Re: Docket No. FDA-2017-N-5105; Review of Existing Center for Devices and Radiological Health Regulatory and Information Collection Requirements

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1 701 Pennsylvania Avenue, NW Suite 800 Washington, D.C Tel: Fax: Division of Docket Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, MD Re: Docket No. FDA-2017-N-5105; Review of Existing Center for Devices and Radiological Health Regulatory and Information Collection Requirements Dear Sir or Madam: The Advanced Medical Technology Association (hereinafter referred to as AdvaMed ) is pleased to provide these comments regarding the Food and Drug Administration (FDA or Agency ) Review of Existing Center for Devices and Radiological Health (CDRH) Regulatory and Information Collection Requirements. AdvaMed is the world s largest association representing manufacturers of medical devices, diagnostic products, and medical information systems. AdvaMed member companies produce technologies that are transforming health care through earlier disease detection, less invasive procedures and more effective treatments. AdvaMed s members produce nearly 90 percent of the health care technology purchased annually in the United States and more than 50 percent of such technology purchased annually around the world. AdvaMed members range from the largest to the smallest medical technology innovators and companies. Nearly 70 percent of our members have less than $30 million in annual sales. Our industry is committed to providing the best tools to diagnose and treat patients. Medical device companies, most with fewer than 100 employees, are creating continuous progress through constant innovation. We also drive economic growth by creating high-paying manufacturing jobs in the U.S. and through net exports to the other countries around the world. We applaud the Agency for its efforts to conduct this review and solicit stakeholder feedback to help support modern and effective regulation. We believe our proposal fits well with CDRH s current efforts to consider effective, efficient approaches to support U.S. public health, medical device innovation, and continual progress in the field. Our proposal follows along with our specific recommendations to assist in meaningful implementation of this review of CDRH regulatory and information collection requirements. Bringing innovation to patient care worldwide

2 Page 2 of 17 Background: Promoting Modern, Effective Regulation for U.S. Medical Technology In response to the FDA request for comments, AdvaMed conducted a review to help identify regulations and related paperwork requirements that are outdated, redundant, or otherwise ineffective or inefficient as part of this review of existing regulatory and information collection requirements. We welcome further discussion with FDA CDRH to consider how we might explore the following recommendations to help ensure a modern and efficient regulatory system consistent with FDA s mission to protect and promote the public health and support medical device innovation. We commend the Agency s effort to review existing regulation and support efficient, effective regulation that supports scientific progress and timely access to critical medical technologies. We note that such measures will have positive impact for all innovators, particularly small company innovators that are often disproportionately impacted by outdated, inefficient regulation. To assist with this information collection, we have provided requested information on expected savings associated with our proposal (including issue description, proposed action, and cost and/or economic data for each of our recommendations). All efforts were made to reflect realistic and conservative estimates of the costs associated with the regulation. However, given the wide range of our technologies and difficulty of accurately assessing any and all relative information collection across industry, these remain approximate estimates. In all cases, we believe adoption would help modernize regulation, build efficiencies, and support smart and meaningful paperwork reduction. We believe our recommendations will also aid CDRH in improved use of resources while ensuring its public health mission and fulfilment of statutory obligations. In light of CDRH s commitment to conduct more timely retrospective guidance review and withdraw or update guidance as needed, which we strongly support, we have also identified several guidances that we believe are also appropriate for consideration. In all cases, we believe that repeal, or in some cases revision, will support a modern and effective regulatory framework and well align with CDRH efforts, such as its recent FY 2018 Focused Retrospective Review of Final Guidance issued on December 12, Ensuring Modern, Effective Regulation: Proposed Measures for Consideration I. Final Tobacco Intended Use Rule We commend FDA for its announcement on January 12 to delay implementation of the amendments to the Agency s existing intended use regulations. Furthermore, we recognize the Agency s thoughtful consideration of the substantive issues raised and commitment to ensuring clear and consistent rulemaking that supports public health in the U.S. The final rule amendments, as articulated in its totality provision, were inconsistent with the long-recognized definition of intended use and harmful to U.S. product research, medical device innovation, and overall patient access to critical medical technologies. As drafted, they created

3 Page 3 of 17 substantial uncertainty for industry and allowed for broadly subjective interpretation for what is considered an intended use of a medical product. The intended use of a medical product is a foundational concept in the application of the Food, Drug, and Cosmetic Act. It not only controls how a medical product is regulated and the premarket pathway that applies to a medical product, but it also dictates the uses for which the product s manufacturer is required to provide adequate labeling, see 21 CFR The Final Rule (issued on January 9, 2017) departed drastically from the proposed rule, did not provide clear guidance, and swept broadly into permitted and protected exchange of truthful, nonmisleading information. By removing the clarifying language in the Proposed Rule, the Final Rule suggested that FDA may consider a manufacturer s mere knowledge as sufficient evidence of an intended use. This is inappropriate. A manufacturer s intended uses should be determined based upon the manufacturer s affirmative conduct and firmly grounded on claims made by a manufacturer to promote its products, not a firm s knowledge of a third-party use. Increased ambiguity regarding what will be considered evidence of an intended use will chill manufacturers willingness to engage in these activities. This will in turn have a direct impact on the public health by hindering access to medical technologies, creating barriers to timely quality and efficient healthcare, and impeding legitimate and protected scientific exchange. In fact, the Final Rule is a departure and does not fit with FDA progress and current efforts to review and appropriately clarify its policies regarding manufacturer communications, including principles in its recent January 2017 draft Agency guidance document entitled Drug and Device Manufacturer Communications with Payors, Formulary Committees, and Similar Entities Questions and Answers among others. Clarity and necessary precision is needed in rulemaking. The current Final Rule is not narrowly tailored; to the contrary, the totality of the evidence standard potentially encompasses a wide variety of lawful and permitted activities. Because the totality of the evidence standard does not directly advance the interest asserted by FDA, the Final Rule s intended uses definition fails to comport with the First Amendment. We strongly concur with the Agency s move not to implement these changes to the intended use regulations. Furthermore and consistent with our prior recommendations to the Agency, we encourage FDA to return to the approach set forth in the Proposed Rule which we strongly supported. At a minimum, if FDA does not revert to that approach, FDA should adopt a properly promulgated standard for determining intended uses that makes clear that (1) legitimate, protected scientific exchange, (2) truthful, non-misleading communications (including commercial speech), and (3) mere knowledge of unapproved use by third parties do not constitute evidence of an intended use. As requested, we have provided conservative estimates below based on FDA s current information collection of 40 hours per premarket notification (which appears grossly underestimated costs of premarket notification submission can range from $50,000 to $5

4 Page 4 of 17 million). This would cover the costs with respect to new submissions and labeling updates as a result of totality of evidence standard as outlined in the rule. Further, this estimate does not consider the anticipated increase in the number of required premarket approval authorizations (PMAs) as a result of entity constructive or actual knowledge as deemed under the rule. We note that PMAs are excluded from the analysis, but costs would rise significantly if integrated into the analyses. Based on previous years manufacturer PMA submissions to FDA, average time to prepare and submit a PMA application, including time needed to assemble supporting data, is approximately 4,380 hours per response. This takes into account multiple individuals (clinical, regulatory and in some cases development) for approximately 15 months. This does not take into account that device manufacturers have experienced total average cost for clinical testing alone of $3.5 million with a general range of $2 to $5 million varying by product. We are aware of cases where clinical trials for a medical device have reached well over $50 million. In the case of even 30 device products that would be affected by the rule and require a PMA submission, the annual total is approximately $17.80 million. Incorporating such PMA annual spending in addition to premarket submission costs, this would be well approaching $100 million and expenditures under the Unfunded Mandates Reform Act of This is illustrative of our concerns with the Final Rule and we encourage the Agency to carefully consider the impact of such proposed changes. Submission Responses (on Annual Basis) 1, hours/each $50,000/each; $75 Million II. Update Part 801 (Labeling/Use of Website in Electronic Era) Revise to allow for use of a website in place of street address in Part 801.1(d), which can be achieved by adding or readily available on the company website home page. to the end of the street address may be omitted if it is shown in a current city directory or telephone directory. Today s modern regulatory framework necessitates flexible and efficient manners to update information, such as use of a company s website. Through better leveraging of readily accessible online information, we can support timely and accurate information rather than require relabeling of all product families due to a change in address. A clarifying update of the underlying regulation would reflect a more up-to-date approach. Even assuming one relabeling for an address change for five product families per device manufacturer for a minority of industry, one-time costs would be $100,000 for an address change. This is a conservative estimate as many larger companies have upwards of 600 product families that would require update to reflect a change in address. The labeling process is highly labor-intensive with multiple steps and process controls, including change order review, control approval, physical

5 Page 5 of 17 review, proof review, and consideration of multiple languages. In this electronic age, an update of this regulation would be an important step forward in promoting efficient and effective regulation and better use of resources to support U.S. healthcare. Although not a direct U.S. regulatory efficiency, the impact of such minor labeling changes outside the U.S. (OUS) is also significant. These costs are usually borne by U.S. companies; in these cases, a mere change of an address could trigger re-registration in most OUS countries. These types of activities can impact a company s decision to export products, which is ultimately harmful to innovators ability to bring new products to the U.S. patient population. Responses hours/each $100,000/ $62.5 Million III. Part 801 Use of Symbols in Labeling Rule Revise to remove the requirement in and (g) for a symbols glossary. Alternatively, consider removing the requirement for English text directing the user to the location of the glossary. In addition to removal of the direction for glossary location, the prescriptive requirements for including the title and designation number of the standard that lists the symbol and the title of the symbol and its reference number should be removed. If FDA continues to believe a glossary is necessary in a modernized and efficient regulatory system, information in the glossary should list the symbol and the meaning or explanation text for the symbol only. FDA issued its final rule, Use of Symbols in Labeling, June 15, 2016, that became effective September 13, The final rule permits the use of symbols in all medical device labeling without adjacent explanatory text (referred to as "stand-alone symbols") if certain requirements are met. For over a decade, prior to issuance of the final rule, in accordance with FDA guidance document and/or premarket approved labeling, medical device manufacturers provided to customers labeling with stand-alone symbols. In contrast to industry practice, the final rule imposed the following two new requirements on industry: (1) identification of the glossary location in the labeling by a prominent and conspicuous statement, and (2) including in the glossary, the title and designation number of the standard containing the symbol and the title of the symbol and its reference number, if any, in the standard located in the following provisions of the regulation. These add-on requirements are unnecessary as evidenced by experience with use-to-date and require the creation of new labeling artwork/formatting to incorporate the new requirements, the symbol, and the meaning or explanation text for the symbol only. We acknowledge FDA efforts to help ease implementation and provide some flexibility through use of enforcement discretion. At the same time, we believe that update of the underlying regulation would provide for long-term regulatory certainty that meets FDA objectives while not

6 Page 6 of 17 imposing excessive, unnecessary burden on manufacturers. Again, estimates are conservative and assume only one product update per manufacturer annually. Realistically, there will be multiple products that will require updated labeling (e.g., in vitro diagnostics) and thereby significantly increase such information collection estimates. Responses (on Annual Basis) 2, hours/each $1500/each; $3 Million IV. Update 21 CFR Part 11 (Option for Use of Electronic Signature and Documentation) From a historical perspective, we note FDA announced in August 2003 that it was re-evaluating Part 11 and exercising enforcement discretion for a narrower application of Part 11 while retaining the regulation in its entirety. Significant resource expenditures associated with Part 11 were identified as the reason for enforcement discretion. Nearly 15 years later, Part 11 remains on the books. Recommendations include: a. Promote Electronic Records in Modern Regulatory Framework: Permit documentation in electronic form in place of paper records. b. Foster Efficient Use of Electronic Signatures: Remove requirement for certification to FDA prior to use of each electronic signature in Part (c) as it is not an efficient method. This is illustrative of the highly outdated nature of this regulation to require a company to register with the FDA if they intend to use electronic signatures. Given the nature of the use of electronic signatures, this regulation no longer seems practical. c. Leverage Electronic Data for Clinical Evidence: FDA issued a draft guidance on the use of newer technologies, such as mobile medical applications, in clinical applications. The clarifications provided were very positive and will facilitate use of these products in the clinical trial setting. While industry appreciates FDA s flexibility, a needed overhaul of the underlying regulation would provide for long-term regulatory certainty. Part 11 remains inefficient for today s medical device technology needs. We appreciate FDA s important step in issuing draft guidance on the use of electronic record requirements for clinical trials in light of technological advances in electronic systems and data collection since issuance of the regulation. We also acknowledge FDA efforts to ease implementation and provide narrow and practical interpretation through use of enforcement discretion. At the same time, FDA enforcement relies on application of the quality system regulations that meets objectives of Part 11. In light of today s environment, we recommend

7 Page 7 of 17 FDA reduce Part 11 in its entirety or at a minimum, implement further significant reductions in Part 11 reflective of the modern era of electronic systems and move from paper recordkeeping. While the cost can vary depending on the size of company and current state of systems, Part 11 compliance can range from $4 million to $400 million per company. FDA itself estimated the costs of electronic signatures (per CFR 11.10, 11.30, 11.50, and ) alone to be a one timeburden of 280,000 total hours (see FR , November 27, 2017, Docket No. FDA-2011-N- 0076). As companies who are significantly invested in quality management systems to support critical practices and processes as part of a compliant and effective risk-based regulatory framework, such change will go far to promote an efficient and streamlined regulatory process. Total Responses (on Annual Basis) 2,500 (Total Hours) 280,000 total per FDA estimates (Total Dollars) $4 to $400 Million/each; >10 Billion V. Part Establishment Registration and Device Listings (Option for Use of Electronic Recordkeeping as an Alternative to Paper) Delete (a)(3) and related provisions (c) and (d) All inquiries regarding a premarket notification submission should be in writing and sent to one of the addresses above to allow for the option of electronic submission. Another option would be to update (c) to allow for the option of submitting electronic copies in place of paper copies to properly update the regulation, which reflects unnecessary and out-of-date regulation calling for paper copies of submissions. Countless reams and paper volumes have been replaced in today s modern regulatory framework with e-copies along with a clear table of content for easy-reference, which is now standardized and required. Paper copies are a burden to both industry and FDA, require substantial creation time, are not environmentally friendly, bog down storage space and acceptance procedures, and reflect overall outdated regulation. These provisions relate to paper copies of 510(k) correspondence, including submission of a paper copy of the 510(k). FDA has moved to an ecopy system, which the device industry supports, and a paper copy is no longer required. Of particular note, we are pleased to see FDA plans for proposed rulemaking to embrace electronic submission in the Unified Agenda of Federal Deregulatory Actions (or Unified Agenda ) released at year-end We have long supported amending the regulations to remove requirements for submission of an unnecessary paper copy in light of current use of ecopy.

8 Page 8 of 17 We strongly support FDA s update of the regulation accordingly to support efficient and up-todate regulation. Responses (on Annual Basis) 3199 (FY2016 MDUFA Performance Report; data for FY complete cohort) 26 hours/each $2,000/each; $6.4 Million VI. Allow Wider Use of Summary Medical Device Reporting (MDR) Revise malfunction reporting requirements to permit manufacturers to submit quarterly, summary reports for malfunctions already known to the manufacturer and FDA, which are not associated with an adverse event. Such revision would enhance usability of malfunction data, streamline MDR submissions, and implement section 227 of the Food and Drug Administration Amendments Act (FDAAA). This is consistent with the recent FDA-industry user fee commitment to expand use of summary reporting, and we suggest such approach could be codified in regulation. We appreciate FDA issuance of its general plans on December 26 for proposed voluntary malfunction program implementation following its pilot as a component of the Medical Device User Fee Amendments of 2017 (MDUFA IV) Commitment Letter, and note such an approach can and should be widely implemented for its success. Over the past decade, we have supported a more streamlined and effective approach that will necessitate increased flexibility and necessary update in the manner of reporting to support an optimal and meaningful reporting program. Because companies assess the full scope of individual complaints, summary malfunction reports will allow FDA to better focus its follow-up activities. Costs below are based on current FDA-proposed burden estimate associated with the current reporting form. We anticipate a 50% time savings if FDA implements as described in section 227 for summary reporting and integrates appropriate updates to Form 3500A (per 21 CFR 301). However, significant time savings and necessary participation is contingent on sufficient eligibility and a substantially improved reporting procedure rather than use of the current Form 3500 (individual reporting form for summary reporting). This would result in time and cost savings for both industry and FDA, enhanced reporting, and improved Agency analysis. Industry impact alone is considerable and covered below.

9 Page 9 of 17 Responses (on Annual Basis) 900,000.3 minutes (18 minutes)/each; 270,000 hours IT costs; minimal VII..9 Exemption Limitation (contained in.9 of the Chapter in 21 CFR Parts ) We strongly urge removal of the limitations to exemption from premarket notification in the.9 provisions. Nearly two decades have passed since FDA first promulgated the limitation provisions, and during that time, the state of technology, scientific and medical knowledge, the availability of standards, and guidance have advanced tremendously. Many technologies and device types that were new and innovative in the late 1990s are now well-characterized. For example, point-of-care devices, limited under (c)(9), are now an integral and recognized part of medical practice and are subject to strict performance standards. Categorically, limiting a device simply because it is at the point-of-care no longer makes sense and does not support the public health in today s healthcare environment. By way of example of its impact, we note that since point-of-care (POC) devices may include some exempt analytes offered on the same strip or cartridge as those that are non-exempt, manufacturers are still requested to submit data on the exempt analytes since they are part of the broader device. This reiterates the far-reaching impact of the existing POC limitation in regulation as the reasoning seems no longer applicable with today s modern medical device innovation. Furthermore, the limitations provisions go beyond what the FDA intended to limit. In fact, the limitations include the same disease areas for devices for which FDA has now exercised enforcement discretion (e.g., some diabetes management mobile apps). In effect, such limitation negates the FDA-proposed exemption in the recent FR notice for continuous glucose monitor secondary display. We do not believe this is FDA s intent, and therefore, urge the FDA to address the regulation to better reflect today s healthcare system and a modernized, risk-based regulatory approach. Responses (on Annual Basis) hours/each $3 Million/each; $90 Million

10 Page 10 of 17 VIII. Electronic Radiation Control for Health and Safety Act of 1968 (EPRC) Revise to remove EPRC s applicability to medical devices since the requirements are redundant with other reporting requirements for medical devices, e.g., Medical Device Reporting, accidental safety reporting, Part 7, initial reports, and annual reports. The EPRC provisions apply to any "electronic product. As such, these regulations apply to medical and non-medical devices. Many of these topics are adequately addressed in the medical device regulations, associated guidance, and recognized consensus standards, and it may be possible to eliminate or consolidate some of these regulations. For example, we believe the requirements for medical devices in 21 CFR 1000, 1002, , and 1005 could be eliminated or consolidated since these topics are covered in 21 CFR 803, 806, and 807. Moreover, the performance standards as specified for medical devices in 21 CFR 1010, 1020, 1030, 1040, and 1050 could also possibly be eliminated or consolidated since these topics are covered in medical device guidance and consensus standards. In that vein, we applaud FDA s recent efforts to rely upon existing International Electrotechnical Commission (IEC) standards instead of outdated performance standards in the regulations for some specific medical devices subject to EPRC requirements, e.g., X-ray. However, this effort to move away from duplicative requirements should be broadened to include other medical devices subject to EPRC and to other EPRC requirements beyond performance standards. Furthermore, we are pleased to see FDA s recent plans for proposed rulemaking related to such provisions in the Unified Agenda to support elimination and in some cases consolidation of these regulations for medical devices in recognition that they are outdated and adequately addressed for medical devices in current applicable medical device regulations, guidance, and standards. We strongly support such efforts and applaud FDA in moving to ensure regulation is modern and up-to-date for device manufacturers. In that vein, the estimate below includes cost for initial reports, annual reports, and assembly reports. Based on previous years manufacturer costs, it is based on one annual report with approximately 125 filled forms. We note that the estimate will likely be much higher depending on the number of annual reports and affected products. For example, completion of 20 annual laser reports on an annual basis would require 300 hours (time burden), which is nearly double the below estimates. Responses (on Annual Basis) hours/ each $50,000/each; $25 Million

11 Page 11 of 17 IX. Part (b)(4)(v) Manufacturing Section of PMA Manufacturing documentation is viewed during the paper review of the PMA process and during the preapproval inspection. We suggest FDA might consider conducting a paper review rather than an on-site pre-approval inspection. Increased use of review via manufacturing section of a PMA would save significant time. Preapproval inspections are intensive in time and resource burden. This estimate assumes five staff full-time for the period of the inspection, noting that time burden may be much higher for manufacturers that may often commit an average of 25 people full-time for a preapproval inspection (excluding time in preparation of the inspection). Thus, leveraging review of the manufacturing section would reduce redundant review and save significant time in support of timely patient access to innovation and reduce time burden of preapproval inspections. Indeed, FDA has recognized value in conducting an abbreviated review of a PMA manufacturing section when a manufacturer has demonstrated quality maturity. Even if impact is limited to approximately 25% of applicants in a given year, impact would be substantial in supporting timely access to new U.S. medical innovation. Responses (on Annual Basis) hours/ each $500,000/each; $10 Million X. Electronic Submission of Labeling for Certain Home-Use Medical Devices While this remains a proposed rule, we continue to urge FDA to withdraw the rule. It is redundant as device labeling is required to accompany medical devices placed into commercial distribution. Device labeling is widely available to users and many manufacturers of home-use devices provide labeling information for products through their websites. Establishment of an FDA database to maintain device labeling creates inefficient and costly regulation for both the Agency in funding for its housing and for affected stakeholders in terms of increased regulatory requirements. Creation and submission of electronic labeling creates an infinite and highly burdensome regulatory requirement for the industry, which will require the establishment and maintenance of IT systems to produce the Structured Product Labeling (SPL)-formatted labeling. Such an approach should not be finalized in regulation. We do not believe the collection of such information is necessary for the proper performance of FDA s functions, and FDA costs are significantly underestimated at $6.6 million. This database is superfluous as industry already provides this information. We note the FDA estimate does not include the burden to move toward establishing and maintaining a SPL system, which is significant, in addition to the burden of establishing software systems, validation, and maintenance. Additionally, we have concerns with the calculation of benefits based on proxies

12 Page 12 of 17 and estimates of training costs as the means to demonstrate the benefit. We do not believe the proposed regulation should move forward as it is redundant in substance and out of sync in magnitude and complexity with the mission of streamlined and effective regulation that promotes the public health. Further, costs would rise significantly with any wider application to other device types into the future. We note that FDA reported its own costs to establish and maintain the database over ten years would be $22 million. Even relying on the FDA s own estimate of affected devices (12,338 devices), annual costs to industry are well in excess of $6.6 million annually. Responses (on Annual Basis) 12, hours/each; $6.6 Million XI. Part 820 Use of Recognized Standard for Quality System Management We encourage FDA to consider, when appropriate, reliance on ISO in place of 21 CFR Part 820 to assess manufacturers quality practice. Such effort will go far to reduce overlap, support international harmonization, promote timely access for patients, and foster more efficient regulation in the U.S. and worldwide. We note that FDA has been moving positively in that direction with its support of the global Medical Device Single Audit Program (MDSAP), which will closely integrate ISO In such case, the MDSAP program promotes greater alignment of regulatory approaches and technical requirements based on international standards and best practices. Our proposal fits well with such efforts. Our companies estimate that FDA reliance on ISO and MDSAP could save costs associated with inspections/audits by percent by reducing the number of overlapping inspections/audits from FDA inspectors and certifying bodies. Even were a manufacturer not to participate in MDSAP, the efficiency of developing and maintaining a single quality system based on ISO both for U.S. and operations outside of the United States likely would produce cost savings. Even assuming a 5% savings on the manufacturer support and response costs for FDA FY 2017 annual inspections, cost savings are at least $73 million annually. This also does not factor the overall reduction of overlapping inspections in moving towards greater regulatory convergence, which would represent much higher savings with levering of programs such as MDSAP.

13 Page 13 of 17 Responses (on Annual Basis) 2, hours/each $25,000/each; $73 Million XII. Expanded Elements Under the Clinical Trials Rule We strongly support clinical trial registration and sharing of clinical trial results information to promote patient and clinician access via ClinicalTrials.gov (or CT.gov). The final rule (issued on Sept. 9, 2016) included several expanded reporting elements, however, that have raised concerns regarding unintended and harmful impact on U.S. innovators and patient access to critical medical technologies. The rule should be revised to allow for flexible and delayed disclosure of applicable device trials and account for situations where product development efforts may be delayed, put on hold, or reprioritized or pursued again at a later juncture due to funding or other business reasons. Without necessary protection of proprietary and commercial information, the final rule jeopardizes investment in medical device research and development, particularly concerning the iterative nature of device innovation where the average life-cycle may be as short as 18 months. Developing innovative technology requires a great deal of time and significant investment. We note small device companies (generally considered with sales of less than $100 million) account for a vast number of device innovations and contribute greatly to maintaining strong value competitiveness across the industry, with particular disparate impact of the rule on these innovators. Under the final rule, FDA is required to enforce compliance with the following expanded reporting requirements that are harmful to the U.S. medical device ecosystem: The final rule requires companies to disclose on ClinicalTrials.gov confidential commercial information, trade secret or financial information. This includes the complete trial protocol, which includes methods of participant selection, randomization, masking, and assignment to arms; methods of collecting clinical trial data; specific information about clinical trial interventions and other elements of care that were provided in addition to the specified interventions; and the statistical analysis plan. The rule also requires this information to be disclosed for products that were not approved or cleared by FDA, even where a company has not abandoned development of the product. The final rule disregards the definition of an applicable device clinical trial in the Title VIII Clinical Trial Databases in the Food and Drug Administration Amendments Act (FDAAA), which only applies to prospective clinical studies comparing an intervention with a device and which excludes small clinical trial[s] to determine the feasibility of a device. The final rule sweeps in inappropriately a number of studies, such as in the in

14 Page 14 of 17 vitro diagnostic and all feasibility studies except early feasibility studies. Yet under commonly understood definitions of interventional, many IVD studies are not interventional because the study results are not used to treat or manage subjects whose clinical samples are tested for purposes of the study. Lastly, the final rule ignores Congressional intent with respect to the statute s device delayed disclosure provision by preventing use of the device delayed disclosure for new uses of a previously approved or cleared device. The delayed disclosure provision was included in FDAAA 2007 with overwhelming support in recognition that disclosure of the existence of a clinical trial through ClinicalTrials.gov could provide significant advantages to device competitors who could potentially speed a competing device into clinical trials and obtain final FDA clearance or approval in order to take advantage of the benefits associated with being first to market. Without address of this provision, companies may be forced to abandon products because the investment can no longer be recouped. Clinical trials alone generally cost between $2 million to $5 million to develop protocols and statistical analysis plans, to obtain FDA approval of the Investigational Device Exemption (IDE) which may require several rounds of presubmission interactions, and to conduct the studies. FDA reported that in FY 2017 there were 293 IDEs. Even assuming individual trial costs of only $1 million, this could result in loss of clinical trial investment of $293 million or more. We note this estimate does not include research and development costs, costs associated with non-significant risk studies that do not require IDE, or costs associated with multiple studies run under a single IDE. Additionally, studies for breakthrough devices can run as much as $50 million. Responses (on Annual Basis) hours/each $1 Million/ $293 Million XIII. Part Good Laboratory Practices (Allowing for Alternative Approaches to Ensure Integrity of Data) We recommend the rule be updated to expressly recognize the appropriate use of alternative approaches from GLPs similar to 21 CFR (b)(6)(i). Such clarification in the corresponding humanitarian device exemption and investigational device exemption provisions is also recommended. Such update would support clarity and consistency in the regulations for both the Agency and industry while supporting data integrity. While we have not provided a cost estimate, we note such approach would support needed transparency in the rule and aid innovators.

15 Page 15 of 17 Ensuring Modern, Effective Guidance: Proposed Measures for Consideration XIV. Third-Party Review Program Guidance This guidance should be withdrawn because it is inconsistent with the MDUFA IV Commitment Letter in imposing unnecessary re-review of submissions through the third-party review program. We note FDA appears to be taking a relook at the guidance and we support such efforts per its inclusion on the CDRH Fiscal Year 2018 (FY 2018) Proposed Guidance Development and Focused Retrospective Review of Final Guidance list issued on December 12, 2017 for proposed reissuance of the draft guidance. Consistent with the MFUDA IV commitment, FDA should make all efforts to best leverage an effective program for all innovators. Beyond strengthening the third-party review process consistent with the MDUFA IV commitment, industry would also welcome the opportunity to discuss other programmatic improvements to support an optimal and effective third-party review program available for all interested innovators that supports high quality medical devices and diagnostics under the program. XV. Total Product Life Cycle: Infusion Pump Premarket Notification [510(k)] Submissions Guidance FDA has imposed a requirement for submission of Safety Assurance Cases (SACs) with all infusion pump 510(k) and PMA submissions. This requirement goes beyond the statutory requirement to demonstrate substantial equivalence to a predicate device, and its legal justification lacks a solid basis. Safety assurance cases are not a proven risk management tool for infusion pumps and require companies to duplicate information already contained in the 510(k) in a separate assurance case format a format which is extremely expensive and resource-intensive to develop, maintain and update. Despite experience gained with SACs, we note the average number of hours to develop a SAC for a new or legacy pump remains high at 2,792 hours with an average cost of $486,110. Since FDA first imposed the requirement for SACs, FDA has issued over 21 guidances which apply broadly to all device types or have special relevance for infusion pumps (e.g., cybersecurity and human factors). In addition, standards relevant to infusion pumps have been significantly strengthened since FDA s imposition of the SAC requirement. These include the third edition of IEC 60601, which requires safety testing to address risks related to design as well as performance, IEC :2012, which addresses the safety and essential performance of infusion pumps, and standards addressing alarms, cybersecurity and usability. XVI. CDRH Appeals Processes Guidance Revise the guidance and ensure any proposed rulemaking allows for escalation to higher level review (otherwise referred to as telescoping ) at the request of a company rather than solely at FDA discretion to ensure assessment at the appropriate level within the Agency, even when a submitter has not yet exhausted other review options through the supervisory chain.

16 Page 16 of 17 Such consideration would take into account the nature of the request and the management level involved in the decision. As FDA itself notes, this might occur, for example, in matters pertaining to regulatory issues, new policy questions, or highly complex scientific questions. Appealing through the supervisory chain may not be appropriate in all cases and can add significant costs and delay access to new medical product innovation. AdvaMed will be providing more specific comments in forthcoming comments to the FDA docket regarding the January 17 proposed rule regarding Internal Agency Review of Decisions; Requests for Supervisory Review of Certain Decisions Made by the Center for Devices and Radiological Health. XVII. Use of Good Guidance Practices AdvaMed members appreciate the Agency s efforts to develop guidance to help provide understanding of Agency thinking. At the same time, guidance should be consistent with Good Guidance Practices (GGPs), contained at 21 U.S.C. 371(h), and GGP regulations promulgated thereafter. GGPs were established by the FDA to assure the appropriate level of public participation while promoting and preserving the public health. For example, the guidance Software as a Medical Device (SAMD) Clinical Evaluation does not provide as FDA itself notes in its preface Agency recommendations for FDA and industry staff, which is a foundational concept in the proper use of guidance. We wholeheartedly support and appreciate the proposed purpose to help provide guidance on when clinical evaluation may be needed to demonstrate a reasonable assurance of safety and effectiveness for such software. Further, we strongly support international harmonization efforts, but adherence to proper procedure is necessary for both guidance as well as rulemaking. Thus, we would welcome further discussion with FDA to ensure clear and transparent policies that meets GGPs. XVIII. Assessing User Fees PMA Supplement Definitions, Modular PMA Fees, BLA and Efficacy Supplement Definitions, Bundling Multiple Devices in a Single Application, and Fees for Combination Products Guidance This guidance should be withdrawn and the panel track definition in footnote 3 should not be utilized moving forward. The types of PMAs subject to user fees are incorrect, and the definition of panel-track supplement in footnote 3 is not consistent with the Food, Drug, and Cosmetic Act (FDCA). The only information in this guidance that is not already covered by other guidance documents is a few Biologics License Applications (BLA) examples. Also, the provisions related to bundling are now outdated and replaced with separate guidance. XIX. FDA Implementation of Retrospective Review of Final Guidance We support FDA efforts to conduct retrospective review of final guidance. In that vein, FDA should complete a comprehensive retrospective review of all current device guidance documents and identify outdated guidance documents for potential removal. AdvaMed is happy to assist the Agency in its efforts to undertake such a review and is willing to provide potential

17 Page 17 of 17 recommendations for withdrawal for both draft and final guidance. Such guidance examples, which in most cases can be withdrawn as outdated and/or no longer necessary include: a. Guidance for 510(k)s on Cholesterol Tests for Clinical Laboratory, Physicians Office Laboratory and Home Use (July 1995). This guidance document is outdated and no longer followed by FDA to support manufacturer validation studies. b. Review Criteria for Assessment of Glycohemoglobon (Glycated or Glycosylated) Hemoglobin In Vitro Diagnostic Devices (September 1991). This guidance document is outdated and no longer followed by FDA to support manufacturer validation studies. c. Guidance for Industry and FDA Staff: Assayed and Unassayed Quality Control Material (June 2007). In light of recent proposed exemption of such controls by the Agency, the guidance on submission elements is outdated and should also be withdrawn. Alternatively, an option would be to revise accordingly as understanding regarding FDA thinking around processes for validation and verification is still useful. d. Abbreviated 510(k) Submissions for In Vitro Diagnostic Calibrators (February 1999). Consistent with previous comment, controls are planned for exemption from submission. Thus, such guidance on what to include in the submission is no longer needed. Alternatively, an option would be to revise accordingly as understanding regarding FDA thinking remains useful. Please note that AdvaMed will be providing additional comments to the docket in review of CDRH s Fiscal Year 2018 Proposed Guidance Development and Focused Retrospective Review of Final Guidance in addition to the illustrative guidances cited for purposes of these comments. AdvaMed has identified a number of proposals for consideration, which are intended to assist in this initiative. Thank you for your efforts to support public health and innovation. Best Regards, /s/ Khatereh Calleja Senior Vice President Technology and Regulatory Affairs