FDA Draft Guidance: Distributing Scientific and Medical Publications on Unapproved New Uses — Recommended Practices
A new draft guidance document released by the U.S. Food and Drug Administration (FDA) aims to clarify the ways in which a pharmaceutical or medical device manufacturer may use scientific and medical literature to promote its products, even if the literature doesn’t conform to the product’s FDA-approved uses. FDA’s guidance forms a checklist of sorts that companies will need to check against each instance of literature they wish to promote.
FDA’s new draft guidance document, Distributing Scientific and Medical Publications on Unapproved New Uses — Recommended Practices, is meant to provide life science companies with a checklist for making sure they stay within the acceptable limits of promotion of scientific and medical publications. The guidance is a revision of a 2009 draft guidance, Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices. As noted by Regulatory Focus, that guidance came under fire from life science companies, which argued that it restricted their ability to “promote the public health” by distributing scientific information informing the safe and effective use of their products.
In an accompanying statement, the FDA stated that it’s currently working on additional guidance on scientific exchange, responding to unsolicited requests for off label information, and interactions with formulary committees.
This draft guidance shows that the agency is getting the message that it must conform its policies and practices to the First Amendment,” said Coalition for Healthcare Communication Executive Director John Kamp in a released statement. “Manufacturers should be able to distribute truthful information – in the form of journal articles, medical textbooks and practice guidelines.”
In an Industry Leaders Alert, Kamp also stated: “These actions, combined with recent guidance on social media and a new study on the effectiveness of current warnings on TV commercials, suggest that the FDA is serious on updating critical marketing policies, perhaps in recognition of the First Amendment challenges it faces is defending current policy.”
“While these are small steps forward, they are significant nonetheless and will enable more reasonable communication between regulated companies and medical professionals, leading to more efficient and effective patient care. The new draft guidance also supports our case with CMS that journal reprints and reference textbooks should be exempt from reporting under the Sunshine Act.”
Public Comment
The Draft Guidance is open for public comment for 60 days, until May 2, 2014. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.
I. INTRODUCTION AND BACKGROUND
In 1997, Congress passed the Food and Drug Administration Modernization Act (FDAMA). Section 401 of FDAMAdescribed certain conditions under which a drug or medical device manufacturer could choose to disseminate medical and scientific information that discusses unapproved uses of approved drugs and cleared or approved medical devices to “health care professionals and certain entities, including pharmacy benefits managers, health insurance issuers, group health plans, and Federal or State governmental agencies,” without such dissemination being considered as evidence of the manufacturer’s intent that the product be used for an unapproved new use. Among those conditions was the expectation that the manufacturer of the product would seek FDA approval for the unapproved new use referenced in the disseminated literature. With this condition, Congress again recognized the important public health value of FDA premarket review and approval.
FDA’s 2009 guidance was intended to provide drug and medical device manufacturers and their representatives with recommendations on distributing scientific or medical information on unapproved uses to health care professionals and health care entities, without such dissemination being considered as evidence of the manufacturer’s intent that the product be used for an unapproved new use.
The 2009 guidance, consistent with the objectives of section 401 of FDAMA (which was no longer law), recognized that the public health may benefit when health care professionals receive truthful and non-misleading scientific or medical publications on unapproved new uses.This information can be particularly important given that a health care professional can generally choose to use or prescribe an approved or cleared medical product for an unapproved use, if the off-label use is appropriate based on his or her judgment. The narrow “safe harbor” recommended in the guidance was also consistent with FDA’s continued belief that FDA premarket review and approval are critical to public health.
FDA is revising its 2009 guidance on good reprint practices in response to stakeholder questions about its application to scientific and medical reference texts and CPGs that include or may includeinformation on unapproved uses. This draft guidance provides recommendations for scientific journal articles, scientific or medical reference texts, and CPGs in separate sections, tailored to each type of publication. Consistent with longstanding FDA policy and practice, if manufacturers distribute scientific or medical publications as recommended in this guidance, FDA does not intend to use such distribution as evidence of the manufacturer’s intent that the product be used for an unapproved new use.
Although this draft guidance, like the 2009 guidance, recognizes the value to health care professionals of truthful and non-misleading scientific or medical publications on unapproved new uses, it also continues to recognize that this information is in no way a substitute for the FDA premarket review process, which allows FDA to be proactive, rather than reactive, in protecting the public from unsafe or ineffective medical products. FDA is issuing this revised draft guidance to enable the public to provide comments on the proposed approach.
II. RECOMMENDED PRACTICES
Often scientific and medical information concerning the safety or effectiveness of a medical product’s unapproved new use may be published in scientific or medical journal articles, scientific or medical reference texts, and/or in CPGs. These publications are available from their publishers or other distribution channels, but have also been commonly distributed by manufacturers to health care professionals and health care entities.
Sections A, B, and C, below, provide specific guidance for scientific and medical journal articles, scientific and medical reference texts, and CPGs, respectively. FDA recommends that manufacturers employ the following practices if they choose to disseminate scientific and medical publications that include or may include information on unapproved new uses of approved, cleared, or 510(k) exempt products.
A. Scientific or Medical Journal Articles
If a manufacturer who chooses to distribute scientific or medical journal articles that include information on unapproved/uncleared uses of its product(s) does so in accordance with the recommendations of this guidance, FDA does not intend to use that distribution as evidence of the manufacturer’s intent that the product(s) be used for an unapproved new use.
A scientific or medical journal article that includes information on unapproved uses and is distributed by manufacturers should first have been published by an organization that has an editorial board that uses experts who have demonstrated expertise in the subject of the article under review by the organization. Experts should be independent of the organization and should review and objectively select, reject, or provide comments about proposed articles. Also, the organization should adhere to a publicly stated policy of full disclosure of any conflict of interest or biases for all authors, contributors, or editors associated with the journal or organization.
Additionally, the scientific or medical journal article distributed by a manufacturer should:
1. Be peer-reviewed and published in accordance with the peer-review procedures of the organization.
2. Be in the form of an unabridged reprint or copy of an article.
3. Contain information that describes and addresses adequate and well-controlled clinical investigations that are considered scientifically sound by experts with scientific training and experience to evaluate the safety or effectiveness of the drug or device. In the case of devices, significant investigations other than adequate and well-controlled studies, such as meta-analyses, if they are testing a specific clinical hypothesis, and journal articles discussing significant non-clinical research (such as well-designed bench or animal studies) may be consistent with this guidance.
4. Be disseminated with the approved labeling or, in the case of a medical device reviewed under section 510(k) of the FD&C Act (21 U.S.C. 360(k)), labeling for the indications in the product’s cleared indications for use statement, for each of the manufacturer’s products that is included in the distributed article.
5. Be disseminated with a comprehensive bibliography, when such information exists, of publications discussing adequate and well-controlled clinical studies published in scientific journals, medical journals, or scientific texts about the use of the drug or medical device covered by the information disseminated (unless the information already includes such a bibliography).
6. Be disseminated with a representative publication, when such information exists, that reaches contrary or different conclusions regarding the unapproved use—especially when the conclusions of articles to be disseminated have been specifically called into question by another publication.
7. Be distributed separately from the delivery of information that is promotional in nature. Similarly, while reprints may be distributed at medical or scientific conferences in settings appropriate for scientific exchange, reprints should not be distributed in promotional exhibit halls or during promotional speakers’ programs.
A scientific or medical journal article that explains a use of a manufacturer’s product and is distributed by, or on behalf of, that manufacturer must not:
1. Be false or misleading. characterized as definitive or representative of the weight of credible evidence derived from adequate and well-controlled clinical investigations if it is inconsistent with the weight of credible evidence or if a significant number of other studies contradict the conclusions set forth in the article; should not have been withdrawn by the journal or disclaimed by the author; and should not discuss a clinical investigation that FDA has previously informed the company is not adequate and well-controlled.
2. Contain information recommending or suggesting use of the product that makes the product dangerous to health when used in the manner suggested.
To be consistent with the recommended practices described in this guidance, a scientific or medical journal article regarding an unapproved use that is distributed by a manufacturer should not:
1. Be in the form of a special supplement or publication that has been funded, in whole or in part, by one or more of the manufacturers of the product that is the subject of the article.
2. Be marked, highlighted, summarized, or characterized by the manufacturer, in writing or orally, to emphasize or promote an unapproved use. (This recommendation does not preclude providing the disclosures discussed elsewhere in this guidance.)
3. Be primarily distributed by a drug or device manufacturer; rather, it should be generally available in bookstores or other independent distribution channels (e.g., subscription, Internet) where periodicals are sold.
4. Be written, edited, excerpted, or published specifically for, or at the request of, a drug or device manufacturer.
5. Be edited or significantly influenced by a drug or device manufacturer or any individuals having a financial relationship with the manufacturer.
6. Be attached to specific product information (other than the approved product labeling or the product’s cleared indications for use statement).
The scientific or medical journal reprint should be accompanied by a prominently displayed and permanently affixed statement disclosing:
1. The drug(s) or device(s) included in the journal reprint in which the manufacturer has an interest
2. That some or all uses of the manufacturer’s drugs or devices described in the information have not been approved or cleared by FDA, as applicable to the described drug(s) or device(s).
3. Any 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, along with the affiliation of the author, to the extent known by the manufacturer, and the nature and amount of any such financial interest of the author or compensation received by the author from the manufacturer.
4. Any person known to the manufacturer who has provided funding for the study.
5. All significant risks or safety concerns associated with the unapproved use(s) of the manufacturer’s product(s) discussed in the journal article that are known to the manufacturer but not discussed in the article.
The following types of journal reprints are examples that would not be considered consistent with the recommended practices outlined in this guidance:
- Letters to the editor
- Abstracts of a publication
- Reports of healthy volunteer studies
- Publications consisting of statements or conclusions but which contain little or no substantive discussion of the relevant investigation or data on which they are based
B. Scientific or Medical Reference Texts
Scientific or medical reference texts diagnosis, pathophysiology and treatments, pharmacology, surgical techniques, and other scientific or medical information). Like journal articles, scientific or medical reference texts often contain information about unapproved use(s) of drugs and devices. However, because these reference texts are considerably longer than journal articles, and generally address a wide range of topics, FDA believes that it is appropriate to make specific recommendations for distribution of reference texts that differ somewhat from the recommendations for journal articles. If a manufacturer who chooses to distribute reference texts that include information on unapproved/uncleared uses of its product(s) does so in accordance with the recommendations of this guidance, FDA does not intend to use that distribution as evidence of the manufacturer’s intent that the product(s) be used for an unapproved new use.
A scientific or medical reference text that is distributed in its entirety by a manufacturer should:
1. Be based on a systematic review of the existing evidence.
2. Be published (in print or electronic format) by an independent publisher, not substantially dependent on financial support from drug or medical device manufacturers, who publishes scientific or medical educational content for health care professionals and students.
3. Be the most current version.
4. Be authored, edited, and/or contributed to by experts who have demonstrated expertise in the subject area.
5. Be peer-reviewed by experts with relevant medical or scientific expertise and published in accordance with the scientific or medical reference text peer-review procedures of the publisher, which should be easily accessible or available upon request.
6. Be sold through usual and customary independent distribution channels (e.g., booksellers, subscription, Internet) for medical and scientific educational content directed at health care professionals and students.
7. Be distributed separately from the delivery of information that is promotional in nature. Similarly, while scientific or medical reference texts may be distributed at medical or scientific conferences in settings appropriate for scientific exchange, they should not be distributed in promotional exhibit halls or during promotional speakers’ programs.
8. Contain a prominently displayed and permanently affixed statement identifying the distributing manufacturer and disclosing that some of the uses for drugs and/or devices described in the reference text might not be approved or cleared by FDA. The statement should also disclose that the author(s) of some chapters also might have a financial interest in the manufacturer or its products, unless the manufacturer has verified that none of the authors for the reference text has a financial interest in the manufacturer or a product being written about. This statement should be placed by sticker, stamp, or other similar means on the front cover of the textbook.
9. In situations where a reference text is distributed in its entirety but one or more individual chapters of that reference text devote primary substantive discussion to an individual product or products of the manufacturer distributing it, be disseminated with the approved product labeling for each such product or, in the case of a medical device reviewed under section 510(k) of the FD&C Act (21 U.S.C. 360(k)), labeling for the indications in the product’s cleared indications for use statement.
If, in lieu of an entire scientific or medical reference text, a manufacturer distributes an individual chapter(s) that includes information on unapproved/uncleared uses of the manufacturer’s product(s), the chapter(s) should:
1. Come from a scientific or medical reference text that follows the recommendations for complete scientific or medical reference texts in this guidance, except that the individual chapter(s) should bear the prominently displayed and permanently affixed statement described below for use on individual chapters, rather than the recommended statement for texts distributed in their entirety.
2. Be unaltered/unabridged and extracted directly from the scientific or medical reference text in which it appears.
3. When necessary to provide context, be disseminated with other unaltered/unabridged chapters extracted directly from the same scientific or medical reference text, such as chapters which provide related or supportive information.
4. Contain a prominently displayed and permanently affixed statement identifying the distributing manufacturer and disclosing:
(a) The drug(s) or device(s) addressed in the individual chapter(s) in which the manufacturer has an interest;
(b) That some or all uses of the manufacturer’s drugs and/or devices described in the attached information have not been approved or cleared by FDA, as applicable to the described drug(s) or medical device(s);
(c) Any 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 individual chapter(s), or who is receiving compensation from the manufacturer, along with the affiliation of the author, to the extent known by the manufacturer, and the nature and amount of any such financial interest of the author or compensation received by the author from the manufacturer;
(d) All significant risks or safety concerns associated with the unapproved use(s) of the manufacturer’s products discussed in the individual chapter(s) 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.
5. Be disseminated with the approved labeling, or, in the case of a medical device reviewed under section 510(k) of the FD&C Act (21 U.S.C. 360(k)), labeling for the indications in the cleared indications for use statement, for each of the manufacturer’s products that is included in the distributed chapter(s).
A scientific or medical reference text, or an individual chapter, that explains a use of a manufacturer’s product and is distributed by, or on behalf of, that manufacturer must not:
1. Be false or misleading.
2. Contain information recommending or suggesting use of the product in ways that make the product dangerous to health when used in the manner suggested therein.
To be consistent with the recommended practices described in this guidance, a scientific or medical reference text, or an individual chapter, that is distributed should not:
1. Be primarily distributed by a drug or device manufacturer; rather, it should be generally available in bookstores or other independent distribution channels (e.g., subscription, Internet) where textbooks are sold.
2. Be edited or significantly influenced by a drug or device manufacturer or any individuals having a financial relationship with the manufacturer.
3. Be marked, highlighted, summarized, or characterized by the manufacturer, in writing or orally, to emphasize or promote an unapproved use. (This recommendation does not preclude providing the disclosures discussed elsewhere in this guidance.)
4. Be written or published specifically at the request of a drug or device manufacturer.
5. Be abridged or excerpted in any particular manner
6. Be attached to specific product information (other than the approved product labeling or the product’s cleared indications for use statement).
C. Clinical Practice Guidelines
CPGs are statements that include recommendations intended to help clinicians make decisions for individual patient care, including in circumstances where there are few or no approved drugs or devices indicated for the patient’s condition or the approved therapies have not proven successful for the individual. A CPG may be much longer and often covers a wider range of topics than a journal article. FDA believes that it is appropriate to make specific recommendations for manufacturer distribution of CPGs that include information on unapproved new uses of that manufacturer’s approved or cleared products that differ somewhat from the recommendations for journal articles. These recommendations are set forth below, along with additional recommendations that incorporate the Institute of Medicine’s (IOM’s) standards for CPG “trustworthiness.” These “trustworthiness” standards, among other things, ensure that CPGs are informed by a systematic review of evidence and an assessment of the benefits and 458 harms of alternative care options.
If a manufacturer who chooses to distribute CPGs that include information on unapproved/uncleared uses of its product(s) does so in accordance with the recommendations of this guidance, FDA does not intend to use that distribution as evidence of the manufacturer’s intent that the product(s) be used for an unapproved new use.
Drug and medical device manufacturers wishing to disseminate CPGs that discuss unapproved or uncleared new uses of products that they market should disseminate only those guidelines that are “trustworthy,” as described below. In keeping with the IOM standards, to be considered “trustworthy,” a CPG should at minimum:
1. Be based on a systematic review of the existing evidence.
2. Be developed by a knowledgeable, multidisciplinary panel of experts and representatives from key affected groups.
3. Consider important patient subgroups and patient preferences.
4. 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.
5. Provide a clear explanation of the logical relationships between alternative care options and health outcomes, provide clearly articulated recommendations in standardized form, and provide ratings of both quality of evidence and the strength of recommendations.
6. Be reconsidered and revised when important new evidence warrants modifications of recommendations.
Manufacturers wishing to distribute a “trustworthy” CPG in its entirety should:
1. Ensure that the most current version of the CPG is disseminated.
2. Distribute the CPG separately from the delivery of information that is promotional in nature. Similarly, while a CPG may be distributed at medical or scientific conferences in settings appropriate for scientific exchange, the CPG should not be distributed in promotional exhibit halls or during promotional speakers’ programs.
3. Ensure that the CPG contains a prominently displayed and permanently affixed statement identifying the distributing manufacturer and disclosing that some of the uses of drugs and/or devices described in the CPG might not be approved or cleared by FDA. The statement should also disclose that the author(s) of some sections might have a financial interest in the manufacturer or its products, unless the manufacturer has verified that none of the authors for the CPG has a financial interest in the manufacturer or a product being written about. This statement should be placed by sticker, stamp, or other similar means on the front page of the CPG.
4. In situations where a CPG is distributed in its entirety but one or more individual sections of that CPG devotes primary substantive discussion to an individual product or products of the manufacturer distributing it, be disseminated with the approved product labeling for each such product or, in the case of a medical device reviewed under section 510(k) of the FD&C Act (21 U.S.C. 360(k)), labeling for the indications in the product’s cleared indications for use statement.
If, in lieu of an entire CPG, a manufacturer distributes an individual section(s) that includes information on unapproved/uncleared uses of the manufacturer’s product(s), the section(s) should:
1. Come from a CPG that satisfies the recommendations set forth in this guidance, including the standards for “trustworthiness,” except that the section should bear the prominently displayed and permanently affixed statement described below for use on individual sections, rather than the recommended statement for CPGs distributed in their entirety.
2. Be unaltered/unabridged and extracted directly from the CPG in which it appears.
3. When necessary to provide context, be disseminated with other unaltered/unabridged sections extracted directly from the same CPG, such as sections which provide related or supportive information.
4. Contain a prominently displayed and permanently affixed statement identifying the distributing manufacturer and disclosing:
(a) The drug(s) or device(s) addressed in the individual section(s) in which the manufacturer has an interest;
(b) That some or all uses of the manufacturer’s drugs and/or devices described in the attached information have not been approved or cleared by FDA, as applicable to the described drug(s) or medical device(s);
(c) Any 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 individual section(s), or who is receiving compensation from the manufacturer, along with the affiliation of the author, to the extent known by the manufacturer, and the nature and amount of any such financial interest of the author or compensation received by the author from the manufacturer;
(d) All significant risks or safety concerns associated with the unapproved use(s) of the manufacturer’s products discussed in the individual section(s) 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.
5. Be disseminated with the approved labeling, or, in the case of a medical device reviewed under section 510(k) of the FD&C Act (21 U.S.C. 360(k)), labeling for the indications in the cleared indications for use statement, for each of the manufacturer’s products that is included in the distributed section(s).
A CPG or individual section(s) of a CPG that explains a use of a manufacturer’s product and is distributed by, or on behalf of, that manufacturer must not:
1. Be false or misleading.
2. Contain information recommending or suggesting use of the product in ways that make the product dangerous to health when used in the manner suggested therein.
To be consistent with the recommended practices described in this guidance, a CPG or individual section of a CPG that discusses unapproved new uses of a manufacturer’s product should not:
1. Be primarily distributed by a drug or device manufacturer, but should be generally available through other independent distribution channels (e.g., subscription, Internet).
2. Be edited or significantly influenced by a drug or device manufacturer or any individuals having a financial relationship with the manufacturer.
3. Be marked, highlighted, summarized, or characterized by the manufacturer in writing or orally, to emphasize or promote an unapproved use. (This recommendation does not preclude providing the disclosures discussed elsewhere in this guidance.)
4. Be written or published specifically at the request of a drug or device manufacturer.
5. Be abridged or excerpted in any particular manner.
6. Be attached to specific product information (other than the approved product labeling or the product’s cleared indications for use statement).