May 2, 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: Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Room 1061 Rockville, MD Re: ; Revised Draft Guidance for Industry on Distributing Scientific and Medical Publications on Unapproved New Uses Recommended Practices Dear Sir or Madam: The Advanced Medical Technology Association (or AdvaMed) provides these comments in response to the Food and Drug Administration (FDA or Agency ) Revised Draft Guidance for Industry on Distributing Scientific and Medical Publications on Unapproved New Uses Recommended Practices. AdvaMed represents 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 treatment. Our members range from the largest to the smallest medical technology innovators and companies. More than 70 percent of our members have less than $30 million in domestic sales annually. GENERAL COMMENTS AdvaMed appreciates FDA s efforts to provide clarity regarding the dissemination of scientific and medical publications on unapproved new uses. We support additional FDA guidance to foster scientific exchange and recognize the public health value of truthful and non-misleading scientific and medical information, including clinical practice guidelines. While the principles are in many respects consistent with concepts set forth in the January 2009 guidance (or Good Reprint Practices Guidance), AdvaMed believes, however, that the draft guidance can and should be revised and clarified in several important respects outlined in our specific comments to more narrowly tailor the guidance in a manner that can support the timely exchange of scientific information without diminishing FDA s regulatory purpose of protecting the public health. As FDA considers approaches with respect to related issues, we note scientific exchange as particularly integral to medical devices. As medical device technology evolves in an iterative progression with continual, incremental improvements over time, new scientific information is particularly important as access to medical devices, versus other therapies, typically requires substantial interaction and discussion with highly trained health care professionals prior to determining whether a device is appropriate and for receipt of truthful, Bringing innovation to patient care worldwide

2 Page 2 of 10 non-misleading scientific information to benefit patient care, in many cases where there is currently no treatment for a patient s condition. These considerations reinforce the fundamental and appropriate role of scientific exchange with respect to medical devices. While not the subject of this guidance, we note that scientific exchange regarding investigational products should also be encouraged and fostered to ensure that the best input is derived from available medical and scientific expertise. Indeed, obtaining input about investigational findings can affect the continuation of an investigation and a device s design to best meet the needs of patients. This exchange therefore may be particularly significant to product development. The dissemination of truthful and non-misleading scientific and medical publications on unapproved new uses constitutes beneficial and long-recognized scientific exchange activities. We appreciate FDA s effort to update its existing guidance and concur that this information is of import to the overall public health. We hope that our comments are helpful and thank FDA for its efforts to develop additional guidance to facilitate understanding of its current thinking and assure full and appropriate scientific exchange of importance to the public health. If I can answer questions or be of further assistance to the Agency, please do not hesitate to contact me. Best Regards, /s/ Khatereh Calleja Vice President, Technology and Regulatory Affairs

3 Page 3 of 10 SPECIFIC COMMENTS With those general comments in mind, we provide the following comments on particular elements of the draft guidance. Proposed revisions are also noted along with a table of remaining questions and comments. I. Disclosure of Potential Conflicts and Biases The guidance states that a manufacturer should not distribute a scientific or medical journal (or reprint ) simply on the basis that it may be written, edited, excerpted, or published specifically for, or at the request of, a drug or device manufacturer. While we understand FDA s intent in this section to ensure the independence of the journal in which articles appear and AdvaMed supports that goal, we are concerned that this language sweeps too far. As currently drafted, this prohibition would exclude distribution of articles in peer-reviewed journals where manufacturer s employees worked with an investigator in a clinical trial, and contributed to the development of a manuscript about the results, and who should then receive an author s credit. This is not an uncommon occurrence in the world of clinical and academic research. This would not serve health care providers well, and we do not believe it was FDA s intent. We recommend that FDA modify the language to eliminate the restriction on authorship by manufacturer employees. Per the guidance, manufacturers are already required, and we strongly support, to disclose such financial relationships by authors and alert readers of potential bias while allowing them access to the relevant information and ability to evaluate articles for themselves. In that vein, major publications require study funding as part of an article and manufacturers are also required to disclose authors known to have financial interest or receiving compensation from the manufacturer. The broad concept and wording as drafted in the guidance would inappropriately stifle dissemination of a number of scientific and medical journals. Notably, a financial relationship with the manufacturer or in the product of the manufacturer and a publication s contributor does not render a publication false or misleading. Similarly, the guidance also states that a manufacturer should not distribute a scientific or medical journal article that may be edited or significantly influenced by any individual having a financial relationship with the manufacturer. As currently drafted, this prohibition is overly broad and would exclude distribution of articles in peer-reviewed journals authored by clinical investigators in company-sponsored or investigatorsponsored clinical trials since these clinicians or their institutions may receive funding to defray the costs of the clinical trials. If extrapolated too far, this language could preclude manufacturers from disseminating reprints in which the principle investigator of a pivotal investigational device exemption trial for an unapproved use was the author since the author would clearly significantly influence the article. Consistent with our previous comments, a financial relationship between a manufacturer and a publication s significant contributor does not render a publication false or misleading. FDA itself recognizes the appropriate role of robust and full disclosure and

4 Page 4 of 10 states that reprints must be accompanied by a disclosure of [a]ny author known to the manufacturer as having a financial interest in the manufacturer or in a product of the manufacturer that is included in the journal article, or who is receiving compensation from the manufacturer Revision is necessary as we do not believe it was the FDA s intent, nor is it appropriate to hinder the dissemination of publications with appropriately disclosed potential conflict or bias and scientific rigor and merit to healthcare professionals. Proposed Revision: As it currently reads, journal articles should not [b]e written, edited, excerpted, or published specifically for, or at the request of, a drug or device manufacturer. We ask that FDA add the following: This does not restrict distribution of reprints that otherwise meet the conditions of this guidance, where an employee of a drug or device manufacturer served as an author of the article, and that authorship is disclosed, along with the employee s relationship with the manufacturer. Alternatively, the section should be revised as follows: Reprints should not [b]e written, edited, excerpted, or published specifically for, or at the request of, a drug or device manufacturer. The following section should also be revised as follows: Reprints should not be edited or significantly influenced by a drug or device manufacturer or any individuals having a financial relationship with the manufacturer. II. Better Recognition/Consistency with Currently Required Disclosures AdvaMed recognizes the importance of disclosing financial interests, and supports the goal of these provisions in the guidance. At the same time, the draft guidance references disclosure requirements in the absence of recognition of existing requirements for manufacturers. FDA should work to better recognize existing disclosures rather than create a parallel set of obligations for manufacturers. Specifically, this includes the disclosures that will be contained in the reprints themselves, pursuant to worldwide standards for disclosure of conflict of interest or biases for all authors, contributors, and editors in particular the International Committee of Medical Journal Editors (ICMJE). The guidance appears to recognize in part the existence of these current disclosures with its reference to ICMJE s definition of author in footnote 28. The disclosure requirements will be contained in the reprints themselves. In addition, the need for a disclosure of the amount of a financial relationship has changed since the 2009 guidance was published. The Open Payments legislation (formerly referred to as the Sunshine Act) now requires drug and device manufacturers to disclose payments that they make to health care providers on a publicly available website. Thus, there is already a source of information on financial relationships based on a separate legal requirement. The draft guidance should strive for better recognition and leveraging of existing disclosures already contained in medical and scientific publications rather than imposing redundant requirements.

5 Page 5 of 10 Proposed Revision: We request that FDA rely on existing and relevant public and private standards rather than create another standard for manufacturers to meet. Specifically, the ICMJE standard for disclosure of financial relationships by authors, along with a process for authors to submit their information, is already in place and should be recognized by FDA when met as acceptable for purposes of disclosure requirements ( roles-and-responsibilities/authorresponsibilities--conflicts-of-interest.html). A link can also be provided in the cover letter to a manufacturers Open Payments page with an explanation that the reader may find a listing of any financial relationships with authors there. III. Settings for Scientific Exchange We support FDA s recommendation that scientific and medical information disseminated under the guidance should be distributed separately from information that is promotional in nature. We also agree that reprints may be distributed at medical or scientific conferences in settings appropriate for scientific exchange. We request clarification, however, about the reference that reprints should not be distributed in promotional exhibit halls. Exhibit halls often contain both promotional booths and booths intended for scientific exchange. Such a booth for scientific exchange might be a booth reserved for physicians to respond to attendees requests for medical information and such scientific exchange activities should not be arbitrarily barred by FDA. Proposed Revision: We recommend that promotional exhibit hall be replaced with promotional exhibit booth. Also we ask to add the following subsequent language: Companies may designate a medical affairs section of a promotional exhibit booth at a medical or scientific conference, staffed by personnel from medical affairs or similar groups and not by promotional personnel, where reprints may be distributed. IV. Clinical Practice Guidelines We appreciate FDA s effort to provide guidance regarding the dissemination of clinical practice guidelines (CPGs). We appreciate explicit recognition of these scientific exchange activities. While we support recognition of existing and relevant standards and appreciate the principles outlined in the Institute of Medicine (IOM) standards for CPG trustworthiness, we note these standards were not developed for manufacturers but for organizations that are developing CPGs. Furthermore, a number of its principles exceed what is generally recognized as necessary to discern trustworthiness. Yet, FDA has proposed to specifically integrate these standards into the guidance. Where a CPG is truthful and non-misleading, FDA should not impede its dissemination. For example, lines appear to go well beyond what is necessary to discern trustworthiness. We also note that CPGs are provided to healthcare professionals, who have knowledge and experience to consider the scientific merit of CPGs, particularly those that come from recognized and reputable organizations.

6 Page 6 of 10 Proposed Revision: FDA should develop its own guidance regarding the determination of truthful and nonmisleading CPGs rather than specific incorporation of the referenced IOM standards. FDA might consider similar principles to the more general concepts listed on lines (currently elements 1-3). Several remaining areas of questions and comments for clarification are included in the attached table.

7 Page 7 of 10 ADVAMED ADDITIONAL SPECIFIC COMMENTS AdvaMed Comments on Draft Revised Guidance for Industry Distributing Scientific and Medical Publications on Unapproved New Uses; Recommended Practices Comment Number Edit number Section Section of the guidance Change Proposed change to the guidance Comment/Rationale Reason for proposed change Line No. Guidance line number Comment Number Section Line No. Change Comment/Rationale 1. General General Clarify that responding to unsolicited requests for off-label information, while constituting scientific exchange, is not the topic of this guidance. 2. General General FDA should specify that the process of dissemination of journal articles, reference textbooks and CPGs can be done electronically (e.g., ) rather than solely by the now increasingly outdated process of handing out hard copy materials. 3. II 81 Revise as follows (delete stricken text and add text in underline): 4. Various Sections , 270, , , 443, , , Similarly a medical device that is intended the manufacturer intends for an unapproved use is considered adulterated and misbranded. Replace indications and indications for use with intended use. It should be clear that this guidance does not reflect all forms of scientific exchange. This guidance relates to affirmative distribution by manufacturers of truthful and non-misleading scientific and medical publications on unapproved new uses. Assuming that any applicable copyright requirements are met, a company should be able to these materials to a healthcare professional (HCP) under this guidance. The would need to contain the required statements from the guidance. Also, there could be a downloadable pdf of the reprint (or textbook or CPG) included in the or a link to it. If a HCP who purchases a device intends to use the device outside of the product s approved labeling, that intent does not make the device adulterated or misbranded under the Food, Drug and Cosmetic Act (FDCA). The FDCA allows HCPs to use products for an off-label use if the use is appropriate based on the HCP s judgment for the best interests of patients. We recommend clarifying that this statement refers to the manufacturer s intended use for the product. The term "indications" is used for medical devices -- the more appropriate term is "intended use". We want to be careful that these terms are not interchanged.

8 Page 8 of 10 Comment Number 5. III.A and III.B. 6. Section Line No. Change Comment/Rationale and III.A Clarify that on-label questions remain permissible and appropriate for response by sales representatives. Clarification regarding settings appropriate for scientific exchange. At present, the term questions is too broad. If an article distributed by a sales representative includes information on both on-label and off-label uses, we agree that any questions directed to the sales representative related to the off-label use should be referred to medical or scientific personnel. However, if the question pertains to an on-label use discussed in the article, the sales representative should be allowed to answer that on-label question in a manner consistent with the product labeling. We appreciate FDA s recognition of settings appropriate for scientific exchange. At the same time, we should take care not to create an artificial litmus test that imposes which forums are scientific exchange or promotion. We note, however, that scientific exchange typically occurs in forums such as medical and scientific meetings, conferences, or symposia, continuing and medical education (CME) programs. In particular, these forums are important as a means for scientists and physicians to exchange information and maintain currency with the medical and scientific literature. 7. III.A FDA should recognize that employees may be significant contributors to scientific and medical publications, such as published animal and bench studies. Care should be taken as not to sweep too broadly under the guidance. Consistent with our general comments that FDA not restrict appropriate distribution of reprints where authors may be employees of a manufacturer and are clearly disclosed, FDA should recognize that employees may be significant contributors to scientific and medical publications, such as published animal and bench studies. FDA recognizes that distribution of scientific and medical journal articles, involving well-designed bench or animal studies, may be within the scope of this guidance document.

9 Page 9 of 10 Comment Number Section Line No. Change Comment/Rationale 8. Various Clarify whether a specifications Sections sheet or other non-promotional product information may be attached. 9. III.B 288 Delete [a]ny person known to the manufacturer who has provided funding for the study. 10. III.A We request that FDA provide clarification regarding how manufacturers should determine what warnings of risk or safety to include in their affixed statement. Specifically, FDA should either delete this language, or provide clear guidance on how manufacturers should determine which warnings to include in their disclosures, or limit such disclosures to situations where the significant risks/safety concerns have been fully investigated and determined to be related to the use. 11. III.A Remove abstracts of a publication and explicitly recognize abstracts and conference posters as valid scientific publications. At present, it appears that the current proposed statement prohibits dissemination of articles with other nonpromotional product information (e.g., specifications sheet) other than the approved product labeling or product s cleared indications for use statement. It is not generally possible for a manufacturer to know what other entities have provided funding for a study. We are also not sure this standard is helpful for health care providers, who would not know if the absence of identification of other sources of funding means that there are no other sources, or just that a manufacturer is not aware of them. As previously noted, publications will already have standards requiring authors of articles to identify financial relationships and sources of funding. FDA should rely on those, and on manufacturers identifying their own financial support. Under the draft revised guidance, manufacturers are required to disclose all significant risks or safety concerns associated that are known to the manufacturers but not discussed in the article. It is not clear what would be sufficient to meet this disclosure requirement in terms of warning. Abstracts and conference posters (published in conference proceedings) can be valid scientific publications. This should be clearly articulated in the guidance.

10 Page 10 of 10 Comment Number Section Line No. Change Comment/Rationale 12. III.B FDA should clarify in criteria 1 that the portion regarding being generally available in bookstores or other independent distribution It would not be possible that an individual chapter of a textbook would be generally available in a bookstore or in another type of independent distribution channel. channels does not apply to an individual chapter of a textbook. 13. III.C Provide examples of CPGs (e.g., Society For Healthcare Epidemiology of America, Centers for Disease Control and Prevention, Clinical and Laboratory Standards Institute). The definition of CPGs could be aided by examples.