FDA is revising its guidance about the proper procedures for distributing journal articles about unapproved uses of approved drugs and medical devices to healthcare providers. The new draft document is not much different from the agency’s 2009 final guidance on good reprint practices, but includes new sections on how these practices apply to medical reference texts and clinical practice guidelines.

The agency announced the availability of the draft guidance, “Distributing Scientific and Medical Publications on Unapproved New Uses – Recommended Practices,” in a Federal Register notice slated for publication on March 3. FDA said it decided to revise the 2009 document in response to stakeholder questions about its application to scientific and medical reference texts and clinical practice guidelines.

FDA said that because reference texts are considerably longer than journal articles and generally address a wide range of topics, it believes it is appropriate to make specific and somewhat different recommendations for their distribution.

The draft guidance says that if a manufacturer distributes the text in its entirety, it should be based on a systematic review of the existing evidence; be published by an independent publisher who publishes scientific or medical education content for health care professionals and students and “is not substantially dependent on financial support from drug or medical device manufacturers;” be authored and edited by experts; be peer-reviewed by experts; and be sold through independent distribution channels, such as bookstores, subscription and the Internet.

Textbook Chapter Distribution Could Be Curtailed

In situations where the reference text is distributed in its entirety but one or more individual chapters focus on an individual product, FDA advises that it be disseminated with the approved labeling for that product. And if a manufacturer distributes an individual chapter it should include other chapters from the same text “when necessary to provide context.”

The guidance says reference text and individual chapters should not be primarily distributed by a drug or device manufacture but rather “should be generally available in bookstores or other independent distribution channels (e.g., subscription, Internet) where textbooks are sold.”

Richard Samp, chief counsel of the Washington Legal Foundation, said bookstores do not sell individual chapters and that drug companies do not distribute entire medical texts but instead buy individual chapters in bulk to disseminate to doctors. He said FDA appears to be saying that this practice will no longer be permitted.

Samp said FDA may have tightened the 2009 guidance somewhat in the new document and that WLF would have the same objections to it. He noted that the revised draft guidance states that journal articles distributed by manufacturers must “contain information that describes and addresses adequate and well-controlled clinical investigations.” He said this essentially means a double-blind, placebo-controlled study necessary for a drug to get approval.

“That kind of restriction can’t be squared with the First Amendment,” Samp stated. He added that it is “irresponsible” for FDA to revise its guidance without discussing the First Amendment or the U.S. Court of Appeals for the Second Circuit’s 2012 decision in United States v. Coronia.

In that case, the Second Circuit ruled that the government cannot prosecute manufacturers or their representatives for speech promoting the lawful, off-label use of an FDA-approved drug Also see "Off-Label Enforcement, Not Promotion, May See First Changes After Free Speech Ruling" - Pink Sheet, 10 December, 2012..

The guidance alludes to a suit WLF brought against the agency challenging its restrictions on dissemination of articles on off-label use. In that case, WLF v. Henney, a district court ruled that certain restrictions are unconstitutional. But in 2000, an appeals court found that legislation had made the case moot.

Meta-Analyses Downplayed In New Draft

The new draft guidance includes many of the same points as those in FDA’s 2009 final guidance, titled “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 U.S.” That guidance noted that well-controlled clinical investigations could include historically controlled studies, pharmacokinetic and pharmacodynamic studies, and meta-analyses if they are testing a specific clinical hypothesis Also see "Off-Label Reprint Guidance: “Definitely Improved,” But Will Waxman Fight On?" - Pink Sheet, 19 January, 2009..

The revised guidance does not mention pharmacokinetic and pharmacodynamic studies and only alludes to meta-analyses with respect to devices. It states: “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.”

Practice Guidelines Should Provide Quality Ratings

With regard to clinical practice guidelines (CPGs), FDA notes that CPGs include recommendations 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 been successful for the individual.

The draft guidance says that at a minimum a CPG discussing unapproved uses should be based on a systematic review of the existing evidence; be developed by a knowledgeable, multidisciplinary panel of experts and representatives from key affected groups; consider important patient subgroups and patient preferences; and be based on a publicly accessible process.

It also states that the CPG should “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.”

Reprints Of Letters To Editor Not Acceptable

The revised guidance is continuing to advise companies to distribute journal articles, reference texts and CPGs separately from information that is promotional in nature. It says the disseminated material should include a “prominently displayed and permanently affixed statement” identifying the distributing manufacturer and whether the authors have a financial interest in the manufacturer or its products. For texts, the guidance says the statement should be placed by sticker, stamp, or similar means, on the front cover of the textbook.

FDA also continues to recommend that manufacturers disseminate with the publication contrary or different conclusions regarding the unapproved use, when such information exists, especially when the conclusions of the material being disseminated have been called into question by another publication.

The revised guidance also notes types of journal reprints that would not be considered acceptable under the guidance: reprints of letters to the editor; abstracts of a publication; reports of healthy volunteer studies; and “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.”

Approximately 400 firms distribute scientific and medical publications that discuss unapproved new uses for FDA-approved products, according to an estimate in the Federal Register notice. These firms distribute an estimated total of about 40,000 scientific or medical journal articles annually, reference texts or CPGs, and it should take each firm about four hours per disclosure recommended in the draft guidance.

FDA also notes that it has not yet reached a final determination on two citizen petitions it received in July 2011 and September 2013 requesting revision of the agency’s policies and regulations on dissemination of information on off-label uses.

Both petitions were submitted by Ropes & Gray and Sidley Austin on behalf of several manufacturers. The second one was submitted on behalf of members of the Medical Information Working Group and the first was filed on behalf of a subset of that group, including Eli Lilly & Co., Johnson & Johnson, Novartis Pharmaceuticals Corp. and Pfizer Inc.

In between the filing of these petitions FDA issued a draft guidance on responding to unsolicited requests for off-label information Also see "Off-Label Use Discussions Should Stay Off-line, FDA Draft Guidance Says" - Pink Sheet, 2 January, 2012..

Comments on the new revised draft guidance are due 60 days from the date of publication in the Federal Register.

FDA Reprint Policy Expands To Clinical Practice Guidelines, Medical Reference Texts

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