On January 13, 2009, the Food and Drug Administration (FDA) issued a notice in the Federal Register regarding the availability of its guidance for industry on the distribution of medical journal articles and scientific publications regarding unapproved new uses (also known as off-label uses) of approved drugs. The guidance seemingly creates a safe harbor for dissemination of information on off-label uses of FDA-approved drugs. The FDA's guidance contains provisions similar to, and potentially more expansive than, the provisions on dissemination of information on off-label uses in § 401 of the FDA Modernization Act of 1997 (FDAMA), which expired in 2006. No similar provision was included in the most recent piece of major FDA legislation, the FDA Amendments Act of 2007 (FDAAA). First, this report outlines the relevant provisions of the Federal Food, Drug, and Cosmetic Act (FFDCA) and related regulations that have been used to address misbranding violations of the act that relate to pharmaceutical manufacturers' promotion of off-label use. Second, the report summarizes the FDA's previous off-label marketing provisions under FDAMA § 401, which are no longer in effect. Third, the report details the January 2009 guidance document and its similarities to and differences from the FDAMA provisions. Fourth, the report outlines First Amendment challenges to FDAMA and older FDA guidance documents addressing off-label promotion. Fifth, the report discusses the nature of guidance documents, in contrast to rules promulgated under the Administrative Procedure Act (APA), as well as administrative law issues associated with the FDA's issuance of the guidance. Sixth, the report provides an overview of the False Claims Act (FCA) and related qui tam cases that addressed off-label marketing practices of pharmaceutical companies. Finally, the report analyzes the interaction of the new guidance document and the FCA. Until the FDA has approved a new drug pursuant to either a new drug application, an abbreviated new drug application, or an investigational new drug submission, the new drug may not be "introduc[ed] or deliver[ed] for introduction into interstate commerce." When a person submits a new drug application to the FDA for approval, the application includes samples of the proposed labeling for the drug. The FDA may refuse to approve a new drug application if the HHS Secretary finds, among other possibilities, that it is not safe or effective "for use under the conditions prescribed, recommended, or suggested in the proposed labeling." In other words, the FDA approves drugs for specific uses that are reflected in their labeling. An unapproved use of a drug, also known as an off-label use, has been defined as a "use for indication, dosage form, dose regimen, population [i.e., the drug is approved for adults but not children] or other use parameter not mentioned in the approved labeling." While a physician may prescribe a drug for off-label uses, a pharmaceutical manufacturer may not market or promote a drug for uses other than those on the label—those uses approved by the FDA in a drug application. Off-label uses have been estimated to account for 21% of all prescription drug use. Manufacturer marketing and promotion of off-label uses is linked to the FFDCA's prohibition against misbranding. The concept of misbranding is one of the basic components of the FFDCA, and persons who violate the act's prohibitions are subject to criminal and civil penalties, as well as injunctions and seizures of the misbranded product. A drug or device shall be deemed to be misbranded if, among other possibilities, the labeling is false or misleading or if its labeling does not bear "adequate directions for use." The phrase "adequate directions for use" means "directions under which the layman can use a drug safely and for the purposes for which it is intended." An "intended use," in turn, "refer[s] to the objective intent of the persons legally responsible for the labeling of drugs," such as the drug's manufacturer, and that person's objective intent may be shown by "labeling claims, advertising matter, or oral or written statements by such persons or their representatives." Intended use may also "be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised." Manufacturers are "required to provide adequate labeling for" off-label uses of a drug that the "manufacturer knows, or has knowledge of facts that would give him notice that [the] drug ... is to be used for conditions, purposes, or uses other than the ones for which he offers it." It appears then that, if a drug manufacturer promotes an intended use that is an off-label use, the drug's label will not bear adequate directions for use and will thus be a misbranded drug. A drug manufacturer would therefore be required to submit a supplemental new drug application for that off-label use and accompanying label or dosage changes. The FFDCA defines labeling as "all labels and other written, printed or graphic matters (1) upon any article or any of its containers or wrappers, or (2) accompanying such article." Labeling includes brochures, motion picture films, and literature, as well as reprints and similar pieces of printed, audio, or visual matter descriptive of a drug and references published (for example, the 'Physician's Desk Reference') for use by medical practitioners, pharmacists, or nurses, containing drug information supplied by the manufacturer, packer, or distributor of the drug and which are disseminated by or on behalf of its manufacturer, packer, or distributor. It appears that a reprint of an article published in a medical journal that is presented to a doctor by a pharmaceutical representative could fall within the FFDCA's labeling provisions and accompanying regulations. Before Congress passed the Food and Drug Administration Modernization Act (FDAMA) in 1997, the FDA had issued several guidance documents regarding off-label promotion in 1996 regarding the industry's dissemination of reprints and reference texts. FDAMA § 401 superceded those guidance documents and generally enabled manufacturers to disseminate information about new, or off-label, uses under specified conditions, but only if the manufacturer submitted a supplemental new drug application for the off-label use. FDAMA § 401 expired on September 30, 2006. Other than the FDA's 2009 guidance document, it does not appear that the FDA currently has another statute, rule, or policy in effect that explicitly addresses the dissemination of reprints or reference texts with regard to promoting an off-label use. This section details the FDAMA provisions, which are similar, in parts, to those in the recent FDA guidance and which provide a basis for understanding current discussions of the FDA's January 2009 guidance. As emphasized in a Federal Register notice post-FDAMA, § 401 created a safe harbor. As long as information dissemination on off-label uses adhered to FDAMA, it was not to be construed as evidence of a new intended use of a drug that differed from the intended use described in its official labeling. Nor was it to be considered labeling, adulteration, or misbranding under the FFDCA. To disseminate information, the manufacturer was required to submit to the Secretary a copy of the information 60 days before distribution, including clinical trials and clinical experience about the safety and effectiveness of the unapproved use, and to comply with the requirements for filing a supplemental new drug application. Manufacturers were required to include a prominent statement showing the following, if applicable: that the information concerned an unapproved use of a drug; that the disseminated information was being paid for by the manufacturer; the names of any authors with financial ties with the manufacturer; the official labeling for the drug; a statement that there were other approved products or treatments for the use for which the information was being disseminated; and the identification of all persons who funded any study about the off-label new use. Manufacturers were also required to include a bibliography of published articles about the unapproved use from scientific or medical journals. If the Secretary determined, after providing notice and an opportunity for a meeting, that the off-label use information failed to provide objective and balanced information, the Secretary could have required the dissemination of additional information, along with a statement of the Secretary about the safety and effectiveness of the drug's unapproved use. Manufacturers were allowed to disseminate information about an unapproved new use only if the information was in the form of an unabridged reprint or copy of an article peer reviewed by experts. The unabridged article was required to originate from a medical journal or a reference publication, describe a scientifically sound clinical investigation, and not be false or misleading. In addition, to disseminate off-label use information, manufacturers were required to prepare and submit biannually to the Secretary a list of articles and reference publications about their drug's unapproved uses that were disseminated for the six-month period prior to the submission of the list. Manufacturers were also required to submit lists that identified the categories of providers that received that material for the same time period. If the Secretary determined that the unapproved use may not have been effective or may have presented a significant risk to the public health, the Secretary could have ordered corrective action, including the cessation of dissemination of the information. In the event that the Secretary required corrective action to be taken, manufacturers had to keep records regarding the dissemination of off-label information that could be used in such situations. Manufacturers were also responsible for reporting results of additional clinical research about the safety and effectiveness of the unapproved use involved. To disseminate off-label use information manufacturers were also required to submit a supplemental new drug application to the Secretary, receive certification that they would file a supplemental application based on completed or planned studies, or receive an exemption from submitting such an application. A manufacturer could qualify for an exemption from the requirement to submit a supplemental application in three situations.