American Journal of Law & Medicine

Off-label prescription advertising, the FDA and the First Amendment: a study in the values of commercial speech protection.

I. INTRODUCTION

In order to protect the nation from harmful or worthless drugs and devices, the Food and Drug Administration (FDA or the Agency) is legislatively authorized to restrict the sale of prescription drugs or medical devices to those whose efficacy and safety have been reviewed and approved by the Agency. (1) Drugs and devices are approved for a specific medical purpose. In numerous instances, however, the medical profession has discovered that treatments approved for one purpose may also serve other valuable medical purposes. (2) Indeed, on a number of occasions such "off-label" treatments have proven to be essential to the successful treatment of some very serious illnesses. (3)

In these off-label situations, the FDA is faced with a dilemma. On the one hand, off-label use of prescription drug and devices gives rise to a series of major problems for the FDA. While the drug and devices in question have been vetted and approved by the FDA for their designated purpose, at no point has the FDA reviewed the supporting scientific data to determine efficacy for the off-label purpose. It is therefore at least conceivable that if such off-label uses are permitted, the drug or device may in reality be worthless or even dangerous for its alternative use, yet doctors may be freely employing it for that purpose. Moreover, widespread off-label use of prescription drugs and devices conceivably undermines the FDA's authority and deters manufacturers from seeking on-label FDA approval for even widespread alternative uses. The fear, then, would be that the FDA's initial approval could serve as a wedge to permit the industry's equivalent of the Wild West, where the rule of law was seen only rarely. It is true that the Federal Government could avoid this danger by categorically prohibiting all off-label uses, instead requiring drugs and devices to gain administrative approval for each use. But this alternative is also not free from problems. As a result of such a ban, potentially valuable treatments--often for the most serious of diseases--could be tied up in years of administrative red tape while their manufacturers seek FDA approval. Even worse is the possibility that manufacturers might decide that seeking FDA approval for the off-label use is simply not worth its costs. In any event, under the current regulatory framework, the FDA asserts that it lacks legal authority to restrict the ability of doctors to prescribe drugs or devices for off-label uses.

The FDA has sought to resolve this dilemma by effectively swimming half way across a river--thereby pleasing no one and avoiding none of its quite legitimate concerns. It has resolved its dilemma by leaving off-label uses essentially unregulated, but to make a manufacturer's promotion of an off-label use categorically illegal. As a result, while the benefits of off-label use are roughly preserved, whatever dangers might accompany such uses are in no way avoided since off-label uses are still generally allowed. At the same time, while it is true that the ban on off-label promotion by manufacturers prevents false or misleading advertising, because the ban is all-inclusive it simultaneously prevents promotion of valuable off-label uses of which doctors otherwise may well be unaware. To be sure, those other than the manufacturer are still permitted to discuss the relative merits of off-label uses, and even manufacturers are authorized to speak about certain circumstances surrounding off-label use, such as accompanying dangers. But the FDA could not have stated more clearly that manufacturers are prohibited from advocating off-label uses in any way. This is so, even where the FDA in no way challenges the accuracy, truthfulness or completeness of that promotion. (4) As a result, in many instances doctors are likely to be deprived of valuable information about important off-label uses that are totally lawful and extremely beneficial to some very sick people. In short, the FDA's policy, as well intentioned as it no doubt is, has made a shambles of off-label use, by simultaneously over-regulating and under-regulating the practice. (5)

Arguably even more important is the shambles the FDA's categorical ban on off-label promotion makes of the First Amendment right of free expression. Indeed, the FDA's treatment of off-label advertising amounts to a virtual how-not-to-do-it manual for reconciling the governmental interest in preserving drug and device safety and effectiveness on the one hand and the constitutional right of commercial speech, on the other hand. In short, the FDA's ban on off-label promotion violates the First Amendment right of free expression. This does not mean that commercial speech must receive absolute protection, or that the FDA should be wholly deprived of authority to regulate drug and device advertising in the interests of public health. It means, simply, that governmental imposition of a categorical ban of truthful promotion of lawful commercial activity contravenes both established commercial speech doctrine and core notions of free speech theory. The First Amendment demands that government employ less sweeping means of achieving its legitimate goals.

In this Article, we seek to accomplish two complementary goals. Initially, we seek to establish the unambiguous unconstitutionality of the FDA's current prohibition on off-label promotion as measured by controlling Supreme Court decisions concerning the First Amendment's protection of commercial speech. (6) Secondly, we seek to glean from this analysis far more significant insights about the core premises of the constitutional protection of free expression. We point to four basic postulates of American constitutional and political theory that, we assert, underlie the social contract between citizen and government implicit in a societal commitment to liberal democracy. (7) These core premises, we believe, represent the normative foundations of the constitutional protection of not only commercial speech, but indeed all speech. By demonstrating this important philosophical overlap, we demonstrate the inherent linkage between commercial speech protection and the broader premises of the constitutional guarantee of free expression.

The first section of this Article provides a detailed description of the history and statutory framework of the FDA's regulation of off-label uses of prescription drugs. (8) In the section that follows, we demonstrate the inconsistency between the FDA's current practice and the existing doctrinal framework for the constitutional protection of commercial speech. In the final section, we explore the deep structure of commercial speech protection, and show how the FDA's prohibition of off-label advertising contravenes the core normative premises that make up that structure. In so doing, we will show that the core premises of commercial speech protection simultaneously rationalize all constitutional protection of free expression.

II. THE FDA'S SUPPRESSION OF OFF-LABEL PROMOTION: DEVELOPMENT OF THE REGULATORY FRAMEWORK

A. OFF-LABEL USE AND ACCEPTED MEDICAL PRACTICE

While the phrase "off-label use" may seem to imply dubious medical practice, the reality is quite the opposite. Two important points must be noted as we begin our analysis of the constitutionality of the FDA's prohibition on a manufacturer's ability to promote off-label use: (1) the prescription and use of approved drugs and medical devices for purposes not set forth in their FDA- authorized labeling is legal, (9) and (2) not only are such practices legal, they are quite common and, indeed, often accepted medical practice. (10)

Government officials have themselves often openly acknowledged the benefits of off-label uses. (11) The FDA has noted that "[g]ood medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment." (12) There may well be instances in which off-label use is effectively required by the dictates of good medical practice. Under these circumstances the failure to prescribe off-label might well be deemed medical malpractice. (13) The conclusion is therefore inescapable that both patients and prescribers would often be aided by the dissemination of information to the medical profession about these valuable off-label uses--uses that health care practitioners may well be unfamiliar with absent such communications. (14)

Despite the indisputable value of off-label uses and the corresponding need for doctors and other prescribers to be informed about them, the FDA has categorically banned manufacturers of drugs and devices from promoting their use for unapproved purposes to the medical profession. This is so despite the obvious reality that manufacturers are in a unique position to provide valuable information about off-label uses to the medical profession.

Manufacturers possess a combination of incentive and resources to disseminate information to doctors about off-label uses. As the FDA itself has long acknowledged, "[s]cientific departments within regulated companies generally maintain a large body of information on their products," (15) including information about off-label uses. As the Seventh Circuit Court of Appeals has persuasively reasoned, "if a given use is lawful, and thus can be written about freely in newspapers or blogs, and discussed among hospitals ... doesn't it make a good deal of sense to allow speech by the manufacturer, which after all will have the best information? Why privilege speech by the uninformed?" (16) To be sure, instances may arise in which particular claims about off-label uses could be deemed false or misleading. The same could be said about the advertising of any product or service. But the FDA's ban draws no such distinctions. Even totally truthful, valuable information provided in the form of promotion is banned. It is difficult to comprehend the logic of such a distorted system.

Equally puzzling is the limited judicial attention that has been devoted to the constitutional issue. While in limited contexts the ban has been found unconstitutional, (17) to this point there has been surprisingly little judicial attention to the constitutional implications of the FDA's prohibition, is It is for these reasons that detailed and thoughtful consideration of the First Amendment's applicability to the FDA's ban is called for. The first step in that analysis must be an attempt to understand the origins, legal source, and rationale of the FDA's actions. It is to those issues that our attention now turns.

B. THE LEGAL SOURCE OF THE OFF-LABEL PROMOTION BAN

Although the Federal, Food, Drug, and Cosmetic Act (FDCA) does not expressly prohibit "off-label promotion" in so many words, the FDA has relied on that statute to justify its ban of off-label promotion. First, the FDA asserts that such promotion violates the FDCA on the ground that it constitutes false or misleading labeling; (19) second, the FDA contends that it causes an approved new drug to become an unapproved new drug all over again, thus triggering the requirement of FDA approval anew; (20) and third, the FDA claims that off- label promotion misbrands the drug because it "is evidence of' a new "intended use" for which "adequate directions" necessarily would be lacking in labeling by virtue of the unapproved status of the use. (21) Although the details of the FDA's theory in a particular case may vary according to the factual scenario presented, the basic point is that the FDA regards the dissemination of any information relating to off-label uses as an action prohibited by the FDCA. (22) The same is true for devices, although the statutory details vary somewhat.

Originally, the FDA invoked these provisions to protect the American consumer against quackery--fraudulent therapeutic claims about products that had never been submitted to the FDA for any kind of review. This approach was limited to the restriction of false or misleading statements in commercial promotion and therefore was generally thought not to raise any First Amendment issue. (23) In the 199Os, however, the FDA dramatically increased its reliance on the FDCA in off-label promotion cases and sought increasingly severe penalties for alleged violations. The shift is attributable primarily to increasing concern over a sphere of activity over which the FDA now largely denies regulatory control: physicians' off-label prescribing decisions.

The FDA's current approach to the regulation of speech about off-label uses originated with physician decisions in the 1960s--right around the time the FDA was struggling to implement statutory amendments requiring robust scientific evidence of efficacy for all marketed drugs--to prescribe drugs for off-label uses despite the lack of information supporting the safety or efficacy of those uses. During this period, the FDA asked the author of a medical textbook to revise the book to warn against an unsafe dosage of a particular drug product, only to be roundly criticized by the medical community--even though the dosage had been linked to several deaths. In response, the FDA issued a public statement assuring physicians that the Agency had no intention of regulating their prescribing decisions. (24) Toward the end of the decade, Congress turned its attention to the off-label use "problem," focusing on the widespread off-label use of the highly toxic drug methotrexate to treat psoriasis.

A Member of Congress became concerned by "the Methotrexate situation" as early as 1968, and in that year invited the FDA's attention to a medical journal article that encouraged the use of the drug to treat psoriasis despite the absence of FDA approval for that use. (25) The FDA had approved the drug solely for treatment of certain cancers, and had authorized only the highly limited and tightly regulated investigational use of the drug in psoriasis and rheumatoid arthritis. The FDA's primary concern involved the risks of bone marrow suppression, leucopenia, thrombocytopenia, and anemia--side effects that might be considered to be justified for a patient with one of the indicated, or labeled, conditions, but not for a patient with a much less serious condition like psoriasis. The FDA was also influenced by the fact that methotrexate appeared to treat, but not "cure," psoriatic disease. Further complicating matters from the Agency's perspective, any action to remove the drug from the market would have interfered with the treatment regimens of the cancer patients for whom methotrexate was being used "on-label."

A House subcommittee convened hearings in the summer of 1971 "to examine an anomalous and apparently dangerous situation in many respects, in which a new drug legally marketed for a restricted purpose has come into widespread use in the treatment of a different medical condition for which it has not been approved." (26) FDA witnesses testified that the Agency's ultimate decision was to avoid interfering in the treatment of cancer patients through enforcement action (e.g., a product seizure) and "to try to deal with it as an educational matter" instead. (27) FDA officials cooperated with key opinion leaders in the dermatology community to prepare an editorial that was published in the September 22, 1969, issue of the Journal of the American Medical Association. The editorial discussed potential risks of the drug and advised careful monitoring of patients being treated with methotrexate. The editorial was republished in the Archives of Dermatologg in 1970, together with a companion editorial on the danger of cirrhosis from the drug and possible need for liver biopsy to ascertain liver function. (28) Denying that the FDA's "educational" approach had been adequate to address the problem and dissatisfied by the heterogeneity of FDA officials' prior statements on the question, Members of Congress requested that the FDA develop a more coherent position on the Agency's ability to constrain prescriber decisions to order the off-label use of approved drugs.29 FDA witnesses, for their part, asserted that the FDCA provided adequate authority for the FDA to constrain off-label uses but acknowledged that Agency officials had not always spoken with one voice. (30)

Pressure from Congress to establish a clear policy on off-label use led the FDA to consider new regulations that would have given the Agency the ability to interfere directly in medical practice by controlling particular off-label uses with which the Agency disagreed. Even as Congress was pressuring the FDA to control indiscriminate prescription of off-label use, the medical community continued its vigorous campaign of resistance to any effort on the FDA's part to constrain prescribers' clinical judgments. Against this backdrop of conflicting influences, the FDA proposed sweeping new rules to constrain physician prescribing habits, despite the Agency's denial that it had any intention to interfere with medical practice. Under the proposed rule, issued in 1972, the FDA would have been "obligated" to take one or more enumerated actions to address an "unapproved use" that endangered the public health. (31)

The FDA sought to satisfy both constituencies--physicians and legislators--by explaining that its statutory authority to control the market introduction and labeling of new drugs did not encompass the power to restrict the uses to which approved drugs might be put. (32) It was at this point in the development of the FDA policy on off-label use that the Agency's official policy began focusing on the dissemination of information about off- label uses by the product manufacturers, and not on the use itself. According to the explanatory statement accompanying the 1972 proposal, the FDA would allow prescribing decisions based on the information set forth in the Agency- approved "labeling" for a drug product, and would even tolerate clinical decision making based on "other adequate scientific data." (33) But it simply would not allow a manufacturer to even hint to a prescriber or patient that an off-label use might be clinically indicated:

   [W]here a manufacturer or his representative, or any person in the
   chain of distribution, does anything that directly or indirectly
   suggests to the physician or to the patient that an approved drug
   may properly be used for unapproved uses for which it is neither
   labeled nor advertised, that action constitutes a direct violation
   of the Act and is punishable accordingly. (34)

What began as an effort to control off-label prescribing by physicians thus shifted to the use of a federal statute to constrain manufacturer speech about such prescribing--purely, it would seem, because physicians so vociferously objected to any insinuation by the FDA into decisions relating to the circumstances in which lawfully marketed drugs would be used. (35)

The FDA's effort both to establish an off-label use policy in order to satisfy Congress and to avoid interfering in medical practice failed, largely because the 1972 proposed rule was fiercely opposed by physicians. (36) In the face of this opposition, the FDA chose not to issue the rule in final form. (37) What followed, instead, was a series of statements from the FDA calculated to soothe the medical community by denying that the Agency's proposal represented any genuine threat to prescribing decisions. (38) The FDA went further, amending its regulations to make clear that the requirement for regulatory authorization for a new drug did "not apply to the use in the practice of medicine for an unlabeled indication of a new drug product approved" by the FDA. (39) During this same period, the FDA even established "safe harbors" for certain types of manufacturer communications about off-label uses in an effort to facilitate off-label prescribing by physicians. (40) Shortly thereafter, however, the FDA, concerned that its liberalization of the environment through this series of measures went too far in allowing manufacturers to promote off-label uses, turned its attention to the regulation of manufacturer speech through a combination of policy refinements and increasingly aggressive enforcement actions.

C. THE FDA's EXPANSION OF ITS AUTHORITY IN THE 1990s

During the 1990s, the FDA sought to crack down on manufacturer dissemination of information about off-label uses through energetic reliance on the Agency's broad enforcement authorities. At the same time, the FDA also pursued policy solutions to the off-label promotion problem. In 1991, the FDA began developing a new written policy on off-label information dissemination in scientific and educational settings. (41) The following year, the FDA refused to allow a manufacturer to distribute free copies of a recognized, widely used oncology textbook at a major medical conference, because the textbook mentioned off-label uses of several of the manufacturer's drugs. (42) In response, the textbook's publisher, J.B. Lippineott, wrote the Agency in protest, noting that publishers had begun to feel the effects of the FDA's crackdown on promotional and educational materials mentioning off-label uses. (43) According to Lippincott, Merck had declined to fund or distribute a supplement on benign prostatic hyperplasia in 1991 because of concern over the FDA enforcement. In another case, Squibb Diagnostics bought 4,000 copies of a textbook on magnetic resonance imaging but did not distribute them. (44)

In February 1993, the FDA announced that it was developing a policy to cover all industry-sponsored "enduring materials," loosely defined as materials of a lasting nature like books, audio, or video tapes, and software. (45) Concerned that the FDA would adopt a restrictive approach to enduring materials, the medical community formed a task force under American Medical Association (AMA) auspices and developed its own proposed guidelines. (46) The FDA also met with the American Medical Writers Association and the American Medical Publishers to address the groups' concerns that the FDA would establish a policy that "impede[s] ... the free flow of information." (47)

On December 6, 1995, and December 8, 1995, the FDA published two draft guidance documents (48) describing the circumstances in which the FDA would permit manufacturers to disseminate journal article reprints and reference texts containing off-label use information to health care professionals. …

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