It has long been recognized, even by FDA, that off-label uses of many drugs and devices may not only be medically acceptable, but in some instances medically obligatory under the standard of care. Many off-label uses have materially improved the quality of care provided to patients in the United States. Medical device and pharmaceutical manufacturers are restricted, however, from promoting their products for any intended use that FDA has not approved as safe and effective or cleared through a substantial equivalence determination. See Federal Food, Drug, and Cosmetic Act § 505(a), 502(o), 501(f)(1)(B), 301(a) and (d); 21 U.S.C. §§ 355, 352(o), 351(f)(1)(B), 331I(a) and (d). Despite this restriction, manufacturers are not prohibited from engaging in “scientific exchange” with physicians and prescribers. In recent years there has been significant uncertainty about the conditions under which certain types of scientific exchange can occur. The greatest amount of uncertainty has affected the dissemination of medical literature discussing off-label uses of a manufacturer’s products.
Historically, FDA’s policy prohibited manufacturers from proactively discussing off-label uses and distributing written materials that address off-label uses. Section 401 of the Food and Drug Administration Modernization Act of 1997, 21 U.S.C. § 360aaa, § 551, (“FDAMA”), set forth a procedure that allowed a drug or device manufacturer to disseminate medical and scientific information discussing unapproved uses of approved drugs and cleared or approved medical devices to healthcare professionals, pharmacy benefits managers, health insurance issuers, group health plans, and Federal or State governmental agencies. In a series of cases brought by the Washington Legal Foundation (“WLF”), the federal District Court for the District of Columbia struck down the requirements of FDAMA and the FDA’s implementing regulations as an unconstitutional restriction on commercial speech. In response, the FDA revised its position on FDAMA to be solely a “safe harbor” for dissemination of journal articles and reference publications. See 65 Fed. Reg. 14286 (March 16, 2000). Although the holdings in the WLF cases constrained the FDA in its use of FDAMA section 401 and certain previously existing guidance documents and regulations, the decisions left a void in guidance for manufacturers as to what types of scientific exchange with prescribers is permissible. Lending further uncertainty to the FDA’s position was the sunset of FDAMA Section 401 and its implementing regulations on September 30, 2006.
On February 15, 2008, FDA published draft Guidance for Industry entitled “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.” Like all such draft guidance, this one comes with a disclaimer stating that the document “does not create or confer any rights for or on any person and does not operate to bind FDA or the public.” Nevertheless, it does provide insights into the FDA’s current position on the topic.
The guidance discusses FDA’s views on two main topics: 1) the types of reprints it deems acceptable; and 2) the manner of dissemination.
Publications FDA Approves
The types of reprints of publications discussing off-label uses that FDA approves for distribution are 1) published by an entity with an expert independent editorial board whose members must and do disclose any potential conflicts of interest, 2) published in accordance with the publisher’s peer review procedures, and 3) not in the form of a special supplement funded in whole or in part by one or more of the manufacturers of the product discussed in the article. According to the draft Guidance, an article to be distributed should not be 1) primarily distributed by the manufacturer, 2) written, edited, excerpted, or published specifically for, or at the request of, the manufacturer, or 3) edited or significantly influenced by the manufacturer or those with financial relationships to it. Finally, the information should not 1) be false or misleading, or 2) pose a significant risk to public health. FDA objects to dissemination of letters to the editor, abstracts, reports of Phase 1 trials in healthy subjects, or reference publications containing little or no substantive discussion of relevant investigation or data.
Manner of Dissemination
The FDA Guidance states that the information distributed should 1) be in the form of an unabridged reprint or copy, 2) not be marked, highlighted, summarized, or characterized by the manufacturer, 3) be accompanied by the approved labeling, 4) be accompanied by a comprehensive bibliography, 5) be accompanied by a representative opposing article if the conclusion of the first article has been challenged elsewhere, and 6) be distributed separately from information promotional in nature. FDA also wants the reprint to be accompanied by a statement disclosing 1) that uses described in the publication have not been approved or cleared by FDA, 2) the manufacturer’s interest in the drug or medical device, 3) any author known to the manufacturer who has a financial interest in the product, 4) any person known to the manufacturer who has provided funding for the study, and 5) any significant risks or safety concerns known to the manufacturer concerning the unapproved use.
The FDA is actively soliciting comments and suggestions over the 60-day period ending April 22, 2008.