In January 2009, the U.S. Food and Drug Administration (FDA) issued guidance that was intended to provide drug and medical device manufacturers and their representatives with recommendations regarding the dissemination of scientific or medical information on unapproved uses to health care professionals and health care entities, without such activities being considered evidence of the manufacturer’s intent to promote the product for an off-label use. Since its publication, however, stakeholders raised questions regarding the extent to which the 2009 draft guidance applies to the distribution of clinical practice guidelines (CPGs) that include (or may include) information regarding off-label use of the manufacturer’s product(s). To address these issues, on February 28, 2014, FDA issued a revised draft guidance entitled "Distributing Scientific and Medical Publications on Unapproved New Uses – Recommended Practices."
In the draft guidance, FDA sets forth “recommended practices” specific to the dissemination of three types of scientific or medical publications—journal articles, reference texts and CPGs. In recognition of the different characteristics of each of these types of publications (e.g., length, scope of topics addressed), the draft guidance sets forth separate principles for each publication type. The draft guidance provides recommendations as to (1) characteristics that a publication should have, (2) characteristics that a publication must not have, (3) characteristics that a publication should not have and (4) the materials/disclosures that should accompany each type of publication. The following table provides a high-level overview of FDA’s guidance.
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Journal reprint |
Reference text |
Clinical practice guidelines |
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Publication should: |
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Be peer reviewed
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Be an unabridged copy or reprint
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Describe/address adequate and well-controlled clinical investigations
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Be disseminated with approved labeling
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Be disseminated with a comprehensive bibliography of publications about the use of the product (if such information exists)
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Be disseminated with a representative publication that reaches contrary or different conclusions (if such information exists)
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Be delivered separately from promotional information
The following types of reprints are not considered consistent with these recommended practices:
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Letters to the editor
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Abstracts
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Reports of healthy volunteer studies
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Publications consisting of statements and/or conclusions but little or no substantive discussion of the investigation on which they are based
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If distributed in its entirety:
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Be based on a systematic review of existing evidence
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Be published by an independent publisher that publishes educational content for health care professionals and students
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Be the most current version
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Be authored, edited and/or contributed to by experts with demonstrated expertise in the subject area
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Be peer-reviewed by experts with relevant expertise
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Be sold through usual and customary independent distribution channels
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Be delivered separately from promotional information
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Be distributed with approved labeling (if one or more individual chapters devote primary substantive discussion to manufacturer product(s))
If distributing individual chapters that include information on off-label use:
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Come from a text that follows the draft guidance’s recommendations for complete reference texts (except chapters should bear the prominently displayed and permanently affixed statement described below for use on individual chapters)
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Be unaltered/unabridged and extracted directly from the reference text in which it appears
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Be disseminated with other unaltered/unabridged chapters from the text (when necessary to provide context)
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Be disseminated with approved labeling
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All CPGs:
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Be based on a systematic review of existing evidence
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Be developed by a knowledgeable, multidisciplinary panel of experts and representatives from key affected groups
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Consider important patient subgroups and patient preferences
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Be based on an explicit and transparent (publicly accessible) process by which the CPG is developed and funded that minimizes distortions, biases and conflicts of interest
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Provide a clear explanation of the logical relationships between alternative care options and health outcomes
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Provide clearly articulated recommendations in standardized form
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Provide ratings of quality of evidence and strength of recommendations
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Be reconsidered when important new evidence warrants modification of recommendations
If distributing guidelines in their entirety:
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Be the most current version of the CPG
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Be delivered separately from promotional information
If distributing guidelines in their entirety, but one or more sections contain primary substantive discussion of the manufacturer’s product(s):
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Be distributed with approved labeling
If distributing individual sections that include information on off-label use:
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Come from a CPG that follows the draft guidance’s recommendations (except chapters should bear the prominently displayed and permanently affixed statement described below for use on individual sections)
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Be unaltered/unabridged and extracted directly from the CPG in which it appears
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Be disseminated with other unaltered/unabridged sections from the CPG (when necessary to provide context)
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Be disseminated with approved labeling
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Publication must not: |
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Be false or misleading
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Contain information recommending or suggesting use that makes the product dangerous to health when used in manner suggested
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Be false or misleading
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Contain information recommending or suggesting use that makes the product dangerous to health when used in manner suggested
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Be false or misleading
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Contain information recommending or suggesting use that makes the product dangerous to health when used in manner suggested
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Publication should not: |
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Be a special supplement or publication funded (in whole or in part) by the manufacturer
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Be marked, highlighted, summarized or characterized by the manufacturer (in writing or orally) to emphasize or promote an off-label use
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Be primarily distributed by the manufacturer
Be written, edited, excerpted or published specifically for (or at the request of) the manufacturer
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Be edited or significantly influenced by a manufacturer or individuals with a financial relationship with the manufacturer
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Be attached to specific product information (other than approved labeling)
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Be primarily distributed by the manufacturer
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Be edited or significantly influenced by a manufacturer or individuals with a financial relationship with the manufacturer
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Be marked, highlighted, summarized or characterized by the manufacturer (in writing or orally) to emphasize or promote an off-label use
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Be written or published specifically at the manufacturer’s request
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Be abridged or excerpted in any particular manner
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Be attached to specific product information (other than approved labeling)
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Be primarily distributed by the manufacturer
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Be edited or significantly influenced by a manufacturer or individuals with a financial relationship with the manufacturer
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Be marked, highlighted, summarized or characterized by the manufacturer (in writing or orally) to emphasize or promote an off-label use
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Be written or published specifically at the manufacturer’s request
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Be abridged or excerpted in any particular manner
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Be attached to specific product information (other than approved labeling)
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Publication should be accompanied by prominently displayed and permanently affixed statement disclosing: |
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Products referenced in the reprint in which the manufacturer has an interest
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That some or all uses of the manufacturer’s product described in the information are off-label
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Any author known to the manufacturer as having a financial relationship with the manufacturer (and the nature of such relationship)
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Any person known to the manufacturer who funded the study
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All significant risks or safety concerns associated with the unapproved use that are known to the manufacturer but not discussed in the article
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If distributed in its entirety:
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The distributing manufacturer
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That some of the uses described in the text might not be approved/cleared by FDA
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That the author(s) of some chapters may have a financial relationship with the manufacturer or its products, unless the manufacturer has verified that none of the authors has such relationship
This statement should be placed by sticker, stamp or other similar means on the front cover of the textbook.
If distributing individual chapters that include information on off-label use:
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The distributing manufacturer
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The product(s) addressed in which the manufacturer has an interest
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That some or all uses of the manufacturer’s product described in the information are off-label
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Any author known to the manufacturer as having a financial relationship with the manufacturer (and the nature of such relationship)
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All significant risks or safety concerns associated with the unapproved use that are known to the manufacturer but not discussed in the chapter(s)
This statement should be placed by sticker, stamp or other similar means on the front page of each chapter.
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If distributed in its entirety:
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The distributing manufacturer
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That some of the uses described in the text might not be approved/cleared by FDA
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That the author(s) of some sections may have a financial relationship with the manufacturer or its products, unless the manufacturer has verified that none of the authors has such relationship
This statement should be placed by sticker, stamp or other similar means on the front cover of the CPG.
If distributing individual sections that include information on off-label use:
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The distributing manufacturer
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The product(s) addressed in which the manufacturer has an interest
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That some or all uses of the manufacturer’s product(s) described in the information are off-label
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Any author known to the manufacturer as having a financial relationship with the manufacturer (and the nature of such relationship)
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All significant risks or safety concerns associated with the unapproved use that are known to the manufacturer but not discussed in the section(s)
This statement should be placed by sticker, stamp or other similar means on the front page of each section.
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If manufacturers distribute scientific or medical publications as recommended in the draft guidance, FDA does not intend to use such distribution as evidence of the manufacturer’s intent that the product be used off-label.
FDA recommends that comments regarding the draft guidance be submitted by May 2, 2014 (to ensure consideration before the agency begins preparing the final guidance).
Implications
With the exception of a few relatively minor clarifications, the principles set forth in the draft guidance are consistent with the principles set forth in the January 2009 guidance. Nevertheless, the draft guidance is important in that it (1) reaffirms the fundamental position FDA took in 2009 relative to the distribution of these types of materials; (2) adds guidance from the agency regarding the dissemination of CPGs; and (3) sets forth separate tailored recommendations for journal reprints, reference texts and CPGs, respectively, based on the unique characteristics of each type of publication. Importantly, the guidance reaffirms the need for care in ensuring a separation between promotional activities and the dissemination of these types of materials. Manufacturers should take this opportunity to review (and revise, as appropriate) their standard operating procedures regarding the dissemination of off-label information to ensure compliance with the draft guidance, assess the need to refresh the training program for sales and marketing personnel, and consider submitting comments to FDA.
