Promoting Off-Label Uses of Approved Drugs: Green Light-or First Amendment Violation?

The FDA recently released its long-awaited but highly controversial final guidance permitting drug and device manufacturers to distribute medical journal articles and medical or scientific texts that discuss off-label uses of approved products.

The guidance, “Good Reprint Practice for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drug and Approved or Cleared Medi­cal Devices,” is available on the FDA’s Web site: http://www.fda.gov/oc/op/ goodreprint.html.

A major critic of the guidance, Rep Henry Waxman (D-Calif), chair of the House Committee on Energy and Commerce, urged the Obama administration “to carefully reexamine” the policy. Waxman accused Bush’s political appointees of giving drug companies “a long-coveted parting gift.”

“Despite revelations that drug companies manipulate medical journal articles to exaggerate the benefits and downplay the risks of their drugs, the guidance gives companies a green light to promote unapproved uses of their products by handing out these journal articles,” he said. “This fun­da­mentally undermines the requirement that companies prove to the FDA that each new use is safe and effective.”

Others, however, perceive the guidance as highly restrictive. In 1998, the Washington Legal Foundation (WLF) obtained a federal court injunction (Washington Legal Foundation v Friedman) that prohibits the FDA from preventing manufacturers from disseminating peer-reviewed medical journal articles and medical texts that contain off-label information. When a draft of the guidance was released last year, the WLF contended that it raised serious First Amendment concerns regarding manufactur­ers’ rights to speak truthfully about important health care issues. The WLF pledged to initiate court action if the FDA adopted a final guidance that violated either the existing federal court injunction or the First Amendment.

When asked about the WLF’s stance on the final guidance, Richard Samp, the organization’s chief counsel, said that the WLF continues to have serious reservations about the reprint guidance.

“Despite what some ill-informed critics on the Left are saying, this guidance is a significant tightening of prior speech restrictions. Just how bad the guidance is depends to a certain extent on how strictly the FDA interprets an ‘adequate and well-controlled study,’” he said. “If the FDA means to limit studies that can be disseminated to those that are sufficient to warrant the granting of an NDA [New Drug Application], then the restriction is so tight that it cannot survive First Amendment scrutiny and the FDA is in contempt of the current federal court injunction that we won against them. We have no plans to pursue litigation at this point; there is no point in doing so until the Obama administration makes clear how it intends to address the issue.”

The guidance published in January encourages manufacturers to seek approvals and clearance for new indications and intended uses. It also acknowledges that health care pro­fes­sionals may lawfully use or prescribe an approved drug or cleared device for off-label treatment.

“These off-label uses or treatment regimens may be important and may even constitute a medically recognized standard of care,” the guidance said, noting that public health may be advanced by health care professionals receiving medical journal articles or texts about such uses.

Comments and changes
The final guidance incorporates some but not all recommendations given in response to the 2008 draft guidance.

As advocated by industry, the final guidance retains a “safe harbor” type statement, which basically says that if a manufacturer follows the recommendations in the guidance, the FDA will not consider the distribution of such medical and scientific information as “establishing intent that the product will be used for an unapproved new use.” But the FDA also warned that compliance with the guidance would not save from enforcement a manufacturer who “engages in other conduct that unlawfully promotes an unapproved use of a medical product.”

Some objected to a requirement that reprints be limited to reports on adequate and well-controlled studies. The final guidance retained the requirement, but it broadened the definition to include historically controlled studies, pharmacokinetic studies, pharmacodynamic studies, and meta-analyses in some cases.

Some organizations, including the American College of Neuro­psycho­pharmacology (ACNP), sug­gested that the FDA continue to require presubmission of the articles and other mandatory review practices. The FDA said it could not do so, because section 401 of the Food and Drug Modernization Act expired in September 2006. Section 401 was a safe harbor provision that described certain conditions (eg, FDA’s previous review of a journal article), which, if met, would enable a drug/medical device manufacturer to disseminate medical and scientific information about unapproved uses of approved drugs without fear of prosecution for off-label promotion.

David Braff, MD, professor of psychiatry at the University of California, San Diego, and ACNP president, told Psychiatric Times that the organization still feels that the unsolicited distribution of literature by pharmaceutical companies regarding unapproved uses needs additional safeguards provided by external review.

“We just think this is a prudent [policy] and protects patients best,” he said. Sharing his personal perspective, Braff added that the dissemination of information on off-label uses “needs to be a well-regulated process driven by patient well-being and not by for-profit motivations.”

What’s in it?
Much of the FDA guidance focuses on the content, type, and manner of distribution of reprints and texts. Among other requirements, sci­entific or medical journal articles should:

• Be published by an organization with an independent, expert editorial board and a publicly stated policy on conflicts of interest
• Be peer-reviewed
• Not be a special supplement or publication that has been funded in whole or in part by manufacturer(s) of the product the article discusses
• Not be letters to the editor, abstracts, or reports of phase 1 studies in healthy persons
• Not be primarily distributed by a drug or device manufacturer, but rather be generally available in bookstores or other independent distribution channels where medical textbooks or periodicals are sold
• Not be written, edited, excerpted, or published specifically for, or at the request of, a drug or device manufacturer
• Not be edited or significantly influenced by a drug or device manufacturer or any individuals who have a financial relationship with the manufacturer

Other sections of the guidance include requirements that distributed information be unabridged; be free of highlighting, markings, and manufacturer summaries; be distributed separately from promotional literature (eg, not be given out in promotional exhibit halls and not be the subject of discussion between the sales representative and physician during a sales visit); be accompanied by approved labeling; and be accompanied by a comprehensive bibliography of publications discussing adequate and well-controlled clinical studies.

In addition, informationcontained in the journal article or text, according to the FDA, cannot be false or misleading or pose a significant health risk if relied on. While the guidance became effective on publication, an FDA spokesperson explained that guidances could be revised, commented on, or withdrawn in compliance with FDA regulations. Electronic comments on the recently released guideline can be submitted at http://www.regulations.gov, and written comments can be sent to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm 1061, Rockville, MD 20852.