General Comments. May 30, 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, Ste. 800 Washington, DC Tel: Fax: Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, MD Re: Docket No. FDA 2012 N 0170: Modernizing the Regulation of Clinical Trials and Approaches to Good Clinical Practice: Public Hearing; Request for Comments Dear Sir/Madam: On behalf of AdvaMed, the Advanced Medical Technology Association, we are pleased to submit these comments in response to the Food and Drug Administration s (FDA s) public hearing on modernizing the regulation of clinical trial approaches to good clinical practice and request for comments. The Advanced Medical Technology Association (AdvaMed) is the world s largest trade association representing medical device and diagnostics manufacturers. AdvaMed's member companies produce the innovations that are transforming health care through earlier disease detection, less invasive procedures and more effective treatments. AdvaMed has more than 400 member companies, ranging from the largest to the smallest medical technology innovators and manufacturers. AdvaMed advocates for a legal, regulatory and economic environment that advances global health care by assuring worldwide patient access to the benefits of medical technology. The Association promotes policies that foster the highest ethical standards, rapid product approvals, appropriate reimbursement, and access to international markets. AdvaMed has general comments, specific comments and several comments that are intended to respond to issues that were raised during the public hearing on April 23. General Comments We would like to take this opportunity to commend FDA for their many recent and positive efforts to update guidances and policies that embrace efficiencies in clinical trial designs and operations methodologies that contribute to the modernization of the clinical trial process while simultaneously enhancing patient safety. FDA has been a leader in efforts to promote Bringing Innovation to patient care worldwide

2 Page 2 of 6 adoption of state-of-the-art methodologies including Bayesian clinical trial design and riskbased monitoring, among others, that promote high quality and efficient clinical trials. With respect to recent helpful guidance, the draft guidance entitled Investigational Device Exemptions for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human Studies clarifies that IDEs can be granted for early feasibility studies without FDA considering the full clinical program plan with which the sponsor intends to achieve marketing approval. Once finalized, we believe this approach will enhance manufacturers ability to obtain the early clinical data necessary to support development of innovative products while protecting patient safety. The guidance also provides manufacturers greater flexibility to make needed changes to the device or to the protocol during early feasibility studies by allowing the following approaches: Permitting a broader array of modifications to the device and the clinical protocol under 5-day notification without prior FDA approval, Allowing a sponsor to seek contingent approval beforehand dependent upon acceptable nonclinical test results without requiring additional FDA action for anticipated changes that would normally require prior FDA approval, and Using a new interactive review process that encourages communication with FDA during the 30-day review cycle for early feasibility study IDE supplements. These options are appreciable process advances and promote the joint FDA and industry responsibility to enhance innovation while protecting patient safety. They also have the potential to accelerate the development of innovative devices. We commend FDA s riskbased approach to flexibility during early feasibility testing of innovative devices. 1 In addition, the draft guidance entitled Oversight of Clinical Investigations: A Risk-Based Approach to Monitoring clearly communicates that FDA understands that 100% on-site data verification is unnecessary for clinical trials and that risk-based monitoring approaches, including centralized monitoring, can and should be incorporated where appropriate. Current informatics and statistical techniques allow for new ways to assure high-quality clinical data during clinical trials and we believe the appropriate, synergistic use of on-site and centralized monitoring methods could lead to both more effective and more efficient monitoring of study data and human protection. 2 1 See AdvaMed s complete set of comments on the draft guidance at Docket No. FDA D See AdvaMed complete set of comments on the draft guidance at Docket No. FDA D 0597.

3 Page 3 of 6 Specific Comments Update of Guidance on Computerized Systems Used in Trials Needed To improve and modernize the conduct of clinical trials, AdvaMed recommends that FDA update the May 2007 guidance for industry entitled Computerized Systems Used in Clinical Investigations to facilitate the use of technological advances while maintaining the protection of research participants. In the five years since FDA s issuance of the guidance, technology development of computerized systems has moved at a rapid pace. Updates to the guidance should both reflect changes to technology and the uses of technology in clinical trials. Suggested areas to address in any update to the guidance include: Clearer expectations and definition for systems; Differentiation of systems used to support business processes from those used to handle patient data, to support key study activities, and to maintain study integrity; and Electronic systems and communication of the outcome of audits. We believe the additional clarity from an update of the guidance would allow for increased definition in clinical protocols regarding the use of systems for specific study activities. Because technology is rapidly advancing, updating the May 2007 guidance should be a high priority. Achieving Better Balance between Device Risk-Benefit and Pre- and Post Market (PMA) Requirements As part of its modernization initiative, we encourage FDA to identify methods that would support practical pre- and post market requirements for certain new PMA products to promote innovation while assuring patient safety. Currently, manufacturers are deciding not to pursue some innovative PMA products because FDA requires large pre-market trials in order to capture what are expected to be infrequent or rare adverse events or even theoretical (and rare) adverse events. Identifying methods that would allow such products to come to market with reasonable pre-market safety data with an agreement for targeted, efficient postapproval data collection to further investigate potential rare adverse events would improve patient access to innovative devices yet provide reasonable protection for patient health. Greater FDA Acceptance of OUS Clinical Data We believe there is uneven acceptance of OUS (Outside the U.S.) clinical data within different divisions of the Office of Device Evaluation (ODE). It appears at times that reviewers reject OUS clinical data even when there are no clinically meaningful patient care or standard of care differences related to the product s intended use. FDA has stated it intends to release revised guidance governing acceptance of OUS clinical data. Issuance of revised draft guidance in this area should be a high priority to ensure more consistency between device review divisions.

4 Page 4 of 6 Need for Faster FDA Feedback and Input on Device Clinical Trial Designs In a number of the recent guidances issued by FDA, FDA promotes early and frequent interaction with FDA before and after an IDE submission to obtain critical feedback. Industry welcomes this interactive approach and believes direct discussion with the agency, especially concerning development plans for novel devices or intended uses, is key to efficient and high quality device development. However, in practice, it appears FDA is not able to respond to requests in a timely manner. The overly lengthy time that it takes to obtain FDA feedback makes product development efforts uncertain and inefficient. We understand that FDA plans to incorporate agreements reached during the Medical Device User Fee Amendments (MDUFA) negotiations on pre-submission meeting process changes in a presubmission guidance. These changes include implementing a more structured process for managing pre-submission meetings. As part of this planned pre-submission guidance and to encourage more efficient use of FDA resources, we encourage FDA to incorporate interactive review processes in the pre-submission meeting guidance to reduce IDE review times. We also recommend the development of small FDA subteams with critical expertise for pre-ide meetings. This latter recommendation is intended to help with the lengthy delays sponsors encounter that are associated with trying to schedule a pre-ide meeting with multiple FDA staff. Sponsors have to schedule meetings many months in advance simply because of the number of FDA staff and their varied schedules that must be accommodated. Smaller subteams comprised of the critical experts could address this simple logistical delay. Comments in Response to Issues Raised During April 23 Public Hearing Medical Device Innovation Initiative During the hearing, an exchange occurred between Ms. Nancy Stade, the CDRH Deputy Director for Policy, and Ms. Christine Chung, American Society of Clinical Oncology, in which Ms. Stade articulated some of the concerns and some of the attributes that had been ascribed to the Center for Devices and Radiological Health (CDRH) innovation pathway and asked Ms. Chung her views on the topic. Ms. Chung endorsed the innovation pathway. We wanted to take this opportunity to reiterate our concerns about the CDRH innovation pathway. While we believe CDRH s intent and motivation to facilitate the development and regulatory evaluation of innovative medical devices is commendable, we nevertheless concur with the comments made by Mr. Robert Temple, Deputy Center Director for Clinical Science, at the April 23 hearing. Dr. Temple indicated that the Center for Drug Evaluation and Research (CDER) also provides a lot of early advice to drug sponsors but CDER principally directs their expertise to whether the clinical trial protocol is designed to achieve its endpoints, thus they are not required to be expert in the science involved in different drug applications. Among others, we understand the objectives of the innovation pathway include establishing a third-party certification program for device test centers. We do not believe it is either necessary or appropriate for FDA to assume a central role in fostering academic centers to, in

5 Page 5 of 6 effect, compete with device manufacturers in the design and development of devices. We also believe the concept is fraught with practical and legal issues as discussed below. AdvaMed is concerned that FDA does not have the resources to certify clinical test sites in an efficient manner. Certifying an adequate number of clinical test sites in the U.S., likely mostly academic centers, could introduce a bottleneck for industry seeking to conduct its clinical testing at an FDA-certified site. Device research is also frequently conducted outside of academic centers because companies sometimes prefer not to conduct their device trials at academic sites because their proprietary information and trial designs can be loosely discussed, raising competitive concerns. Further, academic center research typically does not provide real-world experience, which could make it even more difficult to obtain the clinical data necessary for CMS (Centers for Medicare and Medicaid Services), as CMS requires real-world data to assess whether a new technology is reasonable and necessary for the Medicare population. With regard to practical issues, companies often use the expertise of biomedical engineering facilities at qualified academic institutions when conducting pre-clinical device testing. It is the company s responsibility to ensure that the testing is conducted in compliance with applicable requirements of the Quality System Regulation (QSR, 21 C.F.R. Part 820). It would be counterproductive for FDA to assume this responsibility via site certification. It should be the responsibility of the sponsor to ensure that personnel are qualified; that test equipment is calibrated; that software is validated; and that animal facilities are Good Laboratory Practice (GLP) compliant. AdvaMed s member companies have also expressed concern about partnering with certified sites on device redesign citing intellectual property concerns if these centers have access to a company s device design files. This is a matter of intellectual property rights and related financial considerations as the technology transfer offices in academic institutions typically require an interest in the intellectual property. Finally, we are concerned about potential conflicts of interest associated with government support of academic centers that will design, develop and test devices. Many academic centers already invest in devices they help design, develop or test or request an equity interest from sponsors of R&D that is being conducted at the academic center. Government support, either financial or otherwise, for academic test centers may only exacerbate these potential conflicts and could lead to undue influence by both government and academic centers in determining winners and losers of pioneering or breakthrough devices. However, we believe the innovation pathway could be beneficial as a short-term mechanism for FDA staff to test or pilot both adaptive clinical trial designs and adaptive regulatory mechanisms that are responsive to: Challenges associated with devices intended to treat, diagnose or cure conditions or diseases for small populations or subpopulations (e.g., orphan or pediatric populations),

6 Page 6 of 6 Devices that are pioneering or breakthrough, and/or Improving review times for the existing expedited review program which are significantly longer than review times for non-expedited submissions. We would also bring to your attention AdvaMed s detailed comments 3 to the docket on the innovation initiative. New CDRH Interpretation Related to IDE Approvals During the April 23 hearing, there was a discussion between Ms. Jennifer Kerr, Cook Group Inc. and Ms. Stade on CDRH s new interpretation related to approval of IDEs i.e., that a pivotal study that is unlikely to generate data that would support marketing clearance or approval may be disapproved by CDRH. This new interpretation is reflected in FDA s recently issued draft guidance entitled Clinical Investigators, Institutional Review Boards, and Food and Drug Administration Staff; Food and Drug Administration Decisions for Investigational Device Exemption Clinical Investigations on which AdvaMed commented. 4 We understand that, for any given study, if the risks to the subjects are not outweighed by the potential benefits to the subjects or to the furtherance of knowledge that may benefit future patients, FDA can disapprove the study. FDA, however, does not have the legal authority to disapprove an IDE because it feels the study, in and of itself, will not lead to market approval. FDA s new interpretation of reasons for disapproval is also inconsistent with the reasons for IDE disapproval in 21 CFR (b). We believe it is the sponsor s responsibility to make the decision to begin or not begin the study with the knowledge that the FDA may require further data before marketing approval may be considered. AdvaMed recommends that in lieu of its new interpretation, FDA should approve IDEs (where benefits outweigh risks and/or add to the furtherance of knowledge) and in the approval letter list any elements of concern as future considerations. In conclusion, thank you for this opportunity to comment on FDA s clinical trial modernization initiative. Please don t hesitate to contact me if you have any questions. Sincerely, Tara Federici Vice President Technology and Regulatory Affairs 3 See AdvaMed comments to Docket No. FDA 2011-N See also AdvaMed comments to Docket No. FDA-2011-D-0790.