Off-label use is the common practice of prescribing a drug for an indication other than those approved by the FDA. The physician rationale for prescribing off-label is often based on the lack of FDA-approved effective treatments, reports of clinical effectiveness for the off-label use, or both. A recent study confirms that off-label prescribing continues in earnest, with 21% of drugs listed in a data set being prescribed for off-label uses, most with little scientific evidence of efficacy (2). Although the responsibility for seeking FDA approval for adding new uses to the product label resides solely with the manufacturer, companies are reluctant to invest the resources necessary to develop the evidence required for FDA review, particularly when the off-label uses are already profitable.

In this issue, Steinman and colleagues (1) examine the gabapentin marketing and promotion strategies used by Parke-Davis in the 1990s. The documents examined in the article became available following a whistleblower case brought under the False Claims Act (3) and reveal the varied strategies Parke-Davis used to encourage physicians to prescribe gabapentin for off-label uses, which included teleconferences, speakers bureaus, continuing education programs, advisory boards and consultants meetings, and the selective use of research and publications (1). These efforts were extremely effective. As recently as 2001, gabapentin had the highest proportion of off-label uses prescribed by office-based physicians, with only a small percentage of these uses based on scientific evidence of efficacy (2).

Parke-Davis was engaged in the marketing and promotion of gabapentin when the regulation of off-label marketing was evolving. In 1996 and 1997, the FDA issued 2 Guidance Documents addressing restrictions on industry-supported continuing medical education and advertising and promotion of off-label uses (4, 5). However, shortly thereafter, the enactment of the Food and Drug Administration Modernization Act of 1997 (FDAMA) ended the strict prohibition on off-label marketing and promotion. The new law permitted limited marketing and promotion of off-label uses to certain audiences, including health care practitioners, if the manufacturer had a pending application for FDA approval of the off-label use (6). Despite the legislation's more liberal provisions, industry criticized it as overly restrictive.

Opposition to the FDA Guidance Documents played out in a series of court cases. The Washington Legal Foundation sought to prevent the FDA from enforcing limitations on off-label marketing, claiming the FDA Guidance Documents encroached upon industry's First Amendment right to free speech because they restricted industry-controlled distribution of scientific literature and support of continuing medical education seminars (7). In 1998, a federal district court issued an injunction barring the FDA from taking any official action that unduly restricted commercial speech (7).

The case continued during my tenure as Commissioner of Food and Drugs (November 1998 to January 2001), when the FDA sought to limit the scope of this broad ruling. In response, the federal district court limited the injunction to off-label uses of drugs (8). After hearing arguments on the constitutionality of the FDAMA, the court ruled the relevant sections of the statute unconstitutional because the government had less restrictive ways to encourage manufacturers to seek FDA approval for off-label uses (9). In 2000, the FDA won a hollow victory when the federal appeals court overturned the injunction in response to the government's position that "neither the FDAMA nor the CME [continuing medical education] Guidance independently authorizes the FDA to prohibit or to sanction speech" (10). Without power to prohibit or sanction speech related to off-label marketing, the FDA can only respond to such activity by bringing a misbranding enforcement action against the manufacturer. The ability to act after the fact is too little too late.

The court has also set limits on FDA regulation of commercial speech related to advertising and promotion of compounded drugs (11) and health claims of dietary supplements (12). In response, the FDA sought public comment on how the agency could fulfill its mission of safeguarding public health without abridging industry's right to free speech (13). It was prudent for the FDA to seek input and to subsequently try to shape agency policy in a manner consistent with First Amendment protections; however, it is likely that FDA regulatory authority will continue to be challenged and redefined in the courts. Therefore, it is incumbent on industry and the medical profession to protect the public through voluntary self-regulation. To date, attempts to achieve this goal have fallen short.

The Pharmaceutical Research and Manufacturers of America developed a code that underscores the tension between a company's financial mission and its goal to "benefit patients and to enhance the practice of medicine" by "informing healthcare professionals about products, providing scientific and educational information, and supporting medical research and education" (14). The potential for financial conflicts of interest, bias, and ethical dilemmas impacts both industry and physicians.

Steinman and colleagues' article provides numerous examples of conflicts that arise when physicians receive compensation or other benefits from manufacturers in exchange for assistance with the marketing of drugs for off-label uses. The burden of managing these conflicts is the responsibility of the physician. The first and foremost principle of conflict management is disclosure. Whether the audience is a single patient or a group of fellow physicians, when the physician has accepted financial or other support (for example, slide preparation) from a manufacturer and has not told the audience about the arrangement, then that physician has gone over the line.

In October 2002, the Office of the Inspector General of the U.S. Department of Health and Human Services published a draft Guidance Document for manufacturers (15). It pointed out that the Medicare and Medicaid anti-kickback statute is an avenue for prosecution when industry uses gifts or other inducements to increase prescribing by physicians, whether on- or off-label. The Office of the Inspector General finished the Guidance Document in 2003 after making revisions in response to concerns expressed by both industry and physicians about potential damage to continuing medical education and research programs. A compromise permitted industry to finance continuing education and other activities through grant-making instead of marketing (16). Although prosecution of manufacturers under the anti-kickback statute supplements the FDA's enforcement power by providing another means to restrain the industry's influence over physician decision making, the government will undoubtedly continue to seek a more effective model for managing or eliminating conflicts.

Although the activities permitted under the Pharmaceutical Research and Manufacturers of America's code, FDAMA, and the anti-kickback statute pose ethical challenges for the individual physician, those of us in academic institutions face unique challenges because we have a dual responsibility for patient care and drug development research. Academic health centers and their faculty members must remain objective in carrying out industry-sponsored research and transparent in their interactions with industry. We must implement all measures necessary to disclose and resolve conflicts. In response to such situations as those discussed in Steinman and colleagues' article, numerous institutions have strengthened requirements for faculty to disclose relationships with industry, both to the academic institution and to any subsequent audience they address. Institutional review boards have been strengthened, and post-audit review of clinical studies provides oversight on a real-time basis to ensure that clinical studies are conducted properly and comply with rules and regulations protecting patient safety. Some academic institutions have adopted the Accreditation Council for Continuing Medical Education Standards to Ensure the Independence of CME Activities and have applied the same standards to nonaccredited programs as well (17). Even with all of these measures in place, the system is far from perfect.

Although one can take steps at the individual and institutional level to minimize conflicts, the ethical obligation is for the physician to always place the patient's interest first. Steinman and colleagues' article on gabapentin marketing and promotion points out in stark detail that no patient is well-served when a manufacturer engages in practices, whether inside or outside the law, that involve physicians in activities in which conflicts are present. But physicians are not passive participants: They can say "No."

With limited federal authority and tenuous voluntary compliance by industry, it behooves each and every physician to follow the highest ethical standards. Doing otherwise jeopardizes the integrity and credibility of the physician and the profession as a whole. Who's in charge of safeguarding patient welfare? It is increasingly apparent that we are.