March 19, Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane Room 1061 Rockville, MD 20852

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1 March 19, 2018 Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane Room 1061 Rockville, MD RE: Docket No. FDA-2017-D-6765; Draft Guidance for Industry and Food and Drug Administration Staff; Replacement Reagent and Instrument Family Policy for In Vitro Diagnostic Devices Dear Sir/Madam: On behalf of AdvaMedDx, a Division of the Advanced Medical Technology Association (AdvaMed), we respectfully submit these comments in response to the FDA s Draft Guidance for Industry and Food and Drug Administration Staff: Replacement Reagent and Instrument Family Policy for In Vitro Diagnostic Devices ( hereinafter Draft Guidance ). AdvaMedDx member companies produce advanced, in vitro diagnostic tests that facilitate evidence-based medicine, improve quality of patient care, enable early detection of disease and reduce overall health care costs. Functioning as an association within AdvaMed, AdvaMedDx is the only multi-faceted, policy organization that deals exclusively with issues facing in vitro diagnostic companies in the United States and abroad. Our membership includes manufacturers engaged in the development of innovative diagnostic technologies supporting the advancement of the public health, helping to deliver cutting-edge care to patients worldwide. GENERAL COMMENTS We strongly support the Food and Drug Administration s ( FDA or the Agency ) significant efforts to promote the transparent and consistent application of the FDA replacement reagent and instrument family ( RRIF ) policy, which is a key policy supporting diagnostic product advances. This policy is critical to reflect advances and incremental evolution of laboratory instrumentation, which are a cornerstone of new diagnostic technologies improving care for patients and driving optimal and timely healthcare, and to promote an overall efficient, effective, and consistent regulatory process. We applaud FDA for its statement in the Draft Guidance that FDA believes this is important for public health as it promotes more timely availability of a wider array of clinical laboratory tests for patient benefit. 1 We also strongly agree that providing additional clarity to help manufacturers and FDA better apply the concepts will help ensure realization of the full benefits of the policy. 2 We also appreciate FDA s recognition of the importance of this 1 Draft Guidance, 1. 2 Draft Guidance, 1.

2 Division of Dockets Management (HFA-305) March 19, 2018 Page 2 of 14 Docket No. FDA-2017-D-6765 long- standing innovation policy to industry and opportunities to promote consistency and clarity in application of the policy. We greatly welcome FDA s issuance of the Draft Guidance and seek timely finalization of the Draft Guidance. In particular, we appreciate that this Draft Guidance provides principles and examples to better explain what is and is not covered in the policy. We also particularly support the addition of language throughout the Draft Guidance that contemplates a risk-based assessment by the manufacturer of the types of studies needed to support the new assay/instrument combination or new instrument family member. For instance, the Draft Guidance states that the assay manufacturer should determine appropriate testing based on a risk-based assessment for the specific device and changes involved. 3 The ability to use a risk-based assessment is aligned with the FDA-recognized international voluntary consensus standard ISO 14971, and the new, final FDA Deciding When to Submit a 510(k) for a Change to an Existing Device. Adoption of such a risk-based assessment will promote faster availability of innovative clinical laboratory tests while still protecting patient safety. Also of note, we support language in the Draft Guidance that clarifies that the mere existence of a special controls document does not necessarily trigger the need to submit a 510(k). We would recommend that FDA add language to its discussion of special controls, as it has in other areas of the Draft Guidance discussed above, indicating that the manufacturer will determine relevant testing of an assay subject to a special controls document using a risk-based approach. AdvaMedDx appreciates the opportunity to provide our comments, which are intended to support FDA s efforts to advance diagnostics innovation and patient care. We identify in our specific comments a few areas within this Draft Guidance where we believe additional clarification would be helpful to achieve our shared goals. We provide in those specific comments accompanying recommendations to assist FDA. Respectfully submitted, /s/ Jamie Wolszon Associate Vice President Technology and Regulatory Affairs 3 Draft Guidance, 8. See also Draft Guidance, 7 ( The assay manufacturer is responsible for verifying and/or validating the modified test system as part of design controls (see 21 CFR ). Verification and validation activities should be based upon the manufacturer s quality processes, including its risk-based assessment for the specific device and changes involved ).

3 Proposed additions are indicated in underline. Proposed deletions are indicated in strikethrough. General Please include flowcharts to help illustrate the concepts in the Draft Guidance. We believe that the flowcharts in the 2003 are a useful visual aide, and it would be helpful to include similar flowcharts in the Draft Guidance. General Throughout the Draft Guidance, FDA indicates that in certain scenarios, the submission of a 510(k) is either likely, or unlikely. Please clarify FDA s understanding of these terms to assist manufacturers in making the determination. We believe that the terms likely and unlikely may be ambiguous, and clarification would assist manufacturers in appropriately deciding whether a submission is warranted. General Consider including language outlining the general concept that a special 510(k) may be appropriate as an alternative to a traditional 510(k) for certain new assay/instrument combinations or new family members. The 2003 included a section discussing the role of the special 510(k). We believe that language explaining the general concept that a special 510(k) may be appropriate for certain new assay/instrument combinations or new family members should continue to be included. II. 72 This is not intended to address the following: Devices indicated for use in point of care settings We recommend that FDA remove the limitation stating that point-of-care (POC) devices are outside of the scope of the policy. We believe that this limitation stems from the exemption from premarket notification in.9 of the Chapter in 21 C.F.R. Parts (the.9 provisions). Nearly two decades have passed since FDA first promulgated the limitation provisions, and during that time, the state of technology, scientific and medical knowledge, the availability of standards, and have advanced tremendously. Many technologies Page 3 of 14

4 and device types that were just emerging in the late 1990s, such as POC devices, are now well-characterized. POC devices, limited under (c)(9), are now an integral and recognized part of medical practice and are subject to strict performance standards. We believe that categorically limiting a device simply because it is at the point-of-care no longer makes sense and does not support the public health in today s healthcare environment. Our recommendation is consistent with the recommendation we made in response to FDA s request for comments related to Review of Existing Center for Devices and Radiological Health Regulatory and Information Collection Requirements. II Special cases also exist where FDA has established final for modifications to specific devices and/or specific requirements (e.g., special controls) that are identified in the classification regulation. Some current final device-specific s or special controls state that the Replacement Reagent and Instrument Family Policy is not appropriate for the device type (e.g., Class II Special Controls Guidance Document: Instrumentation for Clinical Multiplex Test Systems ). This, when finalized, will modify such statements so that the Replacement Reagent Policy and Instrument Family Policy described in this may apply to such device types. Based on FDA s current understanding of and experience with currently classified device types, FDA believes that the recommendations provided in this could provide for alternative mitigations that provide equivalent assurances of safety and effectiveness, but there may be As discussed in our general comments, we appreciate the language in this paragraph, including an example, that clarifies that the mere existence of a special controls document does not necessarily trigger the need to submit a 510(k). We seek additional clarification that the Agency intends a similar approach to study types, i.e., that a manufacturer would, as described elsewhere in the document, determine which studies to perform based on a risk-based assessment of specific device and changes involved. See, e.g., Lines and We believe this risk-based approach should apply to all assays, including those having Special Controls, provided the other criteria outlined in this Draft Guidance are met. We believe that patient safety can continue to be protected without repeating all of the testing that supported the original 510(k) where the assay is covered by a special controls (e.g., testing of specific interferences, etc.) Page 4 of 14

5 additional considerations to take into account. This, when finalized, is not intended to supersede anything else contained in such final device-specific s or special controls but may cover areas not addressed in such device-specific s or special controls. As discussed in the remainder of the document, the manufacturer is responsible for determining the appropriate activities using a risk-based assessment that takes into consideration the specific contemplated change. The manufacturer would have on file, available for inspection, detailed rationale for any departures from testing described in a special controls document. We also think that it would be helpful for FDA to clarify the additional considerations to take into account. This could either be in the form of examples or clarifying language. In addition to the proposed revision above, please provide clarification of the language there may be additional considerations to take into account. II. 90 Add a footnote following this line that provides a reference to Guidance for Industry and FDA Staff: Assay Migration Studies for In Vitro Diagnostic Devices. The Assay Migration studies notes that it applies to contemplated changes for which the Replacement Reagent does not apply, and has recommendations for study designs. We believe that a similar reference in this document could be helpful for manufacturers. II Please add an example or clarify what the phrase regulatable as separate articles (e.g., they are detachable) (line 115) means in the context of an assay and instrument combination. We believe clarification of this language would be helpful to industry. Page 5 of 14

6 II For the tables, designed to help illustrate regulatory scenarios, we would propose reverting to the ones used in the We believe the 2003 presents these regulatory scenarios more clearly. III. A To date, the Replacement Reagent Policy has largely been utilized for traditional laboratory automated chemistry and immunoassays. If you have questions concerning how to apply this to an evolving particular technology, we recommend you contact the appropriate review division in FDA. This could be done using the pre-submission process or during premarket review of the initial test system if future modifications can be anticipated. It is important that this policy apply consistently throughout all of the Divisions within OIR. In addition, we would like to encourage sponsors to contact the Division if they have questions about the applicability of the policy regardless of whether the question relates to evolving technology. III. A Please provide one or more examples to elucidate what could constitute a significant change to assay value assignment methods or calibration schemes. We believe that examples to clarify what FDA would consider to be a significant change to assay value assignment methods or calibration schemes would be helpful. III. A2 186 Add the word software to the title A2. Instrument and Software Principles We believe it is helpful to clarify that software is an integral part of instrument-assay combinations. III. A The Replacement Reagent (RR) Policy applies to open systems. For purposes of this, an open system has general purpose features intended for use with a wide array of assay types, including those that share a similar methodology (e.g., similar detection methods, similar processing and interpretive software). An open system generally does not impose restrictions (e.g., through software) for use with only certain types of reagents or for We believe that the current definition could be misinterpreted as categorically excluding closed systems from the entire policy regardless of who is using the policy. We do not believe this is FDA s intent. Manufacturers may have closed systems that they want to add their own reagent to. In order to facilitate the continuation of this acceptable practice, we would propose modifying the language to clarify that the RR policy may be used by the manufacturer of the reagent on a closed system, but Page 6 of 14

7 detection of only certain types of analytes. The Replacement Reagent Policy does not apply to closed systems. For manufacturers of both the assay and the instrument, the replacement reagent policy also applies to closed systems. For purposes of this, a closed system includes an instrument intended for use with specific reagents or reagent types and specific reaction schemes. not by other parties. We believe our proposed language is consistent with the approach taken elsewhere in this document, e.g., the table on line 126. In addition, the 2003 included a definition of partially closed systems. We believe that the definition of partially closed systems provides helpful clarity, and would recommend including it in the Draft Guidance as well. III. A For purposes of this, partially closed systems are analyzers and original equipment manufacturer reagents provided by the same manufacturer that are intended to be used in combination. The analyzers may also be intended to be used with replacement reagents for the analysis of analytes for which the manufacturer does or does not provide reagents. In the latter case, the analyzer serves as a general purpose analyzer in an open system. If software, such as for system integration, system restrictions (noted above), signal processing, data acquisition, interpretation, or other calculations needed to produce clinical results, needs to be modified in such a manner that the modification would affect how a result is generated or how an assay is processed on the system, in order to run the assay on the instrument, then a new 510(k) is likely required. We would recommend modifying this language. System integration, system restrictions, and data acquisition, can be managed differently by software without affecting how a result is generated or how an assay is processed on the system. Page 7 of 14

8 III. B When the risk-based assessment indicates that the performance of the modified test system could significantly change (e.g., statistically or clinically significant changes) relative to performance claims in the labeling for the cleared test system, a 510(k) is likely required. Often, statistically-significant changes are not clinically relevant. Per the regulations, a new 510(k) is required when a change could significantly affect the safety and effectiveness of a device. 21 C.F.R A statistically significant change, if not clinically significant, would not necessarily meet that trigger. We believe the focus should be on clinicallysignificant changes. Documentation should include a description of the rationale, or additional testing performed, to support that a statistical difference in performance claims was not clinically significant. III. B1 231 Significant changes to test system performance characteristics (e.g., precision, linearity or recovery, interference, assay traceability, detection limits, bias or scatter observed in method comparison) from those indicated in the labeling for the cleared test system have the potential to affect clinical decisions. We would propose adding significant to align with the regulation for modifications to a device. 21 C.F.R III. B For example, if reference ranges (or claimed cutoff concentrations) for the intended use population(s) are expected to change as a result of the change in instrument, this is considered a change to clinical performance, and a 510(k) is likely required. See CLSI EP28: Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory, 3rd Edition. In the 2003, reference ranges were explained with respect to NCCLS C28-A2: How to Define and Determine Reference Intervals in the Clinical Laboratory. We would recommend adding a reference to the updated version, CLSI EP28: Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory, 3rd Edition, to provide helpful clarification. Page 8 of 14

9 III. B For example, careful attention should be paid when a new instrument-assay combination includes modifications to reaction conditions, especially for technologies that are sensitive to small variations in assay parameters (e.g., temperature changes within antibody-antigen reactions) or where small differences in results have the potential to affect clinical decisions (e.g., small changes to the analytical sensitivity of troponin certain assays may significantly affect clinical assay performance). Changes that are clinically significant in terms of clinical decision making are likely to require a 510(k). In addition to the proposed revision above, please also provide clarity that FDA would not expect near identical analytical sensitivity for the policy to apply. We would replace the specific reference to Troponin with a more general reference as the statement about analytical sensitivity is not limited to Troponin. In addition, we seek clarification of the term small changes, as we believe it is ambiguous. We would propose that FDA clarify that it would not expect near identical analytical sensitivity for the RR policy to apply. III. C Protocols should be robust and challenging to ensure any significant changes to the performance of the new instrument-assay combination (compared to the performance of the cleared instrument assay system) will be identified. The acceptance criteria should be clinically justified so that the manufacturer can be confident that if no significant changes to the performance are identified, that such results will and ensure that all performance claims in the labeling for the cleared test system will continue to be met. As originally drafted, these two sentences could appear to be inconsistent. We propose this revision for clarification purposes. We believe this is the idea that FDA intended to convey. Page 9 of 14

10 III. C Method comparison studies in accordance with CLSI guidelines EP-09. Sample types (e.g., matrix), range and comparator methods should either be consistent with the original 510(k), or the manufacturer should provide a rationale as to why it is using a different comparator, e.g., the comparator used to support the 510(k) is no longer available. If comparison to a well-known reference method(s) or material(s) or clinical endpoint(s) were needed to support the original 510(k) (e.g., because of known lack of standardization among cleared assays), we recommend you either incorporate the same material(s), method(s), or clinical endpoint(s) to ensure similar performance for the new assay-instrument combination or provide a rationale as to why you are using a different method, e.g., there have been advancements in standardization. We propose revisions to reflect our belief that use of the same comparator method as the one to support the 510(k) may not be warranted. For instance, due to the passage of time since the 510(k) clearance, the original comparator used to support the 510(k) may no longer be available. Or, in the instance where comparison to a well-known reference method was needed to support the original 510(k) because of known lack of standardization among cleared assays at that time, there may have been advancements in standardization due to the passage of time. We also believe that comparing to the family member system would more directly illustrate/estimate the change in performance of the new system. We propose language to reflect that the manufacturer should either use the same comparator method or justify why it has chosen not to do so. That justification would be on file for FDA inspectors to review. III. C Move interferences to the list under the next paragraph of verification and validation activities that the manufacturer should consider including where relevant (lines ). We do not believe that an addition of one or more reagents necessarily affects interference performance. The need for testing interferences should be determined through a risk assessment as discussed elsewhere in the document. III. C1 307 On-board stability for reagent, calibrator and sample stability We would propose revising this language to clarify that that reagent, calibrator and sample stability are all related to onboard stability studies. Page 10 of 14

11 IV. 383 Test systems that include instruments (open or closed systems, part of the cleared system) within a family have 21 CFR (j) compliant design history files that demonstrate that one instrument leverages key system attributes (subsystems in common) related to test reaction and processing such that it can be considered a family member one instrument can be considered a modification of the other, rather than a new instrument. See Section A2 representative 510(k) can be submitted to confirm the new instrument has common detection and measurement methods and basic capacities and it is within a family that was previously cleared. Examples of the types of differences between instrument family members include improvements to some features, or increased data storage. Instrument within a family share a common device classification regulation and product code. We believe that the definition of instrument family is an important aspect of the policy, and propose clarifications. For instance, most manufacturers do not treat instrument family members as a modification. For Design History File ( DHF ) purposes, a new member of a family is usually treated as a new device, and may point to sections of the DHF of the original family member. Moreover, we have proposed language to add clarity and align with Section III A2 Line 193. IV Similar to any instruments to which the Replacement Reagent Policy is applied, the new instrument family member should yield the same result (i.e., no statistical difference in results or statistically different but clinically insignificant) for the same samples using the same assay. We propose this revision to reflect that there can be statistical differences that are not relevant to clinical decision-making. IV We would recommend that FDA outline its expectations for when the instrument that was cleared in the 510(k) is no longer available for comparison. In instances where the instrument cleared in the 510(k) is no longer available for comparison, it would be helpful for FDA to provide on how the manufacturer should compare the new family instrument for purposes of the policy. Page 11 of 14

12 IV If the assay manufacturer and instrument manufacturer are the same, that manufacturer might determine that application of an assay to a new family member does not call for the entire range of testing performed to support the 510(k) for the same assay. In addition, a reagent manufacturer could follow the same approach for a new member of an instrument family manufactured by a different company, including open systems. We support the language that manufacturers can determine the range of studies. We would broaden this language to include instances where the assay manufacturer and instrument manufacturer are not the same, including open systems. V Eliminate or revise scenario 5B. The example involves a determination that the policy does not apply to a POC device. As discussed above, we would remove the language that states that these types of devices are not applicable for use of the Replacement Reagent and Instrument Family Policy (line 72). We believe that FDA should either revise to indicate that a 510(k) is not needed, or develop another example of the changing use environment. Page 12 of 14

13 V. 6 Scenario A Scenario A - The assay manufacturer plans to apply the assay to the SAFR instrument, which is similar in technology to the SAFT instrument, but is designed and manufactured differently (e.g., different sample processing internal layout, different sample workflow, etc.). The assay manufacturer performs a risk-based assessment, which does not identify any new risks or significantly modified existing risks, but design validation and verification activities demonstrate slightly different assay performance, e.g., bias or scatter near the clinical decision point of the assay (e.g., at the low end of the measuring range). This analytical data raises new questions about whether analytical data are sufficient to demonstrate that clinical performance of the assay has not changed such that the change necessitates a different verification and/or validation scheme. The manufacturer further assesses through additional verification activities the analytical performance and determines that the slightly different analytical performance would not affect clinical performance. The manufacturer does not submit submits a 510(k) for the combination of the EZPZ troponin assay with the SAFR instrument. First, we believe clarification is helpful to define what FDA means by slightly different and to explain why FDA mentions the low end of the clinical decision point. More importantly, we propose language to clarify that different analytical performance can be further assessed to determine if there would be impact to clinical performance without doing a new clinical investigation. If such further assessment is performed, and clinical performance is not affected, we do not believe a 510(k) is warranted. V. 6 Scenario B 541 In addition, because the analytical features of the instrument are identical to not significantly changed from the SAFT instrument, the manufacturer determines that no new testing (other than the testing conducted per the risk assessment) is needed to assess the application of the assay to the instrument family member. We propose language that we believe would be helpful for clarification purposes. Page 13 of 14

14 VII A modified instrument (including family member) or new assay-instrument combination categorized in response to a CLIA categorization request based on the Replacement Reagent Policy or Instrument Family Policy, and without a 510(k) clearance for the modification, should not be used as a predicate device for a new 510(k). However, a manufacturer could perform the method comparison to a device that came to market per the Replacement Reagent Policy or Instrument Family Policy even if the identified predicate is different. We would propose either removing this language altogether or narrowing the language to clarify the intent. An assay/instrument combination that came to market under the RRIF pathway would not have a 510(k) reference number associated with the combination. Therefore, the new combination is not qualified as a predicate for a subsequent new 510(k). That being said, we believe it might be appropriate, as discussed in our comment above, for a manufacturer to perform the method comparison to a device that came to market per the Replacement Reagent Policy or Instrument Family Policy even if the identified predicate is different. We understand that the practice of using one product as a predicate, but another for the method comparison, is a well-established practice (sometimes referred to as a paper predicate). Page 14 of 14