October 13, Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, MD 20852

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1 701 Pennsylvania Avenue, NW Suite 800 Washington, D.C Tel: Fax: October 13, 2014 Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, MD Re: Docket No. FDA-2014-D-0900 Dear Sir/Madam: The Advanced Medical Technology Association (AdvaMed) provides these comments in response to a request for comments regarding the Food and Drug Administration (FDA) Center for Devices and Radiological Health draft guidance Benefit-Risk Factors To Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] With Different Technological Characteristics. Notice of this draft guidance and request for comments was published in Fed. Reg. Vol.79, No.135/Tuesday, July 15, AdvaMed is the world s largest association representing manufacturers of medical devices, diagnostic products, and health information systems that are transforming health care through earlier disease detection, less invasive procedures and more effective treatments. Our members range from the largest to the smallest medical technology innovators and companies. We welcome the opportunity to comment on this guidance and look forward to working with FDA to ensure the revised guidance meets the needs and expectations of both FDA and industry. AdvaMed appreciates and supports FDA s efforts to clearly identify the principal benefit-risk factors FDA considers when determining if the new device is as safe and effective as the predicate device. We recognize that these factors may assist FDA reviewers in making substantial equivalence determinations and may help accommodate technological differences that do not raise different questions of safety and efficacy. AdvaMed also understands that knowing these factors may improve the predictability, consistency and transparency of the premarket review process and thereby may help submitters demonstrate substantial equivalence. AdvaMed has provided detailed comments on the content and format of the guidance and the associated line-numbered draft guidance (see attachment C). Of particular concern is the need to align the information provided in this draft guidance with the information in the newly issued guidance The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)]. An explanation of where the benefit-risk factors are assessed in the substantial equivalence decision-making process as described in The 510(k) Program guidance would integrate the two documents. Use of different terminology and the explanation of the substantial Bringing innovation to patient care worldwide

2 Division of Dockets Management (HFA-305) October 13, 2014 Page 2 of 14 equivalence evaluation in the two documents appear to create a three-step assessment: (1) intended use, (2) technological characteristics, and then (3) safety and effectiveness which do not reflect the substantial equivalence statutory provision. Attachment B suggests a format for clearly presenting the benefit-risk relationship and the approach the reviewer should take in assessing the relationship for the device under review. AdvaMed appreciates FDA efforts in preparing this draft guidance and the goal of improving the predictability, consistency and transparency of the 510(k) premarket review process. AdvaMed looks forward to working with FDA to achieve these goals. If there are questions about the AdvaMed comments, we are glad to provide answers and clarifications. Sincerely, /s/ Ruey C. Dempsey RAC Associate Vice President Technology and Regulatory Affairs

3 Attachment A ADVAMED COMMENTS Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics Draft Guidance for Industry and Food and Drug Administration Staff Line(s) No. Line number of the guidance Change Proposed Change to the guidance. Reason Reason/Rationale for the proposed Change. Line(s) No. Change Reason Please ensure that non-clinical data are given sufficient prominence throughout this guidance document. Some specific proposals are provided below. But additional examples and case studies may be warranted for balance. General Comment 1 Although the introduction states that the guidance does not change the 510(k) premarket review standard or create extra burden on a submitter of a 510(k) to provide additional performance data from what has traditionally been submitted for a given device type, future reviewers may reach the conclusion that clinical studies are the primary means for evaluating product risk and benefit when there are technological changes. General Comment 2 General Comment 3 Benefit-risk factors are used when assessing whether the differences in the technological characteristics do not raise different questions of safety and effectiveness, rather than after it has been determined the device has the same intended use as the predicate and the differences in technological characteristics do not raise different questions of safety and effectiveness. Revise guidance throughout. Consider discussing the use of ISO 14971:2012 in determining and evaluating risk. We note FDA released this draft guidance document prior to issuing the final guidance, The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)]. Alignment of where the benefit-risk factors are assessed in context of the 510(k) Decision-Making process, as described in the Program guidance, would better integrate the two documents. That is benefit-risk factors are evaluated at Decision Point 4 of the 510(k) Decision-Making Flowchart found in Appendix A of the Program guidance. Use of different terminology and explanation of the SE evaluation between the documents appears to create, in the Benefit-Risk guidance, a three-step assessment: (1) intended use, (2) technological characteristics, and then (3) safety and effectiveness, which is not reflective in the SE statutory provision. Recognized standard used by most medical device companies. Page 3 of 14

4 Attachment A ADVAMED COMMENTS Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics Draft Guidance for Industry and Food and Drug Administration Staff Line(s) No. Change Reason Remove text as indicated and add text (in red). The sentence has an awkward structure On the other hand, if FDA determines that the different technological characteristics do not raise different questions of safety and effectiveness, FDA will then evaluate the technological differences in the technological characteristics between the new device and the predicate devices to determine their effect on safety and effectiveness (i.e., whether the new device is as safe and effective as the predicate device). Remove reference to draft guidance. Change performance data may be necessary to assess the safety and effectiveness of the new device as compared to the predicate device. To: performance data may be necessary to assess whether the new device is as safe and as effective as the predicate device. Reword the existing text to read: Performance data may be generated from either nonclinical or clinical testing, and either non-clinical or clinical data can play a role in FDA s evaluation of benefits and risks. At the end of line 149, add the following sentence: Published reports of valid scientific studies can be used to document clinical performance of a specific type of device or technological characteristic. This draft guidance is not implemented as a draft so there is no need to describe it in the text as a draft. Clarification. Submitters of 510(k)s for Class II devices are not required to prove the device is safe and effective ; they are required to demonstrate that the device is substantially equivalent and as safe and as effective as the predicate. This change clarifies that it is not necessary to use both clinical and non-clinical data for evaluating risks and benefits. When there are relevant valid scientific studies in the medical literature, a systematic review of these studies can provide a valuable source of information regarding risks and benefits. Appropriate use of published literature is consistent with least burdensome principles. Page 4 of 14

5 Attachment A ADVAMED COMMENTS Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics Draft Guidance for Industry and Food and Drug Administration Staff Line(s) No. Change Reason 150 Delete the sentence: In general, a probable risk and a probable benefit do not include purely theoretical risks and benefits, but rather are supported by valid scientific evidence. Risk management activities for medical devices include creation of a risk analysis which uses theoretical risks to support the submission. Valid scientific evidence is required for Class III devices, not for all medical devices Delete the sentence: However such information may be considered when identifying a device that has questionable safety and effectiveness. Delete the sentence: At this point in the review process, FDA must determine whether the new device is as safe and effective as the predicate device. Reword this section to appropriately balance the requirement for clinical data with the requirements for performance data; add wording to state what percentage of 510(k) typically require clinical data <10%). Add more examples of products without clinical data. Make the following wording change: FDA has determined that is assessing whether the differences in the technological characteristics do not raise different questions of safety and effectiveness. The use of anecdotal information, reports lacking detail, or unsubstantiated opinion in a 510(k) review is not appropriate. There was some justification for allowing use of such evidence during the open-ended work of establishing the initial device classification regulations. However, when evaluating the risks and benefits of specific technological differences between a new device and a predicate device, reviewers should not consider anecdotal or unsupported reports and opinions. See General 2 comment above. The emphasis on clinical data is out of proportion with the actual proportion of performance data to clinical data requirement. The number of 510(k)s with clinical data is relatively low ( less than 10%). However, Section IV on Benefit and Risk Factors focuses primarily on clinical data and information, and 4 of the 7 examples are products with clinical data. See General 2 comment above. Page 5 of 14

6 Attachment A ADVAMED COMMENTS Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics Draft Guidance for Industry and Food and Drug Administration Staff Line(s) No. Change Reason Add the following text after line 192: When evaluating performance data, reviewers need to keep in mind that not all differences in performance reflect a meaningful change in either the level of benefit or the level of risk associated with a new device. Evaluation should consider the following factors: (1) whether the difference is statistically significant, (2) whether the magnitude of the change has practical or clinical relevance, and (3) the importance of the parameter with respect to patient safety and effective treatment or diagnosis. Some example scenarios are given below. 192 If the proposed new device has statistically lower values for force-to-failure in a breakage test than the predicate device, but the results still indicate that the strength is much higher than needed to maintain safety in clinical practice, the difference would not have practical or clinical relevance. The risk level should be considered unchanged. Similarly, if both the predicate device and the new device meet the performance requirements of an FDA-recognized standard, any differences in the test results for the parameters specified by the standard should not be considered as changes in either risks or benefits. In a well-powered clinical study, any differences in safety or effectiveness endpoints that are not statistically significant should not be considered a change in risk or benefit, with the exception of severe, unanticipated adverse events that are attributed to the change in technological characteristics. Comparative data will nearly always show some differences between two devices, and reviewers should have some uniform guidance for how to identify differences that can be considered equivalent performance. Page 6 of 14

7 Attachment A ADVAMED COMMENTS Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics Draft Guidance for Industry and Food and Drug Administration Staff Line(s) No. Change Reason 192 After line 192, please add a table that outlines the general approach for all combinations of benefit-risk changes. (Please see Attachment B for suggested table contents.) This guidance document, when finalized, will have a broad effect on 510(k) reviews and there is benefit to addressing all scenarios, including the ones whose support of the clearance of a 510(k) is obvious (e.g., increased benefit and decreased risk) and those that require more care and judgment (e.g., equivalent risk and slightly reduced effectiveness) Change heading to read: Decreased Benefit/Decreased and Equivalent Risk After for example, please add the following text: the reduction in benefit is relatively small and a delay in effective treatment or accurate diagnosis does not expose the patient to new or more severe risks. When the new device has reduced effectiveness, it is more likely that FDA can determine that the device is SE to the predicate device if Provides commentary on a broader set of benefit-risk scenarios, consistent with the previous comment. There may be scenarios in which it is appropriate to determine that a new device with reduced effectiveness is SE even if there is not a meaningful reduction in risk. This text acknowledges that possible scenario. Page 7 of 14

8 Attachment A ADVAMED COMMENTS Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics Draft Guidance for Industry and Food and Drug Administration Staff Line(s) No. Change Reason 220 Add the following text (in red): For diagnostic devices, a benefit may be assessed in reference to the nature of the public health impact of a particular device due to its ability to identify a specific disease, provide diagnosis at different stages of a disease, predict future disease onset, improve patient workflows, provide better access to patient data, increase efficiency of examination, provide reproducible and quantifiable results contributing to the optimization of therapy and treatment, improve patient outcome (wellbeing, health status, or safety of patients) by facilitating less missed diagnosis ( or the right diagnosis the first time and hence the correct treatment plan) and/or identify patients more likely to respond to a given therapy and therefore enable treatment of the disease or reduce/prevent its spread. Include additional detailed benefits for diagnostic devices and 275 Add the following text after line 229: For devices with tool-type indications, the benefits are usually defined by product performance characteristics rather than specific clinical endpoints. Some examples of increased benefits of such a device are less random variation in the device output, improved reliability, or reduced treatment time to achieve the same effect. Add definition for pre-identified health threshold. Change: Probability of the patient experiencing To: Ability to predict which patients will experience The strong focus on clinical endpoints in the guidance document could lead reviewers to request clinical data when such data are not needed. Clarification of a non-standard phrase This assessment describes the ability to predict which patients or subgroups of patients are likely to have the benefit or harmful event. However, the titles suggest that these categories refer to the probability that the benefit or event occurs overall. Page 8 of 14

9 Attachment A ADVAMED COMMENTS Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics Draft Guidance for Industry and Food and Drug Administration Staff Line(s) No. Change Reason 292 After the current line 292, add the following: In 510(k)s where clinical data are not required, other sources of data should be used to assess potential risks of the technological changes. These include but are not limited to the risk analysis for the product, the human factors evaluation, reports of simulated use tests, modeling, and, where applicable a review of compliance relative to applicable national or international standards. The strong focus on clinical endpoints in the guidance document could lead reviewers to request clinical data when such data are not needed This paragraph describes the potentially increased harm from a patient having multiple adverse events simultaneously. This paragraph should also discuss the impact for coincident benefits in assessing the aggregate effect. Add an explanation of the role of these additional factors compared to the ones listed in section B. Are these factors a required part of the assessment or as appropriate? Please define when they should be used. Add the following text (in red): Additionally, for certain device types and where clinical data is required to determine substantial equivalence, it is sometimes difficult to distinguish between a real effect and a placebo effect in the absence of a design that is capable of blinding investigators and subjects. Furthermore, repeatability of the study results, validation of the analytical approach, and results of other similar studies can all influence the level of certainty. Replace efficacy with effectiveness. Recognize the joint probability of a patient experiencing combinations of benefits and risks. It is unclear if the factors listed in this section are required or factors to consider when appropriate. FDA should use more clarifying language in these lines as well as throughout this guidance that where clinical terminology is used that 510(k) reviews that are within scope of this document are not always expected to contain clinical data. This level of expectation should be consistent with what FDA notes in the July 28, 2014 Guidance on Substantial Equivalence in 510(k)s (p. 23) which states FDA currently requests clinical data for less than 10% of the 510(k) submissions. Appropriate medical device term is effectiveness. Page 9 of 14

10 Attachment A ADVAMED COMMENTS Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics Draft Guidance for Industry and Food and Drug Administration Staff Line(s) No. Change Reason 324, Consider adding reference to ANSI/AAMI HE 75 or IEC for use in assessing patient and healthcare professional tolerance for risk and perspective on benefit. These standards could be helpful as they guide in the design of human factors testing, of the user/patient and professional user. Output from HF testing may help in addressing patient tolerance and professional 341 After line 341, please add the following section: Economic Benefits Economic benefits can be considered in the benefit-risk evaluation, although purely economic benefits will be given less weight than those benefits that apply directly to the patient and/or healthcare professional. Many economic benefits such as a shift from in-patient to outpatient treatment or reduced surgical procedure also have clear benefits to patients and/or healthcare providers. The societal benefits of reduced healthcare costs can be considered as an additional benefit during the review process in such cases. However, in other cases, there may only be a pure economic benefit. Examples of considerations in assessment of economic benefits include: Ability to use device multiple care areas of the healthcare facility Ability to use the device in ambulatory settings (between healthcare facilities) Ability to maintain and access data captured in multiple care areas of the healthcare facility Homecare use (compliance with homecare standards) User interface attributes (simplified UI) that support layperson/patient use If a purely economic benefit is expected to be used as an important factor in the benefit-risk evaluation, the 510(k) Page 10 of 14 user perspective on benefit and ease of use. There are substantial societal pressures on device manufacturers and the healthcare system to reduce the overall cost of treatment. Reduction in these costs has a societal benefit in terms of helping to keep appropriate health care available for all citizens. Because of these pressures, a significant amount of current R&D efforts are focused on finding ways to deliver more affordable treatments and diagnostic procedures. While many of these innovations will also result in direct benefits for some patients (e.g., less hospitalization time), there may need to be trade-offs in that the initial effectiveness of the innovative treatment may be lower than that of the current gold standard. When the innovation is associated with a significant economic benefit, it is appropriate to consider the overall societal benefit when evaluating the risks and benefits of the new treatment or diagnostic procedure.

11 Attachment A ADVAMED COMMENTS Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics Draft Guidance for Industry and Food and Drug Administration Staff Line(s) No. Change Reason sponsor is encouraged to have early interaction with the appropriate FDA review division After tests and/or controls add: or when used in conjunction with other available information, including clinical symptoms and family history. Provide clarifying statement about the rationale for clinical data; under what circumstances would it most likely be appropriate? Suggest there be an example of a material change that does not involve clinical data. Both examples 4 and 7 used clinical data. Replace technical difficulties with technical differences. For certain IVDs, these additional areas may be appropriate forms of risk mitigation. Four out of 7 examples in this guidance document are 510(k)s that contain clinical data. General concern that there is an underlying message that differences in technological characteristics where there are no new questions of safety and effectiveness reach a threshold of needing clinical data to support substantial equivalence. While in the July 28, 2014 Guidance on Substantial Equivalence in 510(k)s FDA notes (p. 23) that FDA currently requests clinical data for less than 10% of the 510(k) submissions. Provide a wider range of examples. It is more likely that material changes will not involve clinical data. The subject of the discussion is technical differences between the new and predicate devices. In the previous section there is no reference to technical difficulties in use of the device. Page 11 of 14

12 Attachment A ADVAMED COMMENTS Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics Draft Guidance for Industry and Food and Drug Administration Staff Line(s) No. Change Reason Please delete the following: Uncertainty: The clinical study design provided was not optimally designed to demonstrate safety and effectiveness. A large number of screened subjects were lost to follow-up and the submitter did not provide effectiveness data for them. Additionally, the 28-day study duration may not be optimal to determine durability of the effect for the treatment of sleep apnea. It is inappropriate for FDA to expect that a clinical study design for a 510(k) product be optimally designed to demonstrate safety and effectiveness as this product is not required to demonstrate safety and effectiveness but rather the product should be evaluated for substantial equivalence to the predicate device. It is also unclear why FDA would expect clinical data to support durability of a 510(k) device. 730 Add the following example: Example 8 An early stage disease process is currently treated by an outpatient procedure that is effective in 80% of cases. However, the treatment is very expensive the cost is equivalent to that of hospitalization for 1-2 days. A manufacturer develops another device intended to treat the same early-stage disease process by another technological approach. It is an outpatient procedure that is effective in 67% of cases. Treatment with the new device does not preclude a later treatment with the current gold standard procedure. The treatment with the new device is much less expensive, approximately 20% of the cost of the original treatment. Benefits: The benefits are mixed: initial effectiveness is reduced, but there is a substantial cost benefit. The disease being treated is early stage, and a delay in effective treatment does not put the patient at risk for serious complications. Risks: The complication rates of the two treatment approaches are equivalent. This provides a hypothetical example of how an alternate, significantly less expensive treatment approach may come to the market, relying primarily on an economic benefit. Page 12 of 14

13 Attachment A ADVAMED COMMENTS Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics Draft Guidance for Industry and Food and Drug Administration Staff Line(s) No. Change Reason Additional factors: The 510(k) sponsor has conducted a thorough cost-benefit analysis which substantiates the proposed economic benefit. The manufacturer provides a patient brochure that explains the alternative treatments that patients can consider and the relative costs and effectiveness of each. Substantial equivalence analysis: The new device may be found to be SE, based on the fact that there are no new risks and the fact that the manufacturer informs patients of the cost-benefit considerations. Page 13 of 14

14 Attachment B Benefit-Risk Matrix Table Referenced in comment on line 192. Benefit Level Risk Level Review Approach Equivalent Equivalent The new device is substantially equivalent to the predicate device from a benefit-risk perspective. Increased Equivalent The new device is substantially equivalent to the predicate device from a benefit-risk perspective. Increased Decreased The new device is substantially equivalent to the predicate device from a benefit-risk perspective. Increased Increased Evaluate the nature and magnitude of the respective changes and the level of uncertainty in the data that have been presented. See additional guidance below. Decreased Equivalent Evaluate the nature and magnitude of the change in effectiveness relative to the known risks and the level of uncertainty in the data that have been presented. Consider whether economic or patient preference factors may justify allowing the new device to reach the market as an alternative to existing treatments or diagnoses. See additional guidance below. Decreased Decreased Evaluate the nature and magnitude of the respective changes and the level of uncertainty in the data that have been presented. See additional guidance below. Decreased Increased Reviewer should generally not determine that the new device is substantially equivalent to the predicate device when there is a clinically meaningful decrease in benefit and a meaningful increase in risk. Page 14 of 14

15 Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics Draft Guidance for Industry and Food and Drug Administration Staff DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Document issued on: July 15, 2014 You should submit comments and suggestions regarding this draft document within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD Submit electronic comments to Identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register. For questions about this document regarding CDRH-regulated devices, contact the Office of the Center Director at For questions about this document regarding CBER-regulated devices, contact the Office of Communication, Outreach and Development (OCOD) by calling or U.S. Department of Health and Human Services Food and Drug Administration Center for Devices and Radiological Health Center for Biologics Evaluation Research 26

16 27 28 Table of Contents 2

17 29 30 Additional Copies Contains Nonbinding Recommendations Preface CDRH Additional copies are available from the Internet. You may also send an request to to receive a copy of the guidance. Please use the document number (1818) to identify the guidance you are requesting. CBER Additional copies are available from the Center for Biologics Evaluation and Research (CBER) by written request, Office of Communication, Outreach and Development (OCOD), New Hampshire Ave., Building71, Room 3128, Silver Spring, MD 20993, or by calling or , or by , ocod@fda.hhs.gov,or from the Internet at ComplianceRegulatoryInformation/Guidances/default.htm. 3

18 Table of Contents I. Introduction... 5 II. Background... 6 A. The Statutory Standard for Substantial Equivalence... 6 B. Performance Data... 7 III. Scope... 8 IV. Benefit and Risk Factors... 9 A. Assessment of the Benefits of Devices B. Assessment of the Risks of Devices C. Additional Factors in the Assessment of the Benefits and Risks of Devices V. Examples of Benefit-Risk Evaluation Appendix A: List of References

19 Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] With Different Technological Characteristics Draft Guidance for Industry and Food and Drug Administration Staff This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. I. Introduction A submitter of a premarket notification submission (often referred to as a 510(k)) must demonstrate to the Food and Drug Administration (FDA) in its 510(k) submission that the new device is substantially equivalent (SE) to a legally marketed (predicate) device. 1 At certain points in the substantial equivalence analysis, the probable benefits and risks of a new device as compared to a predicate device may be relevant. The benefit-risk factors discussed in this guidance may assist FDA reviewers in making substantial equivalence determinations and may help accommodate evolving technology during the 510(k) premarket process. This guidance may also help submitters of 510(k) premarket notifications demonstrate substantial equivalence in their premarket submissions. FDA has developed this guidance in order to improve the predictability, consistency, and transparency of the 510(k) premarket review process. This guidance does not change the 510(k) premarket review standard or create extra burden on a submitter of a 510(k) to provide additional performance data from what has traditionally been submitted during the review process for 510(k) submissions. FDA s guidance documents, including this one, do not establish legally enforceable responsibilities. Instead, guidance documents describe the Agency s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance documents means that something is suggested or recommended, but not required. 1 See section 513(i) of the Federal Food, Drug & Cosmetic Act (FD&C Act) (21 U.S;..C. 360c(i)). 5

20 II. Background A. The Statutory Standard for Substantial Equivalence A submitter of a 510(k) submission must demonstrate to FDA in its 510(k) that the new device 2 is SE to a predicate device. 3 See section 513(i) of the FD&C Act (21 U.S.C. 360c(i)). A predicate device is a device that (i) was legally marketed prior to May 28, 1976 (preamendments device), for which a premarket approval application (PMA) is not required; or (ii) has been classified or reclassified into Class I or II; 4 or (iii) has been found SE through the 510(k) process. See 21 CFR (a)(3). The standard for a determination of substantial equivalence in a 510(k) review is set out in section 513(i) of the FD&C Act (21 U.S.C. 360c(i)): Substantial Equivalence (i)(1)(a) For purposes of determinations of substantial equivalence under subsection (f) and section 520(l), the term substantially equivalent or "substantial equivalence means, with respect to a device being compared to a predicate device, that the device has the same intended use as the predicate device and that the Secretary by order has found that the device (i) has the same technological characteristics as the predicate device, or (ii)(i) has different technological characteristics and the information submitted that the device is substantially equivalent to the predicate device contains information, including appropriate clinical or scientific data if deemed necessary by the Secretary or a person accredited under section 523, that demonstrates that the device is as safe and effective as a legally marketed device, and (II) does not raise different questions of safety and effectiveness than the predicate device. Therefore, in order to find a new device SE to a predicate device, FDA must first find that the two devices have the same intended use. FDA must then determine that the two devices have the same technological characteristics, or that any differences in technological characteristics do not raise different questions of safety and effectiveness and that the device is as safe and For the purpose of this guidance document, a new device means a device within the meaning of section 201(h) of the FD&C Act (21 U.S.C. 321(h)) that is not legally marketed. It can be either a completely new device or a modification of a legally marketed device that requires a new 510(k) under 21 CFR For more information on the 510(k) program, see FDA s Draft Guidance, The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] ( 510(k) Program ), issued on December 27, FDA s draft guidance represents FDA s proposed approach on this topic. Web site addresses for all guidance documents referenced in this guidance can be found in Appendix A: List of References. Section 513 of the FD&C Act (21 U.S.C. 360c) establishes three device classes (Class I, Class II, and Class III) and sets forth device reclassification procedures. 6

21 effective as the predicate device. Different technological characteristics is defined in section 513(i)(1)(B) of the FD&C Act (21 U.S.C. 360c(i)(1)(B)) as: with respect to a device being compared to a predicate device, that there is a significant change in the materials, design, energy source, or other features of the device from those of the predicate device. If FDA determines that there are differences in the technological characteristics between the new device and the predicate device, and that the different technological characteristics raise different questions of safety and effectiveness, FDA will find the new device to be not substantially equivalent (NSE) to the predicate device. 5 On the other hand, if FDA determines that the different technological characteristics do not raise different questions of safety and effectiveness, FDA will then evaluate the technological differences between the new device and the predicate devices to determine their effect on safety and effectiveness (i.e., whether the new device is as safe and effective as the predicate device). Under section 513(a)(2) of the FD&C Act (21 U.S.C. 360c(a)(2)), FDA determines the safety and effectiveness of a device by weighing any probable benefit to health from the use of the device against any probable risk of injury or illness from such use, among other relevant factors. 6 We believe the approach described in this draft guidance document would provide greater clarity regarding the factors that FDA considers in making substantial equivalence determinations when there are different technological characteristics between the new device and the predicate device that do not raise different questions of safety and effectiveness. B. Performance Data When FDA is reviewing a new device that has different technological characteristics than the predicate device, performance data may be necessary to assess the safety and effectiveness of the new device as compared to the predicate device. 7 When evaluating the performance data, FDA may consider the risks and benefits of the new device in comparison to the predicate device before making a substantial equivalence determination. The type and quantity of performance data that may be necessary to support a determination of substantial equivalence depends upon the new device. Performance data may be generated from both non-clinical and clinical testing, and both non-clinical and clinical data can play a role in FDA s evaluation of benefits and risks. Both types of performance data can provide information relating to the benefit and risk factors discussed in this guidance See the proposed 510(k) Decision-Making Flowchart for the critical decision making points in the 510(k) review process, at Appendix A of the 510(k) Program draft guidance. FDA s draft guidance represents FDA s proposed approach on this topic. The criteria for establishing safety and effectiveness of a device are set forth in 21 CFR Subsection (b) notes, In determining the safety and effectiveness of a device the Commissioner and the classification panels will consider the following, among other relevant factors (3) The probable benefit to health from the use of the device weighed against any probable injury or illness from such use. (21 CFR 860.7(b)). For further discussion on requests for performance data, see footnote 3. 7

22 FDA relies on valid scientific evidence 8 when evaluating benefits and risks, including when identifying probable risks and probable benefits. 9 In general, a probable risk and a probable benefit do not include purely theoretical risks and benefits, but rather are supported by valid scientific evidence. Generally, isolated case reports, random experience, reports lacking sufficient details to permit scientific evaluation, and unsubstantiated opinions are not regarded as valid scientific evidence to show the new device s safety or effectiveness in comparison to a predicate device. However, such information may be considered when identifying a device that has questionable safety and effectiveness. 10 III. Scope The 510(k) review standard (substantial equivalence of a new device to a legally marketed (predicate) device) does not require a new device to be identical to a predicate device. In certain circumstances, FDA may find a device with indications for use 11 or technological characteristics that are different from those of the predicate device to be SE to the predicate device. This guidance document does not focus on the first step of the 510(k) review process where FDA must find that the intended use of the device and its predicate are the same, but instead focuses on the step of the review process after FDA has determined that the new device and the predicate device have different technological characteristics and that the new device does not raise different questions of safety and effectiveness. 12 At this point in the review process, FDA must determine whether the new device is as safe and effective as the predicate device. The principal benefit and risk factors that FDA considers during this step in the 510(k) review process to assist in making a substantial equivalence determination are described below. We also provide examples of how these factors may be used during premarket review Clinical data provided in support of any marketing submission, including a 510(k) when those data are relevant to a substantial equivalence determination, should fit the definition of valid scientific evidence in 21 CFR 860.7(c)(2). Valid scientific evidence is defined as evidence from well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device, from which it can fairly and responsibly be concluded by qualified experts that there is reasonable assurance of the safety and effectiveness of a device under its conditions of use. (21 CFR 860.7(c)(2)). In general, probable and probability in this guidance have the same connotation as in 21 CFR 860.7(b)(3), i.e. they refer to the likelihood of the patient experiencing a benefit or risk. Hypothesis testing, formal concepts of probability and predictive probability, likelihood, etc., typically are critical elements in the assessment of probable benefit and risk. FDA does not intend for the use of the term probable benefit in this guidance to refer to the regulatory term used for the approval requirements for Humanitarian Device Exemptions (HDE) under section 520(m) of the FD&C Act (21 U.S.C. 360j(m)), and FDA s implementing HDE regulations. 21 CFR 860.7(c)(2). Under section 513(i) of the FD&C Act (21 U.S.C. 360c(i)), FDA may determine that a new device is SE to a predicate device only if it has the same intended use. Differences in the indications for use, such as the population for which a device is intended or the disease a device is intended to treat, do not necessarily result in a new intended use. Such differences result in a new intended use when they affect (or may affect) the safety and/or effectiveness of the new device as compared to the predicate device and the differences cannot be adequately evaluated under the comparative standard of substantial equivalence. For more information on the processes associated with determining whether a new device with new indications for use has a new intended use, see footnote 3. See footnote 5. 8

23 This guidance applies to both diagnostic and therapeutic devices. Not all the factors listed in this guidance will be applicable to each 510(k) submission. For guidance on the benefit-risk factors considered in the review of PMAs or de novo classification requests, see the FDA Guidance, Factors to Consider When Making Benefit- Risk Determinations in Medical Device Premarket Approvals and De Novo Classifications, issued on March 28, 2012 ( PMA and De Novo Guidance ). This draft guidance addresses benefit-risk factors similar to those in the PMA and De Novo Guidance, but, unlike the benefitrisk determinations during the premarket review process for PMA applications and de novo classification requests which do not require a comparison to any other device, in evaluating benefits and risks during a 510(k) premarket review, FDA considers the benefits and risks of the new device as compared to the predicate device. IV. Benefit and Risk Factors The benefit-risk factors explained below are the principal factors that FDA considers when reviewing performance data to evaluate whether the new device is as safe and effective as the predicate device, where there are different technological characteristics in the new device and FDA has determined that the differences in the technological characteristics do not raise different questions of safety and effectiveness. FDA may make a determination that the new device is SE to the predicate device even if there are differences in the benefits and risks of the new device. Although the degree of difference in the benefits and risks of the new device that FDA may find acceptable in a substantial equivalence decision will be assessed on a case-by-case basis, examples of how differences in benefit and risk of the new device may be evaluated as compared to the predicate device include: Decreased Benefit/Decreased Risk: If there are different technological characteristics between the new device and the predicate device and FDA finds from a review of the submitted performance data that there are decreased benefits with the new device as compared to the predicate device, FDA may still determine that the new device is SE to the predicate device if, for example, there are also decreased risks with the new device as compared to the predicate device. When looking at the smaller benefits in the new device, FDA may consider the amount by which the benefit has decreased when determining whether the device is SE. Depending on the decrease in benefit of the new device as compared to the predicate device, FDA may determine that the new device is NSE to the predicate device, even despite decreased risks of the new device. Increased Risk/Increased Benefit: If the risks associated with the new device increase as compared to the predicate device, FDA may still determine that the new device is SE to the predicate device if, for example, FDA finds from a review of the new device s performance data that there are also increased benefits with the new device as compared to the predicate device. When looking at the increased risks posed by the new device, FDA may consider the degree of risk in comparison to the predicate device. FDA may also consider whether additional measures may help mitigate the increased risks. Depending on the increase in risk of the new device as 9

24 compared to the predicate device, FDA may determine that the new device is NSE to the predicate device, even despite increased benefits of the new device. The factors described below may be considered during the course of FDA s review of the new device s performance data in a premarket submission. Not all factors may be applicable to each 510(k) submission. Each factor that is considered is in comparison to the predicate device. A. Assessment of the Benefits of Devices Extent of the probable benefit(s): FDA assesses information provided in a 510(k) submission concerning the extent of the probable benefit(s) by taking into account the following factors individually and in the aggregate as compared to the predicate device: Type of benefit(s) - examples include, but are not limited to, the device s impact on clinical management, patient health, and patient satisfaction in the target population, such as the effect on patient management and quality of life, probability of survival, improvement of patient function, prevention of loss of function, and relief from symptoms. These endpoints denoting clinical benefit are usually measured directly, but in some cases may be demonstrated by use of validated surrogate endpoints. For diagnostic devices, a benefit may be assessed in reference to the nature of the public health impact of a particular device due to its ability to identify a specific disease, provide diagnosis at different stages of a disease, predict future disease onset, and/or identify patients more likely to respond to a given therapy and therefore enable treatment of the disease or reduce/prevent its spread. Magnitude of the benefit(s) - we often assess benefit along a scale or according to specific endpoints or criteria (e.g., types of benefits), or by evaluating whether a pre-identified health threshold was achieved. The change in clinical study subjects condition or clinical management as measured on that scale, or as shown by an improvement or worsening of the endpoint, is what allows us to assess the magnitude of the benefit in subjects. Absent explicit outcome data, the magnitude of benefit for diagnostic devices is defined in large part by the accuracy and reproducibility of test results and by the expected effect of clinically applying those results. Variation in the magnitude of the benefit across a population may also be considered. Probability of the patient experiencing one or more benefit(s) - based on the data provided, it is sometimes possible to predict which patients may experience a benefit, whereas other times this cannot be accurately predicted. The data may show that a benefit may be experienced only by a small portion of patients in the target population, or, on the other hand, that a benefit may occur frequently in patients throughout the target population. Demonstration of a large benefit experienced by a small proportion of subjects may raise considerations that differ from those in instances where a small benefit is experienced by a large proportion of subjects. Duration of effect(s) (i.e., how long the benefit can be expected to last for the patient) - some treatments are curative, whereas, some may need to be repeated frequently over the patient s lifetime. To the extent that it is known, the duration of a treatment s effect may directly influence how its benefit is defined. Treatments that must be repeated over time may 10