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8 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device Line(s) No. Line or lines numbers of the line-numbered draft guidance Change Proposed change to the draft guidance Reason Reason for proposed change LINE(S) NO. General Provide text within the guidance stating: This guidance applies to device modifications occurring after the effective date of the guidance. Device modifications that occurred prior to the effective date of this guidance, are governed by the January 10, 1997 guidance, where relied upon by the manufacturer to assess the regulatory impact of a change. CHANGE REASON In certain instances, the revised guidance appears to provide a new interpretation of current guidance in which FDA instructions were very clear. In these situations, the manufacturer complied with FDA s guidance and such changes should not be subject to reinterpretation under a new standard. For example, the K97-1 guidance states the Agency believes that 510(k)s are not necessary to add home-use labeling for devices that remain prescription and whose use in the home is accepted medical practice in the United States. The revised guidance states: four other common labeling changes that affect the indications for use and that FDA believes would usually require submission of a 510(k) are:.. changes from prescription use in a clinical setting to prescription use in a home setting (home-use devices). Significant changes in FDA thinking should not invalidate the previous decisions, concluded and documented in accordance with the 1997 guidance, prior to the effective date of the revised guidance. General Finalization of this draft guidance document would be premature before other related guidance documents are released and reviewed. Page A1 of 33 There are at least 3 other FDA guidance documents intimately connected to this guidance that are planned for revision. FDA should ensure these documents provide consistent information. 510(k) Paradigm Guidance Distinguishing and Reporting Medical Device Recalls from Product Enhancements Draft Guidance for Industry and Food and Drug Administration Staff Factors to Consider When Making Risk-Benefit Determinations in Medical Device Premarket Review

9 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. General Describe the role of compliance with the Quality System Regulation (QSR) in ensuring changes to the device or manufacturing process resulting in a safe and effective device. CHANGE REASON When (i) and the current guidance were written, the QSR was not in place, however, the current guidance acknowledges the role of GMP and the future QSR in mitigating the need for a new 510(k). This draft does not acknowledge the roles. General Include discussion of the role of design validation, design verification and risk analysis in assessing changes to determine if the change could significantly affect the safety and effectiveness. The guidance states, FDA believes increased certainty about the regulatory consequences of device modifications is critical to facilitating advancements in device technology. Incorporating existing regulatory tools into the assessment of changes will achieve increased certainty and predictability. As currently written, the document describes a few specific changes that would generally require a new filing and some basic principles to assist in decision-making. Yet the document fails to recognize a mechanism or tool for conducting an evaluation of a change to a device. Recognition of the role of existing regulatory requirements, specifically design verification/validation and risk analysis, in assessing a product change provides the increased certainty and predictability the agency is looking to create. When a manufacturer is contemplating a product change it is assessed through the risk analysis and design verification/validation aspect of the Quality System regulation. When supplemented by the certain specific changes and basic principles provided in the draft guidance, this is a sound mechanism to assess the filing standard, could significantly affect the safety and effectiveness. Recognition of the tools or mechanism via the guidance establishes certainty and predictability because the manufacturer has a consistent mechanism in place to assess a product change. Without this additional recognition the broad principles either require the Page A2 of 33

10 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. CHANGE REASON filing of a new 510(k) for specific changes regardless of the device type or they require contacting the agency for further discussion. The same change contemplated for different device types do not have the same effect. A system that necessitates discussion with the agency for routine individual changes is not certain, predictable, or efficient nor is it sustainable by either the agency or industry. To achieve the stated objective of the guidance, which is increased certainty, recognition of the tool or mechanism to evaluate a potential change is needed in this guidance. The 1997 guidance document recognizes the role of design verification/validation in the decision-making process. We recommend continued recognition of the role of design verification/validation, as well as recognition of the risk analysis process. General For some topics, the language in the guidance is unclear and imprecise. Imprecise and inconsistent language will lead to misunderstanding of FDA intent. This guidance has major impact on industry and FDA. It is essential that FDA policy and expectations are clearly communicated. General Provide consistent language when stating a 510(k) submission is required. Throughout the document different terms are used: should require, should usually require, should be submitted, should result in, may be required, trigger the need for, likely to warrant, would usually require and require. Provide clarity and consistency. Page A3 of 33

11 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. General Provide either flow charts or some type of decision matrix. For example, pose question- if yes then submit 510(k), if no go to question X, until you reach either a submit or a letter to file decision. See Attachment B (Note- this matrix shows how difficult it would be to proceduralize the current document and easily highlights the flaws in the draft guidance). CHANGE REASON The flowcharts in the current guidance document serve as an evaluation tool to be used to assess changes and are very useful to industry in determining the appropriate action to take. In addition, such a tool promotes consistency within industry, benefiting both FDA and industry alike. General Provide several examples for all questions. Include several examples for IVD products for each example section. Several questions provide no examples of any kind. Examples are essential for interpreting the text of this guidance. General Provide more examples of when a 510(k) is not needed. Currently less than 15% of the examples are for when a 510(k) is not required. General Provide a definitions section. Many subjective nouns and adjectives are used in the guidance. These terms can be interpreted differently so definitions specific to this document must be provided (e.g., different fashion, likely). Standard definitions will provide more consistency of interpretation of the guidance. General Provide guidance on determining when a change to an accessory to a 510(k) device requires a new 510(k). An accessory takes on the classification of the device; therefore, guidance is needed concerning changes to these devices. It is inappropriate (and unnecessary) to apply the proposed guidance directly to accessories. The guidance should clarify that a modification to an accessory should be evaluated in terms of its impact to the safety and effectiveness of the device to which it is an accessory. General The language in the guidance is often more restrictive than the examples provided. Page A4 of 33 By using broad, generic language, FDA covers more than we believe FDA intended to cover. For that reason, we believe FDA should reassess the language used, and be as explicit as possible in explaining what FDA intends.

12 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. General Please consider including specific examples of changes to intended use or changes that affect intended use that require a new 510(k). CHANGE REASON It is currently unclear. General In many places in this document, it is recommended that manufacturers discuss the situation with FDA before they make a decision. FDA should minimize the need for individual interpretation of the guidance by providing better decisionmaking tools. For special cases when interaction with FDA is essential, the document should include who, specifically, at FDA should be consulted and give guidance to the FDA staff about the timeliness of responses to industry. Interpreting the guidance on a case-by-case basis leads to inconsistency, lack of transparency and a waste of scarce FDA resources. We question whether FDA has the resources to respond to potentially thousands of queries a year concerning 510(k) filing decisions. General Provide a discussion of the types of 510(k) submissions that are acceptable and under what circumstances or refer to the 510(k) paradigm document. FDA should make it clear that the significant majority of 510(k) modification submissions should be handled as Special or Abbreviated 510(k)s. It is assumed that a Special 510(k) is appropriate for most 510(k) submissions for modifications. However, FDA should define those circumstances in which that is not true and thereby avoid the need for re-submission of a traditional 510(k) causing delay and a waste of FDA resources. General Include guidance on assessing changes when made to conform to recognized, voluntary standards that has been updated or newly adopted. Are new 510(k)s required? Would an Abbreviated 510(k) be appropriate? 10 Delete reference to Heather Rosecrans No longer employed by FDA. Page A5 of 33

13 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. 91 Delete: simply. CHANGE REASON Unnecessary word Add: new 510(k) and changes that do not require a 510(k). 132 Delete the sentence beginning: It is important to note This sentence is too broad, and does not make sense. Considering all improvements to be implicitly significant would propel even small improvements over the threshold of a new 510(k) and cover most changes made to a device. As written, the statement concludes that device changes intended to improve a device s safety and effectiveness are de facto changes that could significantly affect the safety or effectiveness and require a new 510(k). Regardless of the effect of the change to improve safety and effectiveness or not, the requirement is the same, significantly changed or modified in design, components, method of manufacture, or intended use. To require a 510(k) for any change that improves a device s safety and effectiveness is contrary to the regulation. Further, such an interpretation is likely to have a chilling effect on innovation and corrective actions, which would not serve the public health Delete: In most cases testing cannot, however, conclusively show that a change could not affect safety or effectiveness. Replace it with: However, the basis for determining whether a new 510(k) is required is whether the change could significantly affect safety or effectiveness. Testing and/or engineering analysis are typically required by the QSR to fulfill design verification and Page A6 of 33 The Regulatory criterion in 21 CFR (a)(3) is whether a change could significantly affect safety or effectiveness, not whether a change could affect safety or effectiveness. Testing is typically required by the QSR to fulfill design verification and validation requirements, and yields important information about the impact of the change. Test data is useful, and may be the best source of information, for answering the question of whether a change could significantly affect safety or effectiveness. There is no valid scientific or regulatory reason why testing shouldn t aid

14 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. CHANGE REASON validation requirements. In the context of this guidance, test data and/or engineering analysis are useful tools to aid manufacturers in determining whether a change could significantly affect safety and effectiveness. manufacturers in determining whether a change could significantly affect safety or effectiveness. 149 Add: or use of the de novo process. The NSE decision does not automatically result in a requirement for a PMA. The submitter may use the de novo process. 151 Add: or the use of the de novo process. NSE decision does not automatically result in a need for a PMA; the de novo process could be used. Delete the sentence beginning: However Contradicts the previous sentence and is not true. Changes to the indications for use are not necessarily major changes to the intended use (a)(3) does not mention changes to indications for use. 159 Add after combination products : [See 21CFR 3.2(e)] Ensure an accurate definition of combination products (k) is submission is necessary Typo, word not needed. Remove is. 172 Provide additional information on a correction that alters a device compared to a correction that restores a device. Greater clarity on the distinction between the two situations is needed. 191 Provide additional information on the role of the field inspector in reviewing QSR documents for device changes and how a difference of opinion is handled by the Office of Device Evaluation. Provide an understanding of the FDA process. Page A7 of 33

15 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. 194 Add after changes changes; however, these questions are considered the primary questions that FDA and Industry should be asking when determining if a 510(k) is required or not. CHANGE REASON This is subjective, thus FDA needs to accept that these will be the primary questions for making such a decision; otherwise, industry could be questioned on every such decision. 195 Change: manufacturing changes Consistency of terminology (line 301) To: manufacturing process changes 203 Add wording: who plans to market a non-exempt device for Add non-exempt for clarity and accuracy. 212 Delete: To determine whether a device modification is significant and thus requires a new 510(k) The purpose of the guidance is to determine if a modification to the device could significantly affect the safety or effectiveness of the device not whether the modification is significant. 213 Provide clarification of compare in the context of A manufacturer should compare the modified device to the most recently cleared version of the device. 218/220 Add: typically to the first bullet point. The modified device should typically not be compared to multiple devices, only to the most Page A8 of 33 A comparison of specifications or paper comparison differs significantly from an experimental comparison. If FDA expects an experimental comparison in this context, it will be problematic. For IVD analyzers, for example, the earlier analyzer may not be available. In practice, manufacturers have used versions that have been documented under the reagent-replacement policy as the new baseline version. FDA should clarify that this practice remains viable, and that reagent-replacement cleared versions qualify for use as 1) the comparator for assessing changes; and/or 2) the predicate for submission. Comparisons to similar devices, used for the same purpose, and having the characteristic about to be modified are valid and can be important to understanding whether a change could significantly

16 LINE(S) NO. ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device CHANGE REASON recently cleared version of that device, as described in that 510(k) submission. Add the following text to the end of the first bullet point: It may be appropriate to compare the modified device to another similar device that has the modified characteristic and the same intended use where substantial information is known about the safety and effectiveness of the comparison device. affect safety and effectiveness. This is particularly true where substantial information about the safety and effectiveness of the comparison device is known. There is no valid scientific or regulatory reason why manufacturers shouldn t use comparisons to similar devices to aid in determining whether a change could significantly affect safety or effectiveness. It is also an extreme for FDA to say that a device cannot be compared to any other devices. Companies often have families of devices that incorporate a mix of design features and materials, for the same intended use and with the same indications for use. Making changes within that family, while following design controls and demonstrating that the changes could not significantly affect safety and effectiveness should be acceptable (e.g., family of IV sets). In addition, in situations where one of a family of devices is affected by a change but the change has already been implemented in other devices of that family over time and has been shown through iterative testing and/or market performance to be acceptable, the benefit of comparing back to the original 510(k) clearance is unclear. In these situations, market performance and other testing should be leverageable between products and the applicability of the data be explained within a company s robust quality system. Page A9 of 33

17 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. CHANGE REASON Delete lines 227 through 244 Comparisons to other similar devices having the modified characteristic can provide useful information for purposes of determining whether a change could significantly affect safety and effectiveness. For example, a manufacturer may have marketed a similar device with the modified characteristic and same intended use. This prior marketing experience may provide valuable insight into the safety and effectiveness of the modification. There is no valid scientific or Regulatory reason to exclude such comparisons from the 510(k) modification decision process Delete lines 251 through 256 The concept of collective review of changes is contrary to the guidance in the previous bullet, which advises in lines that if a manufacturer is making 3 changes simultaneously it is to review each individually. Further, the guidance, itself, is designed to evaluate changes individually, not collectively. The agency does not provide a rationale or any examples of the benefit of the collective review. It is difficult to identify a situation in which a collective review would trigger the filing of a new 510(k) without any one individual change triggering that filing. This is recognized by the regulation, itself, which is focused on an individual change. The guidance direction to conduct collective review of changes is not aligned with Executive Order because it is beyond the regulation focus on an individual change and does not contribute to additional value to the assessment conducted on individual changes. Therefore, we believe FDA should delete this aspect of the guidance. In the alternative, we request the agency provide specific examples of collective changes that individually do not trigger a new 510(k), but do collectively. Page A10 of 33

18 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. 267 Delete: planned CHANGE REASON The word serves no purpose Delete lines beginning, All changes to the device since its most recent 510(k) clearance should be identified Replace the sentence with: The new 510(k) submission should adequately describe the new device, and identify any differences between the proposed new device and the legally marketed device. This request goes beyond the requirements of the regulation. The regulation does not provide the authority to require submission of all changes. Instead the regulation requires that the manufacturer notify FDA of changes that could significantly affect safety and effectiveness of the device. Note that a modified device is a legally marketed device even when the modifications did not meet the threshold for a new 510(k). When a manufacturer has determined the need for a new 510(k), it is unclear why a description of all changes since the last 510(k) is needed. Complete information is required for a new 510(k) to support a finding of substantial equivalence, including a complete device description and any required testing. Further, this statement does not differentiate between changes that would necessitate evaluation from those that do not. For example, a minor editorial labeling change (not related to indications for use or warnings/precautions) is not relevant to a substantial equivalence evaluation, yet may be expected to be listed in the new 510(k). However, requiring manufacturers to specifically call out modifications that may have been previously implemented without requiring a new 510(k), or to specify which change(s) triggered the need for a new 510(k), are not germane to the substantial equivalence determination and therefore should not be required to be included in the 510(k). As part of compliance with 21 CFR and (b), manufacturers are required to document design changes. These are subject to review by FDA in QSR Page A11 of 33

19 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. CHANGE REASON inspections as part of the agency s establishment inspection program. FDA should not attempt to expand the purpose of the 510(k) review program to include QSR compliance activities such as evaluating whether prior changes should, or should not have, required a new 510(k). Rather, review activities should focus on substantial equivalence. Rather than create certainty and predictability this language adds to the uncertainty and lack of predictability. Because the new 510(k) would contain complete information about the device planned for marketing a list of previous changes is not relevant to the SE evaluation. If FDA desires that information, the agency has access to it during an inspection. 277 Change: Manufacturers should scientifically justify their conclusions To: Manufactures should justify their conclusions Improve clarity. The regulations do not set forth a data requirement, or a documentation requirement. Although we agree with FDA that justification is required and documentation makes sense, FDA should allow flexibility in how decisions are justified and documented. Devices differ significantly. 278 Delete: individually and collectively Add: significantly after could not. The regulatory criterion in 21 CFR (a)(3) is whether a change could significantly affect safety or effectiveness, not whether a change could affect safety or effectiveness in any way. In addition, as discussed elsewhere in this document, modifications should not be subject to collective review since each is reviewed individually as made. 281 Delete: to satisfy basic Quality System requirements for documenting device modifications. See 21 CFR and (b). Page A12 of 33 The questions posed in this guidance are not intended to address basic Quality System requirements for documenting device modifications. Rather, as the Guidance states, it is intended to provide guidance to manufacturers on when to submit a premarket

20 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. CHANGE REASON Replace this text with: to determine whether a change requires the submission of a new 510(k) and to document their decision-making. See 21 CFR (a)(3). notification submission (510(k) for changes or modifications made to that manufacturer s previously cleared device. 287 Provide a better means for resolving gray area situations by revising the document to include guidance on deciding when to file a new 510(k) guidance on proper decision making. Due to the very large number of changes not addressed in this guidance or in device-specific guidances and the lack of clear guidance for decision-making, FDA should anticipate a significant increase in the number of calls from manufacturers. Responding to each manufacturer individually could lead to inconsistency in how similar situations are handled and a lack of transparency of agency policy. In addition, we question if FDA is staffed to respond to a large influx of calls seeking clarification of this guidance Delete this section. Discuss it in a separate guidance. 301 Manufacturing Process Changes It is unclear whether the exemption regarding 510(k)s that did not include manufacturing information applies only to the first sub-section under manufacturing (Section V.1), or to the entire section (Section V). The entire Section V should apply only to those 510(k)s that included manufacturing information or for which a pre-clearance inspection is required. Therefore, the language in Section V.1 should be moved into the general section and Sections V.2 and V.3 become V.1 and V.2. Clarify that this section only applies to those devices for which manufacturing information was required (by special controls or other guidance) in their original or previous 510(k). There is reference to this in lines but it needs to be clearer. 307 Change: Was manufacturing process information part of the original 510(k) submission? To: Page A13 of 33 If manufacturing information was required to be part of the submission by regulation or by guidance, a manufacturer may be responsible for informing FDA of changes to these processes. If manufacturing information was not required to be submitted, then manufacturers should not be required to inform FDA of changes.

21 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. CHANGE REASON Was manufacturing process information required to be part of the original 510(k) submission? Provide examples for this question. If an FDA reviewer requests additional information on a manufacturer s process (not required by guidance), it would therefore have to be assessed as part of any future modification. Without specific product guidance to require manufacturing process information in all submissions, some manufacturers will have to submit 510(k)s on their process changes while others do not. 318 Change: Therefore, in cases where review of an original 510(k) submission includes a review of manufacturing process information To: Therefore, in cases where manufacturing process information is required (by special control or other guidance) Clarity Text should accommodate products that were originally approved under an NDA or PMA and have since been down classified (examples bone cement, constrained liners and percutaneous coronary transluminal angioplasty (PTCA catheters, HepA-Ab). 320 Remove the words: could and likely. Add: could significantly affect safety or effectiveness after specifications. Not all changes affecting device specifications require a new 510(k), e.g., a minor change to the overall dimensions of a nonpatient contacting device would not typically affect safety or effectiveness. It is only if the change could significantly affect safety or effectiveness that a new 510(k) would be required. The revised sentence should read Therefore, in cases where review of an original 510(k) submission includes a review of manufacturing process information (as required in a device specific guidance), changes to manufacturing processes that affect device specifications and could significantly affect safety or effectiveness will require submission of a new 510(k). Page A14 of 33

22 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. 321 Add after the last sentence: If manufacturing information was not required (by special control or other guidance) as part of the original 510(k) this section is not applicable. CHANGE REASON Further clarify the requirement. Delete: (Manufacturers should be aware of these requirements as they apply to their device type. Contact the appropriate review division with any questions.) Unnecessary. These requirements are listed in special controls or other guidances. It is unnecessary to use scarce FDA resources. 322 Add: For devices, in which manufacturing process information was not required in the original 510(k) submission, manufacturing process changes do not result in the need to submit a new 510(k). Although implied, for clarity, certainty and predictability, state explicitly Delete these lines. It is unclear how they relate to question 1. It is inaccurate to assume that any change to a device specification will significantly impact safety and effectiveness. 331 Insert primary before packaging. Provide examples for this question. Clarification Delete these lines. Changes in device packaging or changes in expiration date are within the scope of the Quality System Regulation and should not trigger a new 510(k). Requiring submission and review of protocols or methods for package integrity or shelf-life claims, as part of the 510(k) submission is a new requirement, and akin to the PMA regulations. Page A15 of 33

23 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO Delete current wording and replace with: Changes in sterilization have the potential for changing the performance characteristics of a device. If these changes could significantly affect the safety or effectiveness of the device, the changes in sterilization methods trigger the requirements for a 510(k) submission. When manufacturers make changes in sterilization methods, they should document that the important properties and specifications of the device remain unaffected as part of their compliance with the QS regulations. In addition, if the sterility assurance level (SAL) is changed, manufacturers should consider whether device safety or effectiveness may have been compromised by the new level. If the SAL remains better than 10-6, a new 510(k) submission is not necessary; only if the SAL is less than 10-6 should a 510(k) be submitted. Changes to the sterilization method, such as changing from moist heat sterilization to e-beam radiation, require a new 510(k) if the resulting SAL is less than 10-6 or if there is a significant change in device physical appearance or performance. Changes that result in a device being provided non-sterile when it was previously provided sterile, or vice-versa, also warrant a new 510(k). CHANGE REASON If industry-accepted sterilization methods are used without a change in the SAL and the manufacturer shows verification/validation to industry standards such as ISO/AAMI manufacturers should be able to change from one sterilization method to another (i.e. EO to gamma) if results demonstrate there is no significant change in the device physical appearance or the device performance Delete It is unnecessary to discuss the definition of labeling in this guidance. 375 Add after: to marketing reasons and before to be a major change or other reasons not related to device safety and effectiveness Broaden the description of when limiting or removing an indication does not require a new 510(k). Page A16 of 33

24 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO Add at the end of the third bullet: One exception is providing home-use instructions for low-risk devices that remain prescription and whose use in the home is accepted medical practice in the United States. CHANGE REASON Provide exception listed in the K97-1 guidance that states the Agency believes that 510(k)s are not necessary to add home-use labeling for devices that remain prescription and whose use in the home is accepted medical practice in the United States and, consistent with current FDA thinking, limit it to low-risk devices. 390 Footnote 12 Add to the definition: Implantable devices that do not require patient interaction with the device as opposed to a trained health care professional s interaction with the device---are excluded from the definition of home-use device. The definition in the proposed guidance is not consistent with the definition provided on the referenced FDA website. Inconsistency may lead to confusion. Clarify that devices such as pacemakers and orthopedic implants are not home-use devices. 391 Footnote 12 Add: The Guidance for Industry: General/Specific Intended Use, dated November 4, 1998, was developed to assist manufacturers in determining when a specific indication for use is reasonably included within a general indication. Ensure that FDA s position on labeling and technology changes with regard to general/specific use is consistent with recommendations provided in the General/Specific Intended Use Guidance. 401 Include reference or description on filing CBE. File a Special 510(k) indicating in the cover letter that it is a Change Being Effected. This guidance currently provides limited instructions and given the urgency of the situation, the guidance should provide clear instructions. 414 Delete: Is it a change in instructions for use? Add: Is it a significant change in how the device is used? Page A17 of 33 It is unclear if this is a Traditional or Special 510(k). Clarify in guidance. The title of this section is overbroad and vague and could lead to unnecessary 510(k) submissions. Instructions for Use (IFU) usually refers to the labeling that provides instructions. It is important to make the distinction between the document instructions for use and the issue of how the device is used.

25 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. 415 Provide a detailed definition of different fashion or replace it with a better term. CHANGE REASON The guidance states that these changes are considered major and likely to affect safety and effectiveness but the concept of different fashion is not clear. Delete the sentence that begins with If the labeling instructs... Replace it with the following: Changes that instruct the user to use the device in a different fashion should be evaluated to determine whether the change results in a major change (add definition of major in definitions section) in intended use, or could significantly affect safety and effectiveness. If the change results in a major change in intended use or could significantly affect safety or effectiveness then a new 510(k) is required. Some changes in user instructions that recommend use in a different fashion do not result in major changes in intended use and would not be expected to significantly affect safety or effectiveness. See additional examples Line 431 below. The terminology different fashion is too general to conclude that any change within this broad definition constitutes a major change in intended use. Provide examples of major and minor changes. 417 Add after the sentence ending of the device. Changes to device labeling that clarify how to use the device typically do not require a new 510(k). 418 Delete the sentence beginning: Such changes are likely to significantly affect 420 Insert after prior to marketing : On the other hand, changes to instructions that serve to add detail, clarify or improve the safe and efficient use of a device, in the same fashion as was originally cleared, would not require a new 510(k). Page A18 of 33 Improve understanding. Adding clarifying language to device labeling would not typically have a significant effect on safety or effectiveness. Many of these changes are implemented as part of continuous improvement, to add instructions where they are not clear or to mitigate risks and do not introduce significant risks that should require a new 510(k). This requirement is a disincentive for companies to continuously improve their products and instructions for use. The decision to file should not be black and white in this area, but risk-based for a particular change to a particular device. Because different fashion is ambiguous, it is not clear that such changes would necessitate a new 510(k). Clarifications and refinements to instructions, usually based on customer feedback, will enhance safety and effectiveness.

26 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. 431 Add examples to this section that wouldn t require a new 510(k). For example: Labeling for a wound dressing is modified to clarify how to correctly apply the dressing to the wound. CHANGE REASON Labeling for a wound dressing is modified to simplify the application instructions, e.g., the dressing is pre-cut as opposed to requiring the user to cut it to shape. The device is used in the same manner on the same wound types. Not all changes that instruct the user to use the device in a different fashion require a new 510(k). It depends on the specific device, the reason for the change, what the exact change is, and what is meant by different fashion. Examples that do, and don t require, a new 510(k) would be helpful to convey what is meant by used in a different fashion. 432 Add examples of when a new 510(k) is required and when it is not to this section. Clarity 435 Remove the sentence, Events that precipitate changes of this type should be reported under the Medical Device Reporting regulation (MDR), 21 CFR Part 803. This guidance is not an MDR guidance Delete: however, manufacturers are encouraged to discuss these situations with FDA. It has been stated that it is not likely a 510(k) is needed. It is not practical for FDA to be contacted every time these changes are made Clarify this concept by providing examples. In monitoring field usage of cleared devices, it is possible that some precautions and/or warnings may not be helpful to users of devices. These may have been included originally to err on the side of conservatism, but field experience may reveal that these are not helpful (and even may be confusing) to include in labeling and their removal may not have a significant effect on safety or effectiveness. Page A19 of 33

27 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. CHANGE REASON 441 Add at the end of the last sentence: However, if an FDA Notice or Advisory requires manufacturers to add a warning or precaution, then a 510(k) would not be required. Submitting a 510(k) is not necessary when complying with an FDA Notice or Advisory Change sentence to read: that significantly affect the safety and effectiveness of the device due to change in the fundamental technology of the existing device or a substantial change in performance specifications. It is not true that a 510(k) submission should generally be submitted for modifications to device technology, engineering, and performance. This is true only if the changes significantly affect safety and effectiveness. 459 Delete reference to minor engineering changes to a circuit board layout as an example of a change that could affect the cleared Indications for Use or fundamental technology. It is confusing and does not provide a good example of technology change. 461 Add the following text to the beginning of line 461. Design changes that fall within the following categories do not typically require a new 510(k): there are data supporting that the proposed change will not significantly impact safety or effectiveness; or a risk assessment indicates that the impact to safety and effectiveness is not significant; or the changed device continues to conform to well established and/or FDA recognized performance standards for either product design (e.g., syringes and hypodermic needles) or attributes of products (e.g., biocompatibility, electrical safety). a change in specification that does not affect safety and effectiveness. Provision must be made for a way for the manufacturer to determine the significance of change. In these cases, a new 510(k) should not typically be required. In subsequent examples, FDA seems to imply that changes can be assessed based on risk and/or data: This ergonomics change (in device handle, lines ) is unlikely to significantly affect safety or effectiveness. FDA would not expect a new 510(k) in this instance. The case of an infusion pump that is increased in size in order to facilitate a larger display panel (lines ). This change is not likely to significantly affect the safety or effectiveness of the device because the modified dimension is not directly related to the performance of the device, and therefore the manufacturer does not need to submit a new 510(k). (Regarding software/firmware changes, lines ), some Page A20 of 33

28 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. CHANGE REASON low-risk changes may be made by following the QS regulation (including design controls) and documenting the appropriate validation testing. 472 Provide an IVD example. Provide clarity as to how this relates to IVD products. 473 Delete example and replace it with a more relevant example. Humidifiers are Class I exempt devices. 502 Define energy type. Depending on this definition, not all changes will have a significant effect on safety and effectiveness. Provide additional examples. Eliminate contradictory information. It is unclear if energy type includes different battery chemistry types and changing from a non-rechargeable to a rechargeable battery. It is stated that changes in energy type will always have a significant effect on safety and effectiveness (line 504) but the last sentence (line 506) says that most of these changes should be reviewed. 504 Delete always in the second sentence and replace it with can. Not all changes in energy type will automatically require a new 510(k). Only those changes that could significantly impact safety and effectiveness. 506 Clarify the last sentence as it relates to the second sentence. The paragraph is contradictory. It states that all energy type changes will have a significant effect on safety and efficacy but in the last sentence it states most of these changes should be reviewed in a new 510(k) prior to marketing. Add to the end of this paragraph: For changes of this type, manufacturers should take the design and purpose of the device into consideration when determining if a new 510(k) is required, as well as the availability of accepted methods to confirm that the change had the desired effect and no Page A21 of 33 This is an important clarification that was included in the current guidance and should be included here.

29 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. unintended adverse effects. CHANGE REASON Add: Note: A change in energy type does not include a change from 3V to 9V operation or a change from NiCad to lead acid storage batteries. Such changes would be considered changes in performance specifications or technical specifications. 515 Change from: Does the change have the potential to significantly alter the performance characteristics or specification of the device? Maintain consistent language. Clarify that the comment is limited to performance specifications not all specifications. To: Could the change significantly alter the performance characteristics or performance specification of the device? Consider adding clarification as to how FDA s risk-based approach would affect the decision to submit. The way the changes are described in this section, especially as presented in the examples, seem to decouple risk assessment from the discussion of safety and effectiveness. Each example presented in this section seems to suggest that any change to a performance specification (regardless of the risk level) would trigger a new 510(k) because of a possible impact to safety or effectiveness. Worded as such, this seems to impede FDA s goal of fostering medical device innovation. Manufacturers may be less inclined to make incremental improvements to devices if low-risk changes trigger a 510(k) submittal. Page A22 of 33

30 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. 517 Delete: Such changes directly impact CHANGE REASON Add: If the change in performance or specifications significantly impacts the safety and effectiveness of the device, a 510(k) with comparative testing is required. Provide clarity. It is not clear what such changes are. It is assumed that the answer to the question in line 515 is yes. Requiring that any change that improves safety and effectiveness requires a new 510(k) without allowing for a reasonable evaluation of its significance will place an incredible burden on manufacturers and stifle innovation. Most technical/technological changes would fall within this broad category of improvement. 520 Add after end of sentence: If performance characteristics are unchanged (not improved or worsened), a new 510(k) in not required. Provide specific guidance when performance characteristics are unchanged Add examples of technology/engineering changes that would not significantly alter performance characteristics and therefore, not require a new 510(k). Suggested examples: Dimensional/Tolerance changes made at the assembly/subassembly/ component/sub-component level that do not result in a change to finished device performance specifications do not require a new 510(k). Provide balance and perspective; provide guidance on when a 510(k) is not required. If a performance specification is being changed or a new specification is being added (without affecting other performance specifications) a new 510(k) is not required. 532 Delete: characteristics Replace with: specifications Consistent terminology will add clarity and reduce misinterpretation. 543 Add after comfort : or ergonomics of the patient/user interface Add provision for ergonomic changes. 547 Add IVD relevant examples. Provide clarity as this relates to IVD products. Page A23 of 33

31 ATTACHMENT A AdvaMed Comments Draft-Guidance for Industry and FDA Staff -510(k) Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device LINE(S) NO. CHANGE REASON Delete example. If the material is changed and it provides the same performance results as stated in the currently cleared 510(k) then this would not warrant a submission. If testing demonstrates that the change does not significantly alter the device performance then a 510(k) would not be required. If, after design control testing, it shows the performance is impacted then a 510(k) would be required Delete example. Confusing example. The issues associated with this change are complex and not restricted to user interface. 575 Request clarification of dimensional specifications. A better definition of the type of dimensions must be provided. It is implied but not certain that the question refers to dimensional specifications that influence performance not all dimensional specifications for items such as printed circuit boards, electronic components, wiring, and packaging influence safety and efficacy. 576 Add the following sentence immediately after the first sentence in this paragraph: A new 510(k) would not typically be required if dimensions were not included in the original 510(k). If a device was cleared without detailed dimensions then it s reasonable to conclude that they were unnecessary for purposes of determining substantial equivalence, and would therefore be unlikely to significantly affect safety or effectiveness Provide a definition or clarification of questionable dimensional change. Lack of clarity and specificity will result in a huge number of calls to FDA seeking clarification. Ad hoc, individual questions and answers will result in inconsistency. 588 Change: Device dimensions that are modified To: Device dimensions that significantly affect device performance that are modified Page A24 of 33 Device dimensions that are not related to device performance can be modified beyond tolerance ranges without affecting safety and effectiveness.