Washington Report:
What You Need to Know About "Off-Label" Uses of
Prescription Drugs, Medical Devices, and Biologics

©Copyright 1998 by Emalee Murphy, Esq., McKenna & Cuneo, LLP, Washington, DC, USA
(Explore Issue: Volume 8, Number 6)

The withdrawal of Fen-Phen for obesity and the approval of Thalidomide for leprosy are recent examples of how the Food and Drug Administration ("FDA") continues to grapple with the safety and efficacy issue surrounding the "off-label" uses of prescription drugs. The term "off-label" refers to the practice of prescribing drugs, devices, or biologics for uses that are not identified in the labeling and reflects the fact that any lawfully marketed drug, device, or biologic approved by FDA for a given use may be prescribed for any use that a physician believes will best serve the patient.

Contrary to popular belief, "off-label" use is not only legal but also common and necessary, especially in specialty areas of medicine. For example, a 1991 General Accounting Office ("GAO") report found that 25% of anticancer drugs were prescribed "off-label" and 56% of cancer patients were administered at least one drug for an unapproved use. FDA has recognized the value of "off-label" use of prescription drugs, medical devices, and biologics. In a 1982 FDA Drug Bulletin, the agency stated that: "unapproved" or more precisely "unlabeled" uses may be appropriate and rational in certain circumstances, and may in fact reflect approaches to drug therapy that have been extensively reported in medical literature ...valid new uses for drugs already on the market are often first discovered through serendipitous observations and therapeutic innovations.

Thus, "off-label" use is essential to the "practice of medicine" because medical discovery invariably outpaces the regulatory machinery at FDA. Further, under the Food, Drug, and Cosmetic Act ("FDCA"), the agency has no authority to regulate the "practice of medicine", which includes "off-label" use.

What FDA can do is restrict the manufacturer or marketer's advertising practices and promotional activities directly to physicians. Understandably, the industry wants to promote unapproved uses by providing physicians with: (1) reprints from peer-reviewed scientific journals, such as the New England Journal of Medicine or the Journal of the American Medical Association, that discuss a particular "off-label" use; (2) parts of reference textbooks that discuss any "off-label" use; and (3) continuing medical education ("CME") seminar programs that discuss "off-label" uses. In general, manufacturers believe that "off-label" use is essential to public health and that FDA restrictions on dissemination of information about "off-label" uses have undermined that goal.

FDA has vigorously opposed such promotion for several reasons. First, the agency objects to off-label promotions since a manufacturer could obtain approval for a particular narrow use and then promote the product for broader uses that have not been adequately tested. Second, dissemination of reprints, even from the most prestigious peer-reviewed scientific journals, may present only preliminary positive findings and would not provide a "balanced view." Third, FDA restrictions on promotional activities provide an incentive for manufacturers to conduct the clinical studies necessary for approval of "off-label" uses. Thus, the challenge confronting FDA is balancing the need to regulate the promotion of "off-label" use with the medical community's need for information about new treatments and uses for marketed drugs, devices, and biologics.

The controversy surrounding "off-label" use has not escaped the attention of Congress. The Food and Drug Modernization Act of 1997 ("FDAMA"), which was signed into law in November 1997, permits manufacturers to give health care practitioners written information, including "off-label" use information concerning the safety, efficacy, or benefit of a previously approved drug, device, or biologic as long as specified conditions are met. However, in June 1998, when FDA proposed regulations to implement this provision under FDAMA, the agency included significant barriers which the industry believes not only are unduly restrictive and burdensome but also fail to capture the spirit of the legislation. FDA proposes to permit companies to provide information about off-label uses if it:

• Concerns a product that has been approved, licensed, or cleared for marketing by FDA;
• Is about a clinical investigation of the new use considered "scientifically sound" by qualified experts and which is required as part of a supplement to a new drug, new device, or new biological approval;
• Is in the form of an unabridged reprint or copy of a peer-reviewed scientific or medical journal article (or an unabridged reference publication)
• Does not advocate a use that would pose a significant risk to the public health;
• Is not false or misleading;
• Is not derived without permission from clinical research conducted by another manufacturer; and
• Includes certain disclosures (e.g. that the new use has not been approved by FDA), plus the official product labeling, and a bibliography of other articles relating to the new use that provide "balance."

The most restrictive provision imposed by FDA regulations would bar a company from beginning to disseminate the information until FDA "has for the to study of the unapproved use] is adequate and that the schedule for completing such studies is reasonable." The industry has expressed at least three major concerns about FDA's proposal. First, the proposed regulation has established no timeframe for FDA to determine whether a protocol is "adequate.". Second, FDA should clarify whether (in absence of a "clinical hold" notice from FDA) the proposed regulation would prohibit a manufacturer from commencing the clinical investigation (and the dissemination of information) 30 days after submission of the investigational plan (IND, IDE) to FDA. Third, the meaning of the term "adequate" when applied to the proposed protocol is ambiguous and should be clarified in order to provide a standard for determination.

In the meantime, the D.C. Circuit Court recently decided against FDA in a related lawsuit regarding off-label use information. District Judge Royce Lamberth ruled July 30, 1998 that certain FDA restrictions on drug marketing contained in FDA guidance documents on dissemination of information on unapproved uses for legally marketed drugs and devices, violates First Amendment rights of free commercial speech and cannot be enforced. The D.C. Circuit granted summary judgment to the Washington Legal Foundation, a public interest group that filed the lawsuit in 1994. The decision prohibits FDA from restricting any manufacturer from distributing to physicians reprints from peer-reviewed scientific journals or parts of reference textbooks that discuss "off-label" uses. It also prohibits FDA from restricting a manufacturer's right to suggest content or speakers for continuing medical education ("CME") seminar programs that discuss "off-label" uses of the company's product. While acknowledging that FDA has a "substantial governmental interest" in compelling manufacturers to get approval for "off-label" uses, the court concluded that the restrictions are more extensive than necessary in advancing that interest. It remains unclear what effect this decision will have on the currently proposed regulations.

A question mark in the promotion of "off-label" use that is not specifically addressed in the proposed regulations is the role of the Internet. The enormous amount of instantly available information, the rapidly changing health care delivery mechanisms, and a growing grass-roots campaign for patient rights has dramatically altered the physician-patient relationship. Although many physicians have welcomed a more educated patient, others have remained wary, and for good reason. Dr. Jerome Kassirer, editor-in-chief of the New England Journal of Medicine, recently told the New York Times that "people are finding information their doctors may not have seen, and sometimes it is welcomed and sometimes it is not. The issue is the validity of the information." Many individuals who get product-related information from the Internet accept it as accurate, truthful, and not misleading, and yet validity checks are lacking. Indeed, the explosion of interest in alternative medicine and holistic approaches to health care has brought with it numerous web sites devoted to promoting health care products and medicines, many for purposes considered "off-label" by FDA. Given the recent ruling by the D.C. Circuit Court and the public interest in keeping the Internet free from government intrusion, information relating to "off-label" uses of products for consumers and health care practitioners may overwhelm FDA enforcement resources and significantly erode FDA authority in regulating promotion of drugs, devices, and biologics.

About the Author

Emalee Murphy, whose experience in FDA-regulated industries spans over 20 years, provides regulatory and enforcement counseling for clients in the drug (prescription and OTC), medical device, dietary supplement, cosmetic, food, and food additive industries, with particular emphasis on market entry issues and strategies for new products and new companies. She is experienced in FDA import and export issues and provides assistance to companies involved in FDA compliance, import detention, and enforcement matters.

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