Companies should consider filing written comments on the Draft Guidance; the deadline for comment submission will be approximately April 20, 2008.

On February 15, 2008, the U.S. Food and Drug Administration (FDA) issued a news release announcing the availability for public comment of a Draft Guidance on dissemination of reprints of peer reviewed medical journal articles and other information about unapproved uses of approved new drugs and approved or cleared medical devices. (See  http://www.fda.gov/bbs/topics/NEWS/2008/NEW01798.htmlhttp://www.accessdata.fda.gov/scripts/oc/ohrms/advdisplay.cfm.) Such unapproved uses are generally referred to as “off-label” uses, because the FDA approved “label” defines and generally limits the scope of what can be communicated about an approved product by a regulated entity, such as a drug or device manufacturer, at least in a promotional context. Moreover, in assessing the Draft Guidance, it is important to observe that it does not purport to regulate the dissemination of any information by third parties, such as medical and scientific journals, which are truly independent of the drug or device manufacturer. Nor does the Draft Guidance in any way restrict the ability of a licensed practitioner to use an approved drug or device for any purpose, subject to whatever constraints might exist under applicable standards of medical practice.

The draft guidance—“Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved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”—evoked criticism even before it was issued. On November 30, 2007, Congressman Henry Waxman, Chairman of the U.S. House of Representatives Committee on Oversight and Government Reform, who had obtained an internal agency draft of the draft guidance, sent a letter to FDA Commissioner Andrew von Eschenbach objecting to its release. (http://oversight.house.gov/story.asp?ID=1641.) The letter suggested, among other things, that then-impending draft guidance was part of a concerted effort by the Bush administration to create a “large loophole” that would effectively allow pharmaceutical and device manufacturers to engage in widespread marketing and promotion of approved drugs for unapproved uses. A careful review of the draft guidance suggests, however, that it is a measured—perhaps even overly restrictive—response to the widely acknowledged public health need for physicians to be provided high quality scientific information about “off-label uses or treatment regimens” that “may be important and may even constitute a medically recognized standard of care.” (Draft Guidance at 4 .) Indeed, in certain fields such as oncology, off-label use is often the rule rather than the exception; the ability to provide timely information to the oncology community about high-quality data on off-label uses, and the corresponding need to provide reimbursement for such uses, is widely understood as being a substantial public health imperative. (See, e.g., American Society for Clinical Oncology, “Reimbursement for Cancer Treatment: Coverage of Off-Label Drug Indications,” J. Clin. Oncol. 24: 3206-3208 (July 1, 2006).) Moreover, the Draft Guidance does not appear to be a radical departure from existing law, as Congressman Waxman’s “loophole” characterization suggests. On the contrary, although the Draft Guidance has numerous shortcomings in its own right, it appears to be a legitimate attempt by FDA to maintain some continuity in this area of the law in view of the recent “sunsetting” of the statutory and regulatory safe harbor for dissemination of qualifying “off-label” materials under the Food and Drug Administration Modernization Act of 1997. (See Draft Guidance at 2-3.)

Off-Label Dissemination Criteria

In the Draft Guidance, FDA identifies several criteria for determining whether and when dissemination of reprints of peer reviewed scientific journal articles is permitted and, hence, when such dissemination will not be deemed by FDA to be evidence that the manufacturer “intends” to promote its product for an unapproved use. Put somewhat differently, these standards will help FDA determine whether the dissemination of the off-label information is “promotional,” in which event it is subject to FDA’s prohibition against off-label promotion, or whether, instead, it amounts to “scientific speech” that is categorically beyond FDA’s regulatory jurisdiction, or whether, even if technically within FDA’s jurisdiction, regulation of the reprint dissemination by FDA cannot be squared with the requirements of the First Amendment. (See, e.g., Washington Legal Foundation v. Friedman, 13 F. Supp. 2d 51 (D.D.C. 1998), appeal dismissed and judgment vacated in part by Washington Legal Foundation v. Henney, 202 F.3d 331 (D.C.Cir.2000).) The Draft Guidance imposes significant constraints of the dissemination of medical or scientific journal articles about off-label uses.

Expert Editorial Board

The medical or scientific journal article must be published by an organization that has an independent editorial board composed of experts in the subject of the article. The expert editorial board is required to review and objectively select, reject or provide comments about proposed articles. Moreover, the publisher must have in place and adhere to a publicly stated conflict of interest policy, requiring full disclosure of conflicts of interest or “biases” for all authors, contributors or editors associated with the organization.

Peer Review

The medical or scientific journal article must be peer reviewed and published in accordance with the peer review procedures of the organization.

Special Supplements Not Permitted

The medical or scientific journal article must not appear in a special supplement or other manufacturer-funded publication.

Adequate and Well-Controlled Clinical Investigations

The information in the medical or scientific journal article should address “adequate and well-controlled clinical investigations that are considered scientifically sound by experts with scientific training and experience to evaluate the safety or effectiveness” of the product. In other words, FDA is importing the statutory “substantial evidence” standard that is applied to studies submitted in support of product approval or that is required by FDA to support promotional advertising claims to determine when dissemination of a reprint is “non-promotional” and justified. Perhaps more than anything else in the Draft Guidance, this criterion raises policy and legal concerns that should be addressed in the comment period.

Not False or Misleading

The medical or scientific journal article must not be false or misleading. One way the article might be misleading is if it is “inconsistent with the weight of credible evidence derived from adequate and well-controlled clinical investigations,” e.g., where there exist a significant number of contradictory studies. It would also be considered misleading if the article had been withdrawn by the journal or disclaimed by the author, or where it discusses a study that FDA has previously told the company does not meet the standards for an adequate and well-controlled clinical investigation.

No Significant Risk to Public Health

The use discussed in the article must not pose a significant risk to the public health. There is no mention by FDA of any risk/benefit balancing in this criterion.

Disqualified Publications

Certain publications, such as letters to the editor, abstracts, reports of Phase I trials in healthy volunteers, and reference publications that contain little or no substantive discussion of the relevant investigation or data are categorically disqualified from being disseminated.

Manner of Dissemination

In order to qualify under this guidance, dissemination of a medical or scientific journal article should be: (i) in the form of an unabridged reprint or copy; (ii) accompanied by the product’s FDA approved labeling; (iii) accompanied by, or already include in its text, a “comprehensive bibliography” of the adequate and well-controlled studies published to date about the particular off-label use that is the subject of the article; (iv) accompanied by, in cases where the conclusions of the article being disseminated, have been “specifically called into question” by another article or text, “a representative publication that reaches contrary or different conclusions”; and (v) distributed separately from any promotional information.

Accompanying Disclosures

The medical or scientific journal article should be accompanied by a “prominently displayed and permanently affixed statement” that discloses: (i) the uses discussed are not approved by FDA; (ii) the interest in the product of the manufacturer that is disseminating the information; (iii) any author who has a financial interest in the product or who is receiving compensation from the manufacturer; (iv) any person known to the manufacturer who has provided funding; and, importantly, (v) any significant risks or safety concerns known to the manufacturer concerning the unapproved use that are not discussed in the article. These resemble the “fair balance” disclosure standards that ordinarily apply to promotional communications.

No Discussion by Sales

In order to avoid being characterized as “promotional,” FDA also recommends that sales representatives who disseminate otherwise qualifying off-label information refrain from discussing it in any way and refer any inquiries from doctors to the company’s medical affairs department.

The criteria proposed by FDA on the permissible dissemination of medical or scientific articles about “off-label” uses, while welcome, still appear to impose significant burdens on the appropriate and lawful dissemination of such information in the public interest. Companies should consider filing written comments with FDA respecting the Draft Guidance. The deadline for comment submission is 60 days from the date of publication in the Federal Register, which is approximately April 20, 2008 (as the Federal Register Notice announcing the availability of the Draft Guidance has not yet been published).