FDA's New Guidance For Distributing Articles About Off-Label Uses: Déjà Vu All Over Again?

After years of silence on the issue, the U.S. Food and Drug Administration recently published its latest draft guidance regarding the dissemination of published articles discussing unapproved uses of medical devices and pharmaceuticals. The new proposed guidance, published on February 15, 2008, has something for everybody: Medical manufacturers are relieved from a commitment to seek approval for uses discussed in articles, while industry watchdogs will note the narrowly defined restrictions on what may be distributed and the circumstances under which it may be distributed.

But the new guidance may ultimately satisfy no one. Manufacturers attempting to comply with the distribution and disclosure requirements will find them cumbersome and impractical. Meanwhile, industry critics will argue that the new guidance allows more than what is strictly necessary to avoid violating manufacturers' commercial speech rights, and creates an unwarranted exception to the general prohibition against "off-label" marketing. In the near term, the new guidance appears more likely to revive old controversies than resolve them.

A Brief History of Efforts to Restrict Information About "Off-Label" Uses

Generally speaking, in order for a therapy to be available for physicians to prescribe, the FDA must approve it for one or more indications. Once a therapy has been approved for one indication, however, physicians may exercise their clinical discretion to prescribe it for other, unapproved indications. These latter types of use are referred to as "off-label" because the FDA has not determined whether they are safe or effective. That does not mean, though, that a particular use of a therapy is necessarily unsafe or inappropriate—it just means that the FDA has not reviewed and approved it.

Such off-label uses, both of drugs and medical devices, play an important role in modern medicine. Health care providers frequently prescribe pharmaceuticals and medical devices to treat conditions other than those for which the product was approved. The FDA does not prevent them from doing so, because the agency does not regulate how doctors practice medicine. In fact, in some therapeutic areas, such as the treatment of cancer and HIV/AIDS, most of the available treatments are off-label. Likewise, doctors have discovered many important therapies by using approved products in unapproved ways. Physicians also learn about promising off-label uses through published articles that were written by physicians describing their results, particularly in peer-reviewed scientific journals.

Although doctors frequently prescribe off-label uses of approved products, pharmaceutical and medical device companies are not allowed to market products for those uses without going through the FDA approval process, which is time-consuming, cumbersome and expensive. In recent years, many high-profile civil and criminal prosecutions have been brought against medical manufacturers for violating this prohibition on off-label marketing. Those actions are consistent with the FDA's mission to ensure that manufacturers conduct appropriate clinical trials to support the safety and effectiveness of new uses. But the interest in promoting full-blown clinical trials of new uses sometimes conflicts with the interest in a free and open scientific debate about off-label uses—particularly when manufacturers seek to distribute copies of published articles by independent scientists discussing those uses.

The history of past efforts to restrict distribution of materials on unapproved uses is complicated, to say the least. Until recently, Section 401 of the Food and Drug Administration Modernization Act of 1997 (FDAMA), which expired on September 30, 2006, provided statutory requirements for manufacturers seeking to disseminate publications regarding off-label uses. The FDAMA provisions were in part a reaction to the FDA's issuance of three guidances endorsing the view that a manufacturer's mere distribution of information on off-label uses—even without any endorsement or comment of any sort—constituted illegal marketing and rendered the product "misbranded."

Section 401 of the FDAMA was meant to create a "safe harbor" for manufacturers seeking to distribute published articles on unapproved issues. But the requirements imposed by Section 401 were quite onerous, at least from the manufacturer's point of view. The Washington Legal Foundation (WLF) decided to challenge the constitutionality of the FDA's previous guidances and Section 401, arguing that they violated manufacturers' First Amendment right to distribute truthful, non-misleading and scientifically substantiated information about their products.

In the first case, Washington Legal Foundation v. Friedman, the WLF challenged the FDA's three guidances and obtained an injunction barring the agency from limiting any pharmaceutical or medical manufacturer from disseminating medical journal articles previously published in a bona fide peer-reviewed journal, regardless of whether the publication discussed an off-label use.

The FDA argued, in Washington Legal Foundation v. Henney, that the injunction from the first case should not apply to FDAMA Section 401. But the trial court in that case disagreed and amended its earlier injunction to include FDAMA and its implementing regulations.

The stage was set for the U.S. Court of Appeals for the District of Columbia Circuit to make a definitive ruling on the constitutionality of Section 401 and the FDA guidances. At oral argument of the appeal, however, the FDA rendered the First Amendment issue moot by saying it would not prosecute companies for disseminating articles about off-label use and agreeing that the FDAMA provisions created a "safe harbor" for companies disseminating medical literature on off-label uses. Following the dismissal of the appeal, the FDA insisted that it could still use a company's non-compliance with Section 401 as evidence of the product's true "intended use" in a misbranding action. But the FDA has not pursued any actions based on Section 401 violations in the seven-plus years since the WLF litigation ended, leaving medical manufacturers in the dark about the agency's current views and providing them little or no guidance about how to exercise their right to distribute truthful, non-misleading and scientifically substantiated information about their products.

FDA's New Draft Guidance

On February 15, 2008, more than a year after the expiration of FDAMA Section 401, the FDA issued its latest 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." Like its predecessors, the draft guidance focuses on what types of literature may be distributed to health care providers as well as the conditions under which such literature may be provided.

The draft guidance states that qualifying articles should be: published by an organization whose editorial board uses independent experts with relevant expertise to review the article; peer-reviewed; and not in the form of a "special supplement" or company-sponsored publication. Further, the article should not be primarily distributed by a drug or device manufacturer; written, edited, excerpted or published specifically for, or at the request of, a drug or device manufacturer; or edited or significantly influenced by a drug or device manufacturer, or by any individuals having a financial relationship with the manufacturer.

The draft guidance also specifies formal requirements for how articles are to be distributed. The article must be: 1) unabridged; 2) not marked, summarized or characterized by the manufacturer in any way; 3) accompanied by the product's approved labeling; 4) accompanied by a comprehensive bibliography; 5) accompanied by a representative opposing article that reaches a different conclusion (if one exists); and 6) separate from information that is promotional in nature.

Finally, the manufacturer must prominently display and permanently affix to the article a statement disclosing: 1) that the uses described in the information have not been approved or cleared by the FDA; 2) the manufacturer's interest in the drug or medical device; 3) any author known to the manufacturer as having a financial interest in the product or the manufacturer; 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 that are not discussed in the journal article or reference text.

The draft guidance differs from earlier efforts to create a safe harbor for distributing off-label information in a few very important respects. Manufacturers no longer have to certify, as they would have under the earlier guidances, that they will submit to the FDA an application for approval of the off-label use within a certain time frame. Manufacturers are also relieved of the burden to maintain records of all persons to whom they have distributed articles. There is no requirement to obtain FDA pre-clearance before distributing an article. Finally, manufacturers are not required to inform health care providers that other, FDA-approved therapies exist for the condition discussed in the article. These changes make it far more practical to comply with the terms of the draft guidance.

Nevertheless, despite these important changes, the draft guidance retains many of the cumbersome requirements of Section 401 and the earlier guidances, while adding new requirements—including a mandatory disclosure of risks associated with the unapproved use that are known to the manufacturer. Moreover, the draft provides no assurance that the provisions of the guidance should be viewed as merely a "safe harbor," as the FDA claimed on appeal of the WLF litigation, rather than as a standard for bringing misbranding actions.

Overall, the draft guidance leaves important questions unanswered, and it will undoubtedly face criticism from medical manufacturers and industry watchdogs alike. It represents an important step, however, toward developing a practical approach to regulating the distribution of off-label information without violating the First Amendment. After lying dormant for years, the debate has been reopened, providing a new opportunity to clarify the ground rules for distributing scientific information about unapproved uses.