of the portions of the device that are in direct contact with the drug or biological product, rather than ISO 10993. Note that ISO 10993 is relevant for the safety evaluation of portions of the device that contact body tissues or fluid, including substances that may leach from the device directly into tissues or fluid; however, substances that may elute in the drug or biological product delivery path are more appropriately addressed under the existing CDER/CBER and ICH guidance’s relevant to drugs and biological products.”

The term “unknown” is redundant because these chemicals are included in the term “potentially toxic chemicals.”

The term “unknown” in the original sentence is confusing because toxicological concern and/or risk of unknown chemicals cannot be assessed except by (a) history of use evaluation or (b) conducting analytical or toxicological tests.

Suspected toxicological concern of unknowns can be determined by evaluating clinical use.

195 865-941 We urge the Agency to consider assessment of chemical entities within the device via steps 1-3 not necessary if

The strategy included in this section for the assessment of unknown or potentially toxic chemicals does not focus on what is relevant to

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Comment No.


chemical characterization of the device is conducted. the patient in the use condition or acknowledge the limitations the industry faces in gaining access to proprietary information.

For example, steps 1-3 are prohibitive to innovation as suppliers of materials used in devices are often unwilling to provide this information and device manufacturers may have limited ability to influence suppliers to submit a master file. As such, this may result in the selection of less than optimal materials.

Additionally, steps 1-3 seem to be suggesting that it is also necessary to “deconstruct” the device and determine every potential chemical that could be part of the device and do an individual toxicity risk assessment on that chemical. However, the intent is to show safety of the whole device as manufactured not individual pieces.

196 868-883 Define limit level for identification of chemicals. Address how manufacturers should proceed with proprietary chemicals.

There are unlimited numbers of chemicals present in components. To properly assess, it is necessary to know the minimum amount/concentration that should be considered. Many materials have proprietary chemicals that the vendor will not identify or have a master file.

197 869 Revise to read: “The identity of the chemical by common name, chemical name, and Chemical Abstract 868 Services (CAS) number, if available.”

Not all chemicals have CAS numbers (e.g., oligomers), so add “if available”

198 871-872 Revise to read: “the composition (i.e., if a color additive, whether the colorant is comprised of a pigment or an ink, and whether the colorant is encapsulated in polymer)”

Most colorants in medical devices are comprised of a pigment AND encapsulated in polymer. Typically, colorants are blended with a polymer, then injection molded or extruded into a component, such that the colorant is encapsulated in polymer. It is unclear what information is requested in this part of the sentence.

199 878-879

Revise to read: “The specific amount of each chemical in the formulation by weight percent of the applicable component and total amount (e.g., μg) in the device if available or worst case estimation;”

The vendor may not provide the information. Therefore, worst case estimation should be allowed

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200 881 Provide guidance on how to do this assessment This information is generally regarded as proprietary for most device manufacturers. Not sure how we can get this information.

201 881-883

Revise to read: “The identity of any other devices marketed in the U.S. (by device name, manufacturer, and submission number) where the chemical entity with direct or indirect patient contact has been previously used, if known, and provide comparative information on the composition and amount(s) used.”

Scope is limited to patient-contacting materials.

202 885-898 Provide additional guidance on how to determine that a chemical is “bioavailable,” including conditions and example testing parameters.

Whether or not an additive or chemical is bioavailable determines it’s pathway through the guidance, more guidance is needed on how FDA will interpret whether or not a chemical is bioavailable.

203 888 Provide additional information on exposure assessments methods.

Examples would help industry better understand the Agency’s expectations.

204 889-891 Delete this sentence: “Note that for certain chemicals, elution from the device may not be necessary for the chemical to induce toxicity.”

This sentence is unclear and possibly untrue. For nearly all forms of medical device toxicity, elution of chemicals must occur so that the chemical can interact with cells, biomolecules, etc. Hemocompatibility does depend in part on the surface chemistry of the device, though these interactions are governed more by surface charge and functional groups of the base material or coating rather than by discrete chemicals. The local tissue response is also in part dependent on the surface of the device. Because neither of these endpoints typically can be addressed in a chemical safety assessment, this sentence should be deleted.

205 891-893 Reconsider recommendation to provide bioavailability data as an indication of a chemical’s stability.

Stability of a chemical is not related to bioavailability.

206 895-898 Clarify whether all descriptive information needs to be provided for components that will have no direct or indirect contact with the patient.

If the component does not have any contact whatsoever, there should be no concern with any of the chemicals used. The information gathered would be entirely unnecessary.

207 900 Elaborate and define “bioavailable.” Clarification.

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Comment No.


208 903-909

Revise to read: “Where the full toxicology profile for the chemical entity is not available from literature, either from the supplier, or from a previous medical device submission, the full battery of toxicity tests on the chemical entity . . .”

While the second sentence of Item 6 allows for toxicology profiles from suppliers and prior submissions, there is no provision for literature sources - thereby implying that sole utilization of a published toxicology profile would indicate need for the full battery of tests.

209 904 Revise to read: “…literature, and if available, unpublished studies for all known toxic effects. Where the full…”

Clarification.

210 909

Revise to read: “. . . may also be needed or a scientific rationale provided for not testing omission. Alternatively, Threshold of Toxicological Concern (TTC) may be used if applicable. For example, if extractable and/or leachable data demonstrates exposure will be below TTC, then further toxicological assessment is unnecessary.”

TTC has been accepted by FDA for chemicals present at residual levels and absence of toxicological data (e.g., manufacturing processes and/or unknowns).

211 917

Revise to read: “…, no further information is needed. Alternatively, when toxicological data is incomplete and the chemical is present below TTC, no further information is needed.

New sentence addresses when there is an absence of toxicological data.

212 924-926

Revise to read: “Data to demonstrate the amount of color additive chemical bioavailable (e.g., eluted) from the device over 30 days (or worst-case exposure that might be reasonably encountered in clinical use plus a safety margin).

Use of the term “color additive” is not consistent with the content of this section; not limited to only color additives.

213 924 Please provide additional information with respect to determining a worse case exposure for a permanent implant.

The Agency’s expectation is unclear for determining a worse case exposure for a permanent implant.

214 929-930 Revise read: “Justification for the extraction solvents (which will be dependent on the nature of the color chemical and the polymer matrix);”

Use of the term “color additive” is not consistent with the content of this section; not limited to only color additives.

215 936-941

Revise to read: “If the chemical is confirmed to be bioavailable, assessment(s) of the fate of the chemical should be included in the safety assessment in a clinically relevant animal model should be provided to assess the timing of elimination, and pharmacokinetic analysis (e.g., absorption, distribution, metabolism, and excretion (ADME)).”

ADME should be considered when leveraging unpublished data or data from public domain and conducting a safety assessment to evaluate toxicities of chemicals. (Line 903 to 909). It is an inherent part of animal study.

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Comment No.


216 943-963 Delete the requirements for color additives listed in Section 7.9-11.

Historically colorants have been treated like all other additives. Whether they’re organic or inorganic, they are researched carefully and toxicological risk assessments of the colorants are based on the best available information. On occasions when toxicity data are unavailable for a particular colorant or other additive, information on metabolites or surrogates has been successfully used. This approach has been acceptable to CDRH for several years. If FDA is concerned about a color additive having toxic effects not detectable by normal biocompatibility testing, then a chemical characterization study that includes exhaustive extraction followed by a toxicological risk assessment should sufficiently confirm the safety of the device. The proposed language in this section says that a color additive petition (CAP) must be filed for unknowns colorants. If the device is not a contact lens or a resorbable suture, why is the FDA now requiring industry to submit a time-consuming CAP document? Requiring this CAP documentation seems unnecessary and burdensome.

217 957-962 If requirements for color additives are not deleted, as requested in comment above, clarify Agency definition of bioavailable after 30 days.

This section discusses colorants that are bioavailable for more than 30 days. If >90% of the colorant is eluted in an exhaustive extraction study, then does that mean it would not be classified as being bioavailable after 30 days? Clarification about this issue is critical to making the colorants section understandable.

Also clarify color additive included in this section with respect to IDE product as: The investigational device exemption (IDE) regulations 21 CFR Part 812 exempt from the requirements of section 721 a color additive or any specific use of the color additive when intended solely for investigational use by qualified experts and when such exemption is consistent with the need needs of public health.

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Comment No.


218 965 - 984

Delete this section or reference the Threshold of Toxicological Concern.

This section does not seem applicable to guidance on ISO 19993 and is also redundant to the FDA Draft Guidance, “Draft Guidance for Industry and Food and Drug Administration Staff - Recommendations for Labeling Medical Products to Inform Users that the Product or Product Container is not Made with Natural Rubber Latex.”

If deemed important, the FDA should provide literature or recommended scientific methods to assist sponsors in evaluating their devices. A valuable concept is the Threshold of Toxicological Concern (TTC) which has been shown to have value in risk assessments of regulated products.

219 967 Delete “pyrogen-free.” Inclusion of pyrogens in this section is not appropriate because acceptable levels of pyrogens are defined in current (2012) FDA guidance and previous sections of this draft guidance (line 675)

220 980-983 Define expectation of changing labeling on currently marketed devices.

Section is unclear as to when labeling of currently marketed devices should be updated.

221 1017-1028

Regarding FDA discussion on the Analysis of Results section in biocompatibility test reports, interpretation of results should be performed by a qualified biocompatibility scientist/toxicologist familiar with the device materials of construction, intended conditions of use of the device, and overall fitness for use. The Study Director should not be expected to have that level of knowledge of the product to interpret the results and make a device-specific conclusion in the report.

Clarification.

222 1017-1023

Revise to read: “For any test in which the results indicate a potential toxicity, the report should include a discussion of any test-specific issues that might have affected results, and any other available information (such as the results of animal safety studies) that might provide additional context for interpretation. For example, if a device made from polypropylene results in a grade 2 cytotoxicity in an L929 assay, which might be acceptable per ISO 10993-5, the sponsor should provide additional information regarding the potential source of the

This section and the example presented imply that now device manufacturers need to interpret passing results from standard tests with standard acceptance criteria. The acceptance criteria that are established for ISO 10993 tests are based on world-wide consensus of experts and a decade or more of history (depending on the test). Speculation on why a result was observed for a particular test sample that passed acceptance criteria will not make a device any safer.

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Comment No.


toxicity, since polypropylene is not generally expected to be cytotoxic.”

223 1017-1020;

1031

Make a new section for “Biocompatibility Risk Assessment” and move sentence 1017-1020 and “the clinical significance of the conclusions” to this new section.

This sentence directs the study director of a particular safety study to make risk assessment conclusions based on information from other studies. Because the study director may not necessarily be competent as a risk assessor this is inappropriate, and in many cases individual study directors are not fully aware of the suite of studies being conducted on particular material so this might not be possible. This is more appropriately addressed by an appropriately qualified toxicologist in a risk assessment which summarizes all available information, and is interpreted by someone with appropriate qualifications.

224 1034-1128 Delete this section It is unclear how this example section relates to the preceding guidance material. Such examples may be valuable to sponsors but would be better presented on a Q&A website or other forum.

225 1044-1047

If FDA decides not to delete the section, the following comments should be considered:

Revise to read: “Comparison to test article: "The [polymer/metal/ceramic/composite name] [component name] of the test article is identical to the [component name] of the final sterilized device in formulation, processing, sterilization, and geometry, and no other chemicals have been added (e.g., plasticizers, fillers, color additives, cleaning agents, mold release agents)."

A comparator product may contain a material formulated, processed, stored and used in the same way as a proposed product in a greater material quantity or in a higher biocompatibility device use category that still may be appropriate to leverage for a proposed device that will use less material in a lower risk application.

The geometry statement is a concern as equivalent biocompatibility can be demonstrated for products made with the same manufacturing methods, materials, and very different geometry. Even “similar” geometry would give pause as it becomes very subjective and limits the ability to be efficient in how we rationalize equivalence.

226 1049 - 1053 If “geometry” is not deleted as suggested above, suggest including this definition:

“Geometry – Changes in the device design area, volume, or

If the term - “geometry” is to be used in this clause, then an example and/or definition should be provided:

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Comment No.


joints of similar or dissimilar materials that based on risk require new biocompatibility testing or analysis.”

227 1034-1128 Suggest replacing the words “final sterilized product” with “finished medical device.”

Not all products that go through biocompatibility testing are STERILE. This text appears in all of the DoC’s.

228 1035-1037, 1045, 1050, 1059, 1063

Allow statements such as, “The final sterilized device is similar to the (previously marketed device) in formulation, processing, sterilization, and geometry as long as no other chemical have been added with appropriate justification provided for similarity.

It states that a sponsor may choose not to perform certain tests, based on the fact that the current product is the same as the previously tested product.

However, this does not give any leeway for devices that are slight modifications of marketed devices as the geometry of the new device would likely not be identical to the marketed device. There are some instances where “worst case” testing on similar products would be sufficient for a device. Sponsors should be allowed to provide appropriate justification for similarity between products.

229 1068-1128 Revise to read: “…chemical or substantial physical properties’ in every paragraph.

“Physical” is not defined. Process or sterilization change is likely to have minor physical changes. However, what matters most is to ensure “no chemistry change.” Therefore, the word “substantial” is added in front of the word “physical.”

230 1090-1095

Revise to read: “NOTE: Changes in raw material suppliers or raw material specifications could introduce different types or quantities of residual chemicals, and could result in a toxic response (even if the base material has a long history of safe use in similar applications). Chemical characterization at the raw material level may be used to show comparability and may eliminate the need for device level testing.”

Changes in raw materials should be testable at raw material level to show chemical comparability (unless they require manufacturing changes which may require testing at a component or subassembly level to show chemical comparability). This should not require device level biocompatibility testing unless differences are detected that cannot be justified through a safety assessment.

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Comment No.


231 1094-1096

Revise to read: “NOTE: The impact of surface alterations due to processing, even at the micron or submicron level, should be evaluated when there is reasonable possibility that they could result in a deleterious biological effect (even if the base material has a long history of safe use in similar applications).”

Although geometric surface alterations (topography) can certainly be a consideration, no one ideal topography exists for all our components or applications. A variety of surface topographies are used on our metal and polymer components. For polymers, there have been a wide range of surface topographies that have successfully been used in implant applications (“smooth” silicone and polyurethane surfaces to plasma treated surfaces). For metals, we have used polished electrodes and platinized and coated electrodes. From a root cause point of view, surface topography (within the notable range of topographies that we have utilized in our products), although a consideration, has not proven to be a major factor in device performance. Usually other factors (e.g., choice of material type, the particular design) are more important.

Concerns about surface alterations are relevant where risk analysis shows a reasonable possibility that surface alterations will have deleterious biological effect.

232 1119-1120 “…, may require new risk assessment or new testing” ISO 10993 suggests risk assessment prior to biological testing.

233 1133 In Table 1, External communicating device – circulating blood – A, remove “X” for genotoxicity, or limit to note ^ for extracorporeal circuits

Genotoxicity is not required for implant device – blood – A; why would external device have more stringent requirement?

234 1133 In Table 1, Implant Device – Blood – A, there should be an “X” for genotoxicity and none for subchronic toxicity

Correction

235 1133 Delete “see 5.2” and “see 5.3” The table contains references to ISO 10993-1 (“see 5.2” and “see 5.3”), which are confusing because one would normally assume that these references refer to the document in hand.

236 1133 The table does not include the footnote from ISO 10993-1 (2009) for Intact skin, contact Duration A to state: testing may not be required. Suggest adding this back in.

Please include the information that is missing from 10993-1.

See mark ups of the flow chart in Attachment 2.

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Comment No.


237 1133 The headers in this table: Nature of Body Contact and Contact Duration reference sections of 10993-1 (2009). Suggest adding an * to note that this is where these headers come from.



238 1133

There is no text in the guidance to define the nature of body contact and the contact duration. This being said implies that FDA is accepting the definitions provided in 10993-1 – is this correct?



239 1135-1137 Use X to designate tests required by ISO 10993-1 (2012), and O to designate additional tests required by FDA.

It is unclear what distinction the FDA is making between the X and O designations in this table. As written, X tests could be considered and decided against without justification whereas for O tests not conducting would need to be justified. In practice, all relevant biological effects should be discussed in a risk assessment conducted by a competent individual and the rationale for not conducting any of such tests should be justified regardless if they are X or O tests.

240 1141

Attachment B Table 2

Sections 5H and 5I instruct that reproductive and developmental toxicity and biodegradation should be assessed in certain situations; however, this is not indicated in Table 2.

Add O’s to Table 2 to indicate the situations in which reproductive and developmental toxicity and biodegradation should be considered.

241 1143 Populate the final two columns, or delete them if left blank. The columns are not populated in this table, which is confusing. The draft guidance provides recommendations on when these tests should be conducted in lines 420 and 813

242 1143 Combine tables 1 and 2 There is no clear reason why tables 1 and 2 are separated. It would be more clear if they were combined into a single table

243 Attachment

C Provide additional guidance on flow box “Does it contain any toxic substances (eg, Pb, Ni, Cr, Zr)?”

There is no other discussion in the guidance of what steps sponsors should take if these chemicals will be used in their devices. The next step in the flow chart to “consult the modified ISO matrix” does not suggest anything specific for these materials.

244 Attachment

C Revise to read: “Consult modified ISO matrix for suggested tests (page X of Y standard)”

Which matrix?

245 1149 Revise to read: “Attachment C: Flow Chart for Deciding if The title “Biocompatibility Flow Chart for the Selection of Tests“ does

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Comment No.


Biocompatibility Requirements are Met” not appear appropriate for the process outlined in the chart. The purpose of this chart appears to guide the decision or if the requirements are met or if biocompatibility tests are necessary.

246 1149

Define indirect contact.

247 1149

Be consistent in these statements to match the verbiage in the DoC for 10993. Refer to the marked up FlowChart C in Attachment 3.

248

1149 – In The flow chart -

second box down from

the top

“Are materials same as marketed device” The flow chart does not address devices manufactured using multiple materials.

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Comment No.


249

1149 – In Flow Chart -third box

down

Delete this box, everything to the right and below this box and replace with attached Flow Chart.

The suggested flow chart does not address devices manufactured using multiple materials. For example how should a reviewer answer the question “Is the device a polymer?” when the device is manufactured using both metals and polymers?

250 1149

Attachment C

Toxicities associated with a device depend on the form and amount of chemical that leaches out as well as the duration and route of exposure, but not by formulation alone. We recommend greater reliance on chemical characterization data to make this decision.

Additionally, every chemical is potentially toxic and toxicity is dependent on dose and duration of exposure. It is not accurate to list any metals as toxic substances here without a context.

Revise flow chart to acknowledge chemical characterization with safety assessment as a pathway to meeting biocompatibility requirements.

Delete ‘(e.g., Pb, Ni, Cr, Zr)’

Attachment 3

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Attachment 3

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Documents

Docket No, FDA-2013-D-0350 Comments on 'Use of ......characterization, (2) toxicological risk assessment, and (3) biological testing. This updated paradigm for the appraisal of medical