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The Ban on "Off-Label" Pharmaceutical Promotion: Constitutionally Permissible Prophylaxis Against False or Misleading Commercial Speech?

falseGreenwood, Kate American Journal of Law and Medicine 37.2/3 (2011): 278-98.

Abstract (summary)

Critics of the Food & Drug Administration's ban on off-label promotion often claim that it violates the First Amendment because it suppresses pharmaceutical manufacturers' truthful speech about their legal-and beneficial-products. Characterizing the ban on off-label promotion in this way has more than rhetorical significance. Bans on truthful, non-misleading speech elicit special skepticism because of the belief that they "usually rest solely on the offensive assumption that the public will respond 'irrationally' to the truth." The legislative history of the provisions of the Food Drug and Cosmetic Act that underlie the ban on off-label promotion, however, reveals that Congress was concerned that physicians were responding rationally to false and misleading promotional claims. In this Article, I explore the doctrinal questions raised by conceiving of the ban on off-label promotion not as a ban on "truthful speech to physicians" but instead as a prophylaxis against false and misleading pharmaceutical promotion. I review the evidence that false and misleading claims were commonplace before the ban's adoption and persist today, along with the enforcement challenges the FDA confronted at that time and would confront were the ban lifted, and conclude the government likely could develop the factual record necessary to establish that Congress' rejection of an after-the-fact case-by-case approach to combating false and misleading prescription drug promotion is constitutional. [PUBLICATION ABSTRACT]

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Headnote

I. INTRODUCTION

In 1962, a physician named Miles Robinson testified before the House Committee on Interstate and Foreign Commerce about the advertising and promotion of prescription drugs, including the tranquilizer Mellaril, the side effects of which include both the serious movement disorder tardive dyskinesia and sudden death. Mellaril's manufacturer was promoting the drug to general practitioners to treat, in the manufacturer's words, "tense, nervous patients seen in everyday practice ... for chronic fatigue, insomnia, anxiety, and apprehension, vague digestive disorders, etc."1 Dr. Robinson testified that he was "impressed with that 'etc' It just tapers off into the wide, blue yonder where tranquilizers are claimed to be good for everything."2

Promotional abuses like those Dr. Robinson described were part of the impetus for Congress to amend the Food and Drug Administration's (FDA) organic statute, the Federal Food, Drug, and Cosmetic Act (FDCA), to require that a manufacturer demonstrate to the FDA's satisfaction that, in addition to being safe, a drug is effective for a given use before marketing it for that use.3 The 1962 amendments to the FDCA (often termed the Harris -Kefauver Amendments after their congressional sponsors) require that manufacturers seeking agency approval of a new drug, or- importantly- of a new use for an already-approved drug, produce:

evidence consisting of adequate and well -controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.4

This statutory language underlies the FDA's requirement that a drug undergo preclinical testing followed by clinical trials in humans before an indication, method of administration, patient population, or, in some circumstances, dose, is enshrined on the product's agency-approved label.5 While physicians are free to prescribe a drug that has been approved for one use for any other use they deem appropriate, manufacturers may only promote it for its approved use or uses.6

The precise contours of the ban on off-label promotion derive from the Harris-Kefauver Amendments and the FDCA's misbranding provisions, as well as the FDCA's implementing regulations, court decisions, and various agency interpretations of the governing law.7 While manufacturers are not permitted to promote their products for unapproved uses, multiple avenues for dissemination of information about such uses remain available to them. For example, manufacturers are not limited to the label when they engage in scientific exchange.8 Their physicians and scientists can discuss research into off-label uses via medical journal articles,9 and they can respond to physicians' requests for information about such uses.10 Subject to certain limitations, manufacturers are also permitted to fund off-label continuing medical education programs for practicing physicians11 and to provide physicians with, among other things, peer-reviewed medical journal articles discussing offlabel uses.12 These avenues notwithstanding, the disconnect between off -label use and the rules governing off-label promotion forces manufacturers to leave promising sales opportunities unexploited. Manufacturers also complain that the ban prevents them from providing physicians who are prescribing the manufacturers' products for off-label uses with important information about those uses.

It is not surprising, then, that the ban on off-label promotion is controversial. Its critics argue that it is also unconstitutional. Specifically, they claim that the ban violates the First Amendment because it suppresses pharmaceutical manufacturers' truthful speech about their legal products.13 The manufacturer in a recent constitutional challenge to the ban, Allergan v. United States, pointedly limited its complaint to the ban's effect on "truthful speech to physicians."14

Characterizing the FDA's requirement that a drug that is approved for one use may not be promoted for another as a "ban[] against truthful, nonmisleading commercial speech" has more than rhetorical significance.15 Such bans elicit special skepticism because of the belief that they "usually rest solely on the offensive assumption that the public will respond 'irrationally' to the truth."16 By contrast, regulations targeting false and misleading speech merit much more relaxed review, because "[w]hen a State regulates commercial messages to protect consumers from misleading, deceptive, or aggressive sales practices, or requires the disclosure of beneficial consumer information, the purpose of its regulation is consistent with the reasons for according constitutional protection to commercial speech . . . ."17 The legislative history of the Harris-Kefauver Amendments reveals that one of Congress' principal concerns was that physicians were respondingrationally- to false and misleading promotional claims.18 This Article explores the doctrinal questions raised by conceiving of the ban on off-label promotion not as a ban on "truthful speech to physicians" but instead as a prophylaxis against false and misleading pharmaceutical promotion.

The Article proceeds as follows. In Part II, I review the circumstances under which the government can adopt a prophylactic rule that targets false and misleading commercial speech but incidentally sweeps in some truthful, non-misleading speech. I also review the discussions of false and misleading prescription drug promotion in Washington Legal Foundation v. Friedman, the highly-influential district court decision invalidating the ban on off-label promotion as applied to continuing medical education courses, medical textbooks, and peer-reviewed journal articles, and Thompson v. Western States,19 in which the Supreme Court invalidated restrictions on pharmacists' promotion of drug compounding. Notably, while the WLF Court used broad freedom-of-speech favoring language, the injunction it adopted was "narrowly applicable"20 and incorporated requirements- for example that companies could only distribute reprints of articles that originally appeared in bona-fide peer-reviewed journals- that without doubt excluded truthful, nonmisleading speech from constitutional protection. In Part III, I analyze a number of prophylactic bans of other types of commercial speech that have withstood constitutional challenge and point to commonalities they share with the promotion of pharmaceuticals to physicians. Finally, in Part IV, I review the extant empirical evidence of false and misleading prescription drug promotion, as well as the enforcement challenges the FDA confronted before the adoption of the ban on off-label promotion and would confront were the ban lifted. I conclude that the government likely could develop the factual record necessary to establish "that in fact [off-label promotion] is subject to abuse" and, thereby, establish that Congress' rejection of an after-the-fact case-by-case approach to policing such promotion is constitutional.21

II. COMMERCIAL SPEECH DOCTRINE, FALSE OR MISLEADING SPEECH, AND THE BAN ON OFF-LABEL PROMOTION

To determine whether commercial speech regulation comports with the Constitution, courts apply the familiar test set forth in Central Hudson Gas & Electric Corp. v. Public Service Commission.22 The test's first prong is "whether the expression is protected by the First Amendment."23 Speech that concerns unlawful activity or is false, deceptive, or misleading is unprotected and thus the analysis ends.24 If "truthful and nonmisleading expression will be snared along with fraudulent or deceptive commercial speech,"25 a court must move to the Central Hudson test's second prong, "whether the asserted governmental interest is substantial," third prong, "whether the regulation directly advances that interest," and fourth prong, "whether the regulation is more extensive than necessary to serve the asserted interest."26 The government bears the burden of demonstrating that its regulation meets the Central Hudson test and if it can "achieve its interests in a manner that does not restrict speech, or that restricts less speech, [it] must do so."27

A. THE SUBSTANTIAL GOVERNMENT INTEREST IN ENSURING THE ACCURACY OF PRESCRIPTION DRUG PROMOTION

In Washington Legal Foundation v. Friedman, the court determined as a preliminary matter that the off-label information contained in the continuing medical education courses, medical textbooks, and peer-reviewed journal articles at issue was true, or, at least, not always or necessarily false.28 In response to an argument from the FDA that the FDCA "prescribes a specific system for determining the 'truth' of claims about drugs and devices"- making off-label promotion per se false or misleading- the court famously wrote that the agency "exaggerate[d] its overall place in the universe."29 The WLF court concluded that the government did not have a legitimate interest in "ensuring that physicians receive accurate and unbiased information so that they may make informed prescription choices . . . ."30

By contrast, the WLF court found that the government's interest in "providing manufacturers with ample incentive to get previously unapproved uses on label" was both legitimate and substantial.31 The court explained that it would not revisit Congress' conclusion that "it benefits the public health to require manufacturers to get all uses approved by the FDA" because doing so would require the court to decide a policy question, namely "whether compelling manufacturers to get new uses on-label is wise government policy when considered against the backdrop of present day medical realities, financial constraints and procedural burdens . . . ."32 The WLF court also determined that the ban on off-label promotion was a reasonable means to the end of preserving the integrity of the new drug approval process.33 As the FDA has explained, "[t]he new drug approval process would be crippled if drug manufacturers could obtain approval of a drug for one use, then promote the drug for other, unapproved uses without first demonstrating through the approval process that the drug was safe and effective for each new use."34

While the WLF court declined to hold that off-label promotion was per se false or misleading, its discussion of the issues suggests that it took seriously the government's concerns about false or misleading pharmaceutical promotion. First, the WLF court explained that there were "less-burdensome alternatives" to the challenged restrictions on disseminating journal articles and textbooks and supporting continuing medical education programs. The "most obvious" alternative was "full, complete, and unambiguous disclosure by the manufacturer"35 that the FDA had not approved the use or uses discussed. Such a disclosure would not seem to advance the government's interest in preserving manufacturers' incentive to file supplemental new drug applications, however. The court did not deny this, explaining that the purpose of the disclosure would be to "assuage[] concerns that the message communicated is inherently or potentially misleading."36

Relatedly, the WLF court took pains to emphasize that there remained a number of levers available to the FDA "to ensure that the information manufacturers wish to distribute is scientifically reliable."37 The FDA could require that companies limit their distribution of off-label article reprints to those that appeared in "bona fide peer-review journal[s]" and their distribution of textbooks to those published by "bona fide independent publisherCs]."38 The FDA could also bar companies from funding off-label continuing medical education sessions unless they were developed and presented by an accredited "independent program provider."39

The WLF court did not spell out why the First Amendment permitted these limits which, while less restrictive than a blanket ban on off -label promotion, nonetheless sweep in a significant amount of true, non-misleading speech. There is no connection between these requirements and the government's interest in preserving manufacturers' incentive to file supplemental new drug applications, except that they limit the type (and thereby, perhaps, the amount) of off-label promotion that companies can do.40 If restricting the amount of off-label promotion to preserve the incentive to file were the only goal, a system in which manufacturers could engage in a limited amount of off-label promotion using the method or methods of their choice might hew more closely to First Amendment ideals. For example, a company could choose to promote an off-label use by having its sales representatives conduct a limited number of sales calls, sponsoring a limited number of speaker programs, or buying a limited number of print advertisements in medical journals. That the WLF court did not consider alternatives like this, or, for that matter, question the need to ensure that the information disseminated was "scientifically reliable," is further evidence that it did not discount the FDA's concerns about false or misleading off-label promotion. The outcome of the case is telling: the court's injunction was "narrowly applicable,"41 and the off-label promotion ban continued to be sweeping.

In Thompson v. Western States, the Supreme Court did not tarry on the initial inquiry into whether the regulated speech was protected by the First Amendment because the government did not claim that an advertisement informing patients that a pharmacist could compound particular drugs would be false or misleading.42 The government's concern was that if compounding services were advertised, more patients would ask their doctors to prescribe compounded drugs. This would upset the delicate balance that Congress hoped to strike between maintaining the integrity of the new drug approval process, on the one hand, and preserving access to unstudied compounded formulations for individual patients in need, on the other.

Like the WLF court, the Western States court held that preserving the integrity of the new drug approval process is a sufficiently substantial government interest to support regulation.43 The court nonetheless invalidated the proscription of compounding advertising because it found that Congress gave inadequate consideration to "non-speech-related means of drawing a line between [small-scale] compounding," which would not threaten the new drug approval process, "and large-scale manufacturing," which could.44 After arriving at this holding, the court went on to state that even if compounding advertising were misleading, banning it would not be a reasonable response because the government could take "the far less restrictive alternative of requiring each compounded drug to be labeled with a warning that the drug had not undergone FDA testing and that its risks were unknown."45 This suggestion should be limited to the facts of the case. It is hard to believe that the First Amendment would limit the government's arsenal against misleading advertising to the use of a disclaimer that consumers would only be exposed to once they had already purchased the product being advertised.

As a general matter, "[t]here is no question that [the governmental] interest in ensuring the accuracy of commercial information in the marketplace is substantial,"46 and neither WLF nor Western States creates an exception for pharmaceutical marketing. The government cannot limit physicians' access to scientifically reliable materials solely because they demand critical evaluation. It can, however, place limits on prescription drug promotion, to preserve the integrity of the new drug approval process, but also to ensure that the information conveyed is not false or misleading.47

B. THE QUESTION OF "FIT"

Once a court holds that a speech regulation serves a substantial government interest, the court must evaluate whether the regulation directly and materially advances the interest and whether in doing so the regulation sweeps in no more truthful speech than necessary.48 In determining whether a regulation sweeps more broadly than necessary, courts consider whether the regulation leaves alternative speech channels open and whether there are lessspeech-limiting approaches that would achieve the same ends.49

While there is not a perfect fit between the very rigorous new drug approval process and the false and misleading off-label promotion that the FDA would like to suppress, perfection is not required,50 particularly where the false or misleading speech in question has potential public health implications.51 The agency's focus in deciding whether to approve a drug for a new use is on the advisability of using the drug to treat a given disease or condition; its primary concern is not what truthful claims the manufacturer can make about the drug. That said, the approval process does directly and materially advance the goal of ensuring that pharmaceutical product promotion is truthful and non-misleading, because manufacturers are required to develop "a certain 'floor' of risk-benefit information" for each approved use.52 As a result, manufacturers are likely to have the information they need to contextualize, qualify, and otherwise ensure that their on-label promotional claims are not misleading. Also of relevance to the question of fit is the fact that while "off-label promotion" is banned, avenues for dissemination of off-label information exist. In addition, the ban can, in many cases, be surmounted by conducting the necessary further research and submitting a supplemental new drug application.

III. RECENT CASE LAW REGARDING PROPHYLACTIC COMMERCIAL SPEECH REGULATION

A. CASE LAW UPHOLDING LEGISLATIVE DETERMINATIONS OF THE TRUTH OF PARTICULAR CLAIMS

In several recent false advertising cases, courts reviewed legislative determinations of the truth of particular claims and upheld them against First Amendment challenges. These holdings are not directly applicable to the ban on off-label promotion, which extends beyond any particular claim or claims. They do, however, indicate courts' openness to what Professor Rebecca Tushnet terms a "wholesale" approach to commercial speech regulation.53

In Benson v. Kwikset, a California appeals court upheld a state statute forbidding the use of the claim "Made in the U.S.A." unless the product in question was substantially made here from parts that were also substantially made here.54 The Benson court held that the statute was constitutionally permissible because it "constitute[d] a legislative determination that representations suggesting merchandise was made in the United States are misleading unless the producer's manufacturing processes satisfy the strictures of the statute."55

In another California case, Bronco Wine Company v. Jolly, an appeals court found similarly, that a state statute prohibiting the use of the word "Napa" to advertise a wine unless a large percentage of the grapes used to make the wine were grown in Napa County was "a valid regulation of inherently misleading commercial speech."56 Of relevance to the ban on offlabel promotion, the court also held that while "more sophisticated wine consumers may not be misled . . . the Legislature could reasonably conclude that not all wine consumers are equally knowledgeable."57

Lastly, in Piazza's Seafood World v. Odom, the Fifth Circuit found that a statute providing that "[n]o person shall advertise, sell, offer or expose for sale, or distribute food or food products as 'Cajun,' 'Louisiana Creole,' or any derivative thereof unless the food or food product . . . [was] produced, processed, or manufactured in Louisiana" could not be enforced against the plaintiff in the case.58 The plaintiff imported fish from China and sold the fish under the labels "Cajun Boy" and "Cajun Delight."59 Because the plaintiff labeled his fish with the country of origin and sold mainly to wholesalers, the Fifth Circuit affirmed the district court's finding that the plaintiff's use of the word "Cajun" was not misleading.60 Despite its finding that the word "Cajun" was not misleading under the circumstances, the district court declined to find the statute facially invalid.61 The district court noted that "in some cases the use of the term Cajun to describe non-Louisiana products would be inherently misleading and inherently misleading speech is not subject to First Amendment protections."62 The district court concluded that there "surely" would be "factual scenarios where the Cajun Labeling Law will apply unfettered by a First Amendment challenge."63

B. CASE LAW UPHOLDING BANS OR OTHER REGULATION OF PARTICULAR PROMOTIONAL METHODS

There are also a number of recent false advertising cases in which the courts have upheld bans or other regulation not of specific claims but of particular promotional methods. In Walraven v. NC Board of Chiropractic Examiners, the Fourth Circuit affirmed a district court decision finding constitutional a ninety-day waiting period for in-person or telephonic solicitation of accident victims by chiropractors.64 After concluding that "nondeceptive advertising of chiropractic services is protected speech under the First Amendment," the district court determined that the challenged regulations materially advance at least one substantial governmental interest- "the protection of a particular segment of the public from invasive (and potentially coercive and/or misleading) solicitation tactics under circumstances in which they may be particularly vulnerable."65 The court went on to find that the regulations satisfied the third and fourth prongs of the Central Hudson test because they "singl[ed] out for regulation only speech which is particularly susceptible to fraud and overreaching (i.e., in -person and telephonic solicitation) and which is targeted at a protected class (i.e., recent victims of car accidents)."66

The court next examined whether the plaintiff's proposed less-restrictive alternative, that she be permitted to telemarket using a proposed script "from which . . . her contracted telemarketers would be instructed not to deviate," was a viable substitute for the challenged regulations.67 The court found that it was not, explaining as follows:

Written solicitations are capable of being screened for compliance by a state regulatory authority before they are ever mailed. By contrast, telephonic solicitations (even scripted ones) do not take place in a controlled environment and improper deviations from the script are not susceptible to detection until after the harm is done (provided that a disgruntled consumer even bothers to report the violation to the relevant authorities) . . . .68

Similarly, in Goodman v. Illinois Department of Financial and Professional Regulation, the Seventh Circuit upheld an Illinois law forbidding medical professionals from using agents to market their services against a challenge from a chiropractor who wanted to engage in telemarketing.69 The plaintiff chiropractor "claimed that he would take special care to ensure that his telemarketers did not deviate from their prepared script and did not impart false and misleading information."70 He also claimed that his efforts would benefit the recent car accident victims he planned to target because there are health benefits associated with immediate treatment.71 The government argued that the ban furthered significant interests including "protecting the public against overreaching and protecting the medical profession's integrity and professionalism."72 The government also noted that other forms of advertising were allowed and "that policing chiropractor telemarketing throughout the state of Illinois would be impractical, as there are over fifty chiropractors in Springfield alone, and many telemarketers make over twenty calls per day."73

The Seventh Circuit upheld the district court's denial of the plaintiffs motion for preliminary injunction for two related reasons. First, because professionals render services rather than sell standardized products, the Supreme Court has held that there is a "consequent enhanced possibility for confusion and deception if they were to undertake certain kinds of advertising."74 Second, the case involved personal solicitation, which the Supreme Court has held to be "rife with possibilities of overreaching, invasion of privacy, the exercise of undue influence, and outright fraud."75 Personal solicitation also "present[s] 'unique difficulties' for regulation because it [is] not open to public scrutiny."76 If the government were forced to take a caseby-case approach to regulation, such solicitation "would be virtually immune to effective oversight and regulation."77

Although health care professionals approached in their professional capacity would seem to have little in common with vulnerable recent accident victims, the discussion in both Walraven and Goodman is highly relevant to the ban on off-label promotion, because so much pharmaceutical promotion occurs in private. The traditional one-on-one encounter between a sales representative and a doctor in the doctor's office is still commonplace.78 Companies also engage physicians to give promotional talks to their fellow doctors, typically over a restaurant meal.79

In a recently-published article presenting the results of a study of fortyone complaints containing allegations of off-label marketing that were filed by whistleblowers and taken up by the Department of Justice between January 1996 and October 2010, Aaron Kesselheim and his co-authors wrote that in most such cases, whistleblowers "reported that private conversations between sales representatives and prescribers were a leading strategy for off-label promotion."80 The study authors noted that "[t]he fact that so many of the communications are oral and take place in private offices makes them very difficult for regulators to monitor and sanction."81 Perhaps in response to such concerns, the WLF court emphasized that it was not holding that companies could "initiate person-to-person contact with a physician about an off-label use."82

IV. OFF-LABEL PROMOTION: FALSE OR MISLEADING?

Whether a commercial speech regulation is a fit with the government interest it serves is a mixed question of law and fact.83 In a recent election law decision, Chief Justice John Roberts, joined by Justice Samuel Alito, suggested that this is not the case when a regulation governs political speech.84 They wrote that it would not be appropriate to look to the facts to determine "the actual effect speech will have."85 Doing so: "'puts the speaker . . . wholly at the mercy of the varied understanding of his hearers.' It would also typically lead to a burdensome, expert-driven inquiry, with an indeterminate result," which would "unquestionably chill a substantial amount of political speech."86

In commercial speech cases, by contrast, the courts do consider speech's "actual effect[s]."87 Regulations are permissible "where the record indicates that a particular form or method of advertising has in fact been deceptive."88 Commercial speech doctrine does not precisely specify the level of deception necessary to justify a prophylactic regulation. Must the government show that a given claim or promotion method is more often deceptive than not89 or is a "serious" risk of deception sufficient?90 Should the rule that governs in Lanham Act false advertising cases, that a claim is misleading if a substantial percentage (typically fifteen to twenty percent) of a company's customers is misled by it, be imported into commercial speech cases?91 The answer to these questions is likely to vary from case to case, with courts balancing the cost of suppressing more speech than necessary against the cost of failing to suppress false or misleading speech, taking into account the nature of the speech at issue.92

Courts often rely on their common sense and intuition in determining whether deception has occurred. For example, in Bates v. State Bar of Arizona, the Supreme Court invalidated a ban on attorney advertising in part because "[w]e suspect that, with advertising, most lawyers will behave as they always have: They will abide by their solemn oaths to uphold the integrity and honor of their profession and the legal system."93 Similarly, the WLF court asserted that physicians are knowledgeable and sophisticated and that their "livelihood depends upon the ability to make accurate, life-and-death decisions based upon the scientific evidence before them."94 As a result, the court concluded, "[t]hey are certainly capable of critically evaluating journal articles or textbook reprints that are mailed to them, or the findings presented at CME seminars."95

The better approach is for a court to evaluate a commercial speech regulation based on the facts that support it. In Florida Bar v. Went for It, the Court relied on the government's "106-page summary of its 2-year study of lawyer advertising and solicitation to the District Court," as well as an "anecdotal record . . . noteworthy for its breadth and detail" in upholding a thirty-day moratorium on direct-mail solicitation of accident victims and their families by personal injury lawyers.96 The Bronco Wine court held that the legislative finding that the descriptor "Napa" was inherently misleading was adequately supported by "the regulatory history of brand names of geographic significance," hearing testimony, and a survey.97 By contrast, in invalidating a ban on in-person solicitation by accountants, the Supreme Court in Edenfield v. Fane cited the Board of Accountancy's failure to present either studies or anecdotal evidence to "validate[] the Board's suppositions."98

The evidence that misleading off-label claims were commonplace before the ban's adoption and persist today, combined with the enforcement challenges the FDA confronted at that time and would confront were the ban lifted, suggest that the government would be able to make the factual showing necessary to support the ban on off-label promotion. As Congressman Henry A. Waxman has highlighted, the hearings leading up to the adoption of the 1962 Harris-Kefauver Amendments to the FDCA included testimony that "'educational' efforts by detailmen, widely used by the pharmaceutical companies to promote products out of sight of regulatory scrutiny, and relied on more heavily by physicians than any other source of drug information, were misleading physicians about the true merits of prescription drugs."99 Congress had heard testimony that "physicians were being inundated with promotional material from drug companies that was misleading and unreliable, often in subtle ways."100 A physician, Dr. Ian Stevenson, testified that "advertising brochures" frequently included "partially or completely spurious" bibliographies of "ostensibly scientific publications to which the reader can turn for fuller details of the benefits claimed for the drugs."101 After the passage of the 1962 Amendments, the FDA asked the National Academy of Sciences-National Research Council (NAS-NRC) to conduct a review of 16,500 claims made regarding 4,000 drugs marketed under new drug applications between 1938 and 1962. 102 The NAS-NRC found that seventy percent of the claims lacked substantial effectiveness evidence.103

While studies of the false or misleading nature of drug promotion are not numerous, what evidence there is suggests that the problems Congress uncovered in the 1950s and 1960s have not been completely eradicated. Writing in the American Journal of Bioethics in 2010, the physician and professor Paul S. Appelbaum characterized the quality of the verbal and written information that sales representatives disseminate to doctors as "questionable at best."104

A study of 106 statements about drugs made by pharmaceutical sales representatives over the course of thirteen lunchtime presentations in 1993 found that eleven percent of the statements were inaccurate, and that physicians generally failed to recognize the inaccuracies.105 For example, one sales representative claimed that "[w]e are the only SSRI that has long-term data[,]" while the authors found, among other things, that there was a competing drug with "much-longer-term clinical and research data."106 Another representative claimed, 'Your Medical Letter this month has a favorable review of drug E. This is with regard to rapid hemodynamic effect of drug E after a single dose increasing the cardiac index," but the researchers found that "[a] copy of the Medical Letter available at this talk stated that a drug different from drug E was preferred and made no mention of a rapid hemodynamic effect or of the cardiac index."107

With regard to off-label promotion in particular, Dr. Kesselheim and his colleagues found that three-quarters of the complainants in the cases they reviewed alleged that "off-label use was frequently encouraged through selfserving presentations of the scientific literature through which physicians were given false or unbalanced study data supporting the unapproved use."108 Among the alleged techniques were (1) "selective presentation of favorable studies, where dangers from the off-label uses allegedly being promoted were not mentioned," (2) "presenting one drug as being superior to another when no head-to-head studies had been conducted," and (3) "characterizing reports of individual cases or poorly designed studies as definitive evidence supporting an off-label use."109

Written advertisements and promotional materials have also been found wanting. A 2009 systematic review of twenty-four studies of medical journal advertising found that "all studies that assessed misleading claims had at least one advertisement with a misleading claim," with the reported rate of misleading claims varying widely from "relatively few" to all.110 The rate of "unambiguous clinical claims" as a proportion of all claims was consistently low.111 The review authors acknowledged that "it is difficult to judge misleading claims," and opined that there is a "need for development of a widely accepted definition of a misleading claim and development of well described methods that can be used in different countries and years to enable comparisons."112

Existing empirical evidence aside, we can predict that the government would be able to develop new evidence of false or misleading off-label promotion for a number of reasons.113 It is difficult for anyone to adequately describe and characterize the quality and quantity of a body of scientific evidence in a one-page leave behind, never mind in a several minute verbal encounter. Doing so may be especially challenging for the many pharmaceutical representatives who lack a scientific background. These difficulties are compounded in the case of off-label uses because there is no label neatly summarizing the most relevant data in a non -misleading fashion for companies to use as a guide, and because there are frequently large gaps in our knowledge about such uses. A study analyzing on- and off-label use of 160 commonly prescribed drugs for 2001 found that "most [off-label uses] (73%) lacked evidence of clinical efficacy, and less than one third (27%) were supported by strong scientific evidence . . . ."114

It is not enough for claims to be true; they must also be non -misleading.115 The FDCA provides as follows:

If an article is alleged to be misbranded because the labeling or advertising is misleading, then in determining whether the labeling or advertising is misleading there shall be taken into account (among other things) not only representations made or suggested by statement, word, design, device, or any combination thereof, but also the extent to which the labeling or advertising fails to reveal facts material in light of such representations or material with respect to consequences which may result from the use of the article to which the labeling or advertising relates under the conditions of use prescribed in the labeling or advertising thereof or under such conditions of use as are customary or usual.116

To be non-misleading, promotional claims must be contextualized, qualified, and tempered with information about contraindications and side effects. Sales and marketing personnel are under intense pressure to put products in the best possible light. They have little to no incentive to gather and present the evidence underlying an off-label use in a nuanced way. As a result, claims that drugs are safe and effective for uses that do not appear on their FDAapproved labels are likely to state or imply that the scientific support for the off-label use is stronger than it is.

Busy, boundedly rational physicians are an inadequate check on companies' tendencies to overstate the scientific support for off-label uses.117 Without "detailed expertise in the field . . . the physician being detailed is hard-pressed to contextualize the information being presented, or even simply to distinguish true from false information."118 Even if physicians had the time and training needed to fact check sales representatives' claims, the promotional materials representatives provide do not facilitate such research. A study of 196 advertisements distributed by pharmaceutical companies to three different practice settings in California in late 1993 and early 1994, for example, found that eighty percent included unsupported claims.119 Finally, even with time and training, adjusting for advisor bias is difficult.120 Adjusting for falsity is impossible.

In addition to evidence of widespread false or misleading drug promotion, the hearings leading up to the adoption of the 1962 Harris-Kefauver Amendments to the FDCA also revealed that "postmarket enforcement actions against misleading claims were almost always futile because they took 'months or even years.'"121 While the enforcement actions were pending, the drugs stayed on the market causing harm. Congressman Waxman cites a Federal Trade Commission report showing "that actions against misleading advertising completed between 1955 and 1957 took from several months up to nine years," which gave companies time to develop "new, often equally misleading" marketing messages.122

Currently, the FDA's Division of Drug Marketing, Advertising, and Communications (DDMAC) is responsible for policing claims made in prescription drug advertisements after they are made, but DDMAC only has the resources to review a tiny percentage of such claims.123 While the agency has grown somewhat in recent years, it "still has just 57 officials charged with reviewing roughly 75,000 marketing items a year."124 DDMAC frequently cites companies for on-label yet false or misleading advertisements, including those that: (1) overstate a drug's efficacy;125 (2) include unsubstantiated comparative claims;126 or (3) omit or minimize risk information.127

In August 2009, FDA Commissioner Margaret Hamburg announced the FDA Enforcement Initiative.128 Reversing a policy that had been in place since January of 2002, she authorized DDMAC to release warning and so-called "untitled" letters without subjecting them to Office of Chief Counsel review. 129 While DDMAC issued an average of just twenty-four letters a year in the last six years of the Bush Administration, it sent out forty-one letters in 2009 and it had already sent out forty by July 22, 2010. 130 Despite the uptick, Commissioner Hamburg testified before Congress as follows: "We do review the ads and can take action when we think there are misrepresentations or inadequate presentation of risks, but the volume makes it very, very difficult. . . . The fact is: we don't review them, sign off, and then they go up."131

If the ban on off-label promotion were lifted, DDMAC's job would become much more difficult, because the FDA-approved label is the foundation of the Division's review. Moreover, the Division has very limited ability to police the thousands of individual, in-person interactions between physicians and sales representatives.132 Manufacturers find it difficult to self-police under these circumstances.133

In addition to the FDA, the Department of Justice, state Attorneys General, and other government actors actively and aggressively enforce the ban on off-label promotion; companies are also exposed to liability under the False Claims Act when off-label promotion causes government payors to reimburse for uncovered off-label uses.134 If the off-label promotion ban were lifted, a cause of action for misbranding under the FDCA would still be available, but only where the government could show that a product's labeling or advertising was false or misleading.135 Because most pharmaceutical promotion takes place in private, in doctors' offices and at restaurants, sussing out false or misleading claims would be difficult or impossible. Where the government did become of aware of such claims, enforcement actions would take months or even years, as they did before the adoption of the Harris - Kefauver Amendments, and they would require significant resources to prosecute successfully. Defendants would benefit from the fact that, as Professor Tushnet has argued, it is not easy, "at the granular level," to determine whether a particular advertisement is false.136 The fact patterns of false advertising cases like those discussed above parsing "Cajún," "Napa," and "Made in the U.S.A.," lead Professor Tushnet to conclude that "falsity, misleadingness, and meaning itself are often debatable."137 It is especially difficult to determine whether claims about the safety and efficacy of drugs are true, because of the nature of biomedical science. In this arena, all stakeholders- including the FDA, manufacturers, clinical investigators, epidemiologists, prescribers, and patients- contend with complexity, uncertainty, and ignorance in their struggle to understand the effects of drugs on the human body.

V. CONCLUSION

Invalidating the prohibition on off-label promotion would not affect the FDA's requirement that a drug be approved by the agency before it can be sold in interstate commerce.138 Once a drug was approved as safe and effective for one use, however, its manufacturer would be free to promote it for any other use. Regulators and prosecutors would be limited to policing manufacturer speech after-the-fact on a case-by-case basis. This is problematic because it would be ineffective.

Courts deciding commercial speech cases often repeat the refrain that false and misleading speech is entitled to no protection at all. And free speech advocates often claim that they are only concerned about a particular regulation to the extent that it applies to truthful speech. But there is no way to gain the benefits of false advertising law without sweeping in some truthful speech. Even consumer fraud suits can be decided incorrectly or have a chilling effect. Given medicine's high stakes, it is neither surprising nor unconstitutional that the prophylactic rule that governs drug claims suppresses some truthful speech.

Footnote

1 Drug Industry Act of 1962: Hearing on H.R. 11581 and H.R. 11582 before the H. Comm. on Interstate and Foreign Commerce, 87th Cong. 505 (1962), at 505 (statement of Miles H. Robinson, M. D.).

2 Id.

3 Drug Amendments of 1962 (Kefauver-Harris Amendments), Pub. L. No. 87-781, 76 Stat. 780, 781 (codified as amended 21 U.S.C. § 505(b) (2008)).

4 Drug Amendments of 1962, § 102(c), 76 Stat, at 781 (2008).

5 Barbara J. Evans, Seven Pillars of the New Evidentiary Paradigm: The Food, Drug, and Cosmetic Act Enters the Genomic Era, 85 Notre Dame L. Rev. 419, 434 (2010).

6 Wash. Legal Found, v. Friedman, 13 F. Supp. 2d 51, 55-56 (D.D.C. 1998), order amended by 36 F. Supp. 2d 16 (D.D.C. 1999), vacated in part by Wash. Legal Found, v. Henney, 202 F.3d 331 (D.C. Cir. 2000).

Footnote

7 See Kate Greenwood, TAe Mysteries of Pregnancy: The Role of Law in Solving the Problem of Unknown but Knowable Maternal-Fetal Medication Risk, 79 U. Cin. L. Rev. 267, 291-94 (2010).

8 See Investigational New Drug Application, 21 C.F.R. § 312.7(a) (2010) (banning promotion of investigational new drugs with the caveat that this "is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media").

9 See Citizen Petition Regarding the Food and Drug Administration's Policy on Promotion of Unapproved Uses of Approved Drugs and Devices; Request for Comments, 59 Fed. Reg. 59,820, 59,823 (Nov. 18, 1994) (providing that "information on unapproved uses may be disseminated through the submission of original research to peer-reviewed publications").

10 Id. (providing that "companies may . . . disseminate information on unapproved uses in response to unsolicited requests for scientific information from health care professionals").

11 Final Guidance on Industry-Supported Scientific and Educational Activities, 62 Fed. Reg. 64,074, 64,093-100 (Dec. 3, 1997).

12 See Office of Policy, Office of the Comm'r, Food and Drug Admin., Guidance for Industry - 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 (2009), available at http://www.fda.gov/ReguIatoryInformation/Guidances/ucml25126.htm.

13 See, e.g., John. E. Osborn, Can I Tell You the Truth? A Comparative Perspective on Regulating Off-Label Scientific and Medical Information, 10 Yale J. Health Pol"y L. & Ethics 299, 318 (2010) ("However ... no federal appellate court and very few other federal district courts have had the occasion to opine on the question of whether the FDA's policy of prohibiting the dissemination of truthful, non-misleading off-label scientific and medical information is unconstitutional"); Ralph F. Hall & Elizabeth S. Sobotka, Inconsistent Government Policies: Why FDA Off-Label Regulation Cannot Survive First Amendment Review Under Greater New Orleans, 62 Food & Drug L.J. 1, 8 (2007) ("The issue that concerns the authors is whether FDA can prohibit truthful, off-label speech"); A. Elizabeth Blackwell & James M. Beck, Drug Manufacturers' First Amendment Right to Advertise and Promote Their Products for Off-Label Use: Avoiding a Pyrrhic Victory, 58 Food & Drug L.J. 439, 451 (2003) ("Further, FDA cannot justify the prohibition on truthful promotion of offlabel uses by asserting concern that physicians might misuse the information provided in making their prescription choices.").

Footnote

14 Memorandum of Law in Support of Motion for Preliminary Injunction at 3, Allergan v. United States, No. l:09-cv-01879-JDB (D.D.C. Oct. 1, 2009).

15 44 Liquormart v. Rhode Island, 517 U.S. 484, 503 (1996) (Stevens, J., Kennedy & Ginsburg, JJ., joining).

16 Id.

17 Id. at 501 (citation omitted).

18 Henry A. Waxman, A History of Adverse Drug Experiences: Congress Had Ample Evidence to Support Restrictions on the Promotion of Prescription Drugs, 58 Food & Drug LJ. 299, 303 (2003).

19 Wash. Legal Found, v. Friedman, 13 F. Supp. 2d 51, 74-75 (D.D.C. 1998); Thompson v. W. States Med. Ctr., 535 U.S. 357, 357 (2002).

20 Wash. Legal Found, v. Friedman, 13 F. Supp. 2d at 87.

Footnote

21 In re R.M.J., 455 U.S. 191, 203 (1982).

22 Cent. Hudson Gas & Elee. Corp. v. Pub. Serv. Comm'n, 447 U.S. 557, 566 (1980).

23 Id.

24 Ibanez v. FIa. Dep't of Bus. & Profl Regulation, Bd. of Accountancy, 512 U.S. 136, 142 (1994) ("[0]nly false, deceptive, or misleading commercial speech may be banned.").

25 Edenfield v. Fane, 507 U.S. 761, 768-69 (1993).

26 Intl Dairy Foods Ass'n v. Boggs, 622 F.3d 628, 636 (6th Cir. 2010).

27 Thompson v. W. States Med. Ctr., 535 U.S. 357, 371 (2002).

28 Wash. Legal Found, v. Friedman, 13 F. Supp. 2d 51, 67 (D.D.C. 1998).

29 Id.

30 Id. at 69-70.

Footnote

31 Id. at 56, 69-71.

32 Id. at 71.

33 Id. at 66 (explaining that because "the drugs subject to off-label prescriptions are already in interstate commerce . . . the obvious restriction on conduct is unavailable. Therefore, one of the few mechanisms available to FDA to compel manufacturer behavior is to constrain their marketing options; i.e. control the labeling, advertising and marketing."). Without the ban on off-label promotion, companies' incentives would weigh heavily in favor of ignorance. See generally Greenwood, supra note 7, at 280-306 (explaining that neither the three additional years of data exclusivity awarded under the Drug Price Competition and Patent Term Restoration Act of 1984 nor products liability law provide adequate incentives for knowledge-development).

34 Defendants' Reply in Support of Motion to Dismiss or for Summary Judgment and Response to Cross-Motion for Summary Judgment at 2, Allergan v. United States, No. 1:09CV-01879-JDB (D.D.C. Mar. 29, 2010).

35 Wash. Legal Found, v. Friedman, 13 F. Supp. 2d at 73.

36 Id.

37 Id. at 68.

Footnote

38 Id.

39 Id. at 69.

40 In fact, in a later decision the WLF court opined that "restricting] constitutionally protected speech as an incentive device" is "a kind of constitutional blackmail" that "cannot survive judicial scrutiny." Wash. Legal Found, v. Henney, 56 F. Supp. 2d 81, 86 n.7, 87 (1999).

41 Id.

42 Thompson v. W. States Med. Ctr., 535 U.S. 357, 368 (2002).

43 Id. at 369 ("Preserving the effectiveness and integrity of the FDCA's new drug approval process is clearly an important governmental interest, and the Government has every reason to want as many drugs as possible to be subject to that approval process.").

Footnote

44 Id. at 372.

45 Id. at 376.

46 Edenfield v. Fane, 507 U.S. 76l, 769 (1993).

47 Wash. Legal Found, v. Friedman, 13 F. Supp. 2d 51, 72-73 (D.D.C 1998).

48 Central Hudson, 447 U.S. at 566.

49 See 44 Liquormart v. Rhode Island, 517 U.S. 484, 529-30 (O'Connor, J., joined by Rehnquist, C.J., Souter & Breyer, JJ., concurring) (explaining that "[i]f alternative channels permit communication of the restricted speech, the regulation is more likely to be considered reasonable!]]" and that "[t]he availability of less burdensome alternatives to reach the stated goal signals that the fit between the legislature's ends and the means chosen to accomplish those ends may be too imprecise to withstand First Amendment scrutiny").

50 Lorillard Tobacco Co. v. Reilly, 533 U.S. 525, 556 (2001) ("We have made it clear that 'the least restrictive means' is not the standard; instead, the case law requires a reasonable 'fit between the legislature's ends and the means chosen to accomplish those ends, ... a means narrowly tailored to achieve the desired objective.'").

51 See Pearson v. Shalala, 164 F.3d 650, 659 (D.C. Cir. 1999) (taking issue with four specific FDA decisions regarding health claims about dietary supplements and remanding to the FDA to "draft precise disclaimers for each of appellants' four claims[,]" without "rul[ing] out the possibility that where evidence in support of a claim is outweighed by evidence against the claim, the FDA could deem it incurable by a disclaimer and ban it outright"). Notably, when passing the revisions to the FDCA at issue in Pearson, Congress found that "safety problems with supplements are relatively rare." Dietary Supplement Health and Education Act of 1994, Pub. L. No. 103-417, § 2(14), 108 Stat. 4325, 4326 (finding that dietary supplements are "safe within a broad range of intake, and safety problems with the supplements are relatively rare"). Given the absence of a risk that consumers would be harmed, except by having their too-high expectations dashed, the court's paternalism concerns were heightened. Pearson, 164 F.3d at 656. The Pearson court took care to distinguish dietary supplements from drugs, which "appear to be in an entirely different category- the potential harm presumably is much greater." Id. at 656 n.6.

Footnote

52 Evans, supra note 5, at 488 ("FDA's traditional premarket study requirements continue in effect and will provide a certain 'floor' of risk-benefit information that will be available for all approved drugs (although, as has been the case before FDAAA, this floor will be somewhat moveable based on the choice of clinical trial endpoints).").

53 Rebecca Tushnet, It Depends on What the Meaning of "False" Is: Falsity and Misleadingness in Commercial Speech Doctrine, 41 Loy. L.A. L. Rev. 227, 227-28 (2007) ("A key issue in advertising law is whether regulation of deception can be wholesale or retail.").

54 Benson v. Kwikset Corp., 152 CaI. App. 4th 1254, 1268 (CaI. 2007); see aho, e.g., Joe Conte Toyota, Inc. v. La. Motor Vehicle Comm'n, 24 F.3d 754, 754 (5th Cir. 1994) (upholding ban on use of "invoice price"); Adams Ford Belton, Inc. v. Mo. Motor Vehicle Comm'n, 946 S.W.2d 199, 203-05 (Mo. 1997) (same); Barry v. Arrow Pontiac, Inc., 494 A.2d 804, 815 (N.J. 1985) (same).

Footnote

55 Benson, 152 CaI. App. 4th at 1268.

56 Bronco Wine Co. v. Jolly, 129 CaI. App. 4th 988, 999 (2005).

57 Id. at 1011.

58 Piazza's Seafood World, LLC v. Odom, 448 F.3d 744, 747 n.7 (5th Cir. 2006).

59 Id. at 747.

60 Id. at 753.

61 Id.

62 Piazza's Seafood World, LLC v. Odom, No. 04-690, 2004 U.S. Dist. LEXIS 25991, at *23 (E.D. La. Dec. 22, 2004).

63 Id.

Footnote

64 Walraven v. NC Bd. of Chiropractic Exam'rs, 273 F. App'x 220, 226 (4th Cir. 2008).

65 Id. at 224-25 (quoting Walraven v. Cooper, No. 3:04-cv-21-W, 2007 WL 656284, at *2 (W.D.N.C. Feb. 27, 2007)).

66 Id. at 225 (quoting Walraven v. Cooper, 2007 WL 656284, at *3).

67 Id. at 225-26.

68 Id. at 226.

69 Goodman v. 111. Dep't of Fin. & Profl Regulation, 430 F.3d 432, 435 (7th Cir. 2005); see also Capobianco v. Summers, 377 F.3d 559, 560 (6th Cir. 2004) (upholding thirty-day moratorium on solicitation of accident victims by chiropractors or their agents); cf. Fla. Bar v. Went for It, Inc., 515 U.S. 618, 620 (1995) (upholding thirty-day moratorium on direct-mail solicitation of accident victims or their families by personal injury lawyers); Alexander v. Cahill, 598 F.3d 79, 82 (2d Cir. 2010) (upholding similar rule in New York).

70 Goodman, 430 F.3d at 436.

71 Id.

Footnote

72 Id.

73 Id.

74 Va. State Bd. of Pharmacy v. Va. Citizens Consumer Council, 425 U.S. 748, 773 n.25 (1976).

75 Shapero v. Ky. Bar Ass'n, 486 U.S. 466, 475 (1988) (quoting Zauderer v. Office of Disciplinary Counsel of the Supreme Court of Ohio, 471 U.S. 626, 641 (1985)).

76 Goodman, 430 F.3d at 438.

77 Ohralik v. Ohio State Bar Ass'n, 436 U.S. 447, 466-67 (1978).

78 Greenwood, supra note 7, at 295.

79 Id.; David Grande & Kevin Volpp, Research Letter, Cost and Quality of IndustrySponsored Meals for Medical Residents, 290 JAMA 1150, 1150-51 (2003).

80 Aaron S. Kesselheim et al., Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints, PLoS Med., Apr. 2011, at 2, 6.

81 Id. at 6.

Footnote

82 Wash. Legal Found, v. Friedman, 13 F. Supp. 2d 51, 73 (1998); see also id. at 59 (holding that physicians are "certainly capable of critically evaluating journal articles or textbook reprints that are mailed to them, or the findings presented at CME seminars" (emphasis added)).

83 Fed. Election Comm'n v. Wis. Right to Life, 551 U.S. 449, 466-68 (2007) (Roberts, J., Alito, J., joining).

84 Id. at 467-69.

85 Id. at 469.

86 Id.

87 Id.

88 In re R.M.J., 455 U.S. 191, 202 (1982).

89 Wash. Legal Found, v. Friedman, 13 F. Supp. 2d at 66-67 (citing Central Hudson for the proposition that speech is "inherently misleading" if it is "more likely to deceive the public than to inform it," Cent. Hudson Gas & Elee. Corp. v. Pub. Serv. Comm'n, 447 U.S. 557, 563 (198O)).

90 Shapero v. Ky. Bar Ass'n, 486 U.S. 466, 474 (1988).

91 Tushnet, supra note 53, at 234.

92 See, e.g., Pearson v. Shalala, 164 F.3d 650, 656 n.6 (D.C. Cir. 1999)

Footnote

93 Bates v. State Bar of Ariz., 433 U.S. 350, 379 (1977).

94 Wash. Legal Found, v. Friedman, 13 F. Supp. 2d at 70.

95 Id.

96 FIa. Bar v. Went for It, 515 U.S. 618, 626-27 (1995).

97 Bronco Wine Co. v. Jolly, 129 CaI. App. 4th 988, 1007 (2005).

98 Edenfield, 507 U.S. at 771; see also Rubin v. Coors Brewing Co., 514 U.S. 476, 490 (1995) (noting the government supported its argument mainly with "anecdotal evidence and educated guesses," that the legislative history was scant, and that the government failed to update it with empirical evidence of current market conditions).

99 Waxman, supra note 18, at 303.

100 Id. at 302.

101 False and Misleading Advertising (Prescription Tr anquilizing Drugs), Hearings Before the Subcomm. of Legal and Monetary Affairs of the H. Comm. on Gov't Operations, 85th Cong. 177 (1958) (statement of Dr. Ian Stevenson, Chairman, Dep't of Neurology and Psychiatry, Univ. of Va.).

Footnote

102 Supplemental Declaration of Robert Temple, M.D., at 3, Allergan v. United States, No. I:09-cv-01879-JDB (D.D.C. Mar. 29, 2010).

103 Id.

104 Paul S. Appelbaum, Contact with Pharmaceutical Representatives: Where Does Prudence Lead?, Am. J. Bioethics, Jan. 2010, at 11.

105 Michael G. Ziegler et al., The Accuracy of Drug Information from Pharmaceutical Sales Representatives, 273 JAMA 1296, 1296-97 (1995); see also Joel Lexchin, What Information Do Physicians Receive from Pharmaceutical Representatives?, 43 Can. Fam. Physician 941, 944 (1997) (reviewing study by Dr. Ziegler and his colleagues along with three other studies and finding that they "consistently demonstrated that detailers selectively transmit only positive information about their companies' products. Side effects and contraindications are rarely mentioned, and the information that detailers give to physicians is frequently inaccurate.").

106 Ziegler et al., supra note 105, at 1298.

107 Id.

108 Kesselheim et al., supra note 80, at 5.

Footnote

109 Id.

110 Noordin Othman et al., Quality of Pharmaceutical Advertisements in Medical Journals: A Systematic Review, PLoS ONE, July 2009, at 7-8.

111 Id. at 8.

112 Id. at 10.

113 Some doctors will be misled by any off-label promotion, true or false, because they will believe that the use for which the drug is promoted has the FDA's seal of approval. This would be minimized if the rules limiting off-label promotion were liberalized, however. If it were no longer impermissible to promote drugs for unapproved uses, promotion of a given use would no longer be as strong an indicator that the use was approved. Moreover, concern that offlabel promotion will mislead physicians into thinking that unapproved uses are approved may be founded on an overestimation of the degree to which physicians are attuned to the actions of the FDA. The authors of a recently published national survey of physicians concluded that while "[t]here was a strong association between physicians' belief that an indication was FDAapproved and greater evidence supporting efficacy for that use . . . 41% of physicians believed at least one drug-indication pair with uncertain or no supporting evidence . . . was FDA approved." Donna T. Chen et al., U.S. Physician Knowledge of the FDA-Approved Indications and Evidence Base for Commonly Prescribed Drugs: Results of a National Survey, 18 Pharmacoepidemiology & Drug Safety 1094, 1099 (2009).

114 David C. Radley et al., Off-Label Prescribing Among Office-Based Physicians, 166 Archives Internal Med. 1021, 1023 (2006).

115 Tushnet, supra note 53, at 245 ("'Not treated with [synthetic growth hormone].' The dispute is over whether the implications of 'not treated with [synthetic growth hormone]' mislead consumers and distort their purchases.").

Footnote

116 21 U.S.C. § 321(n); see also 21 C.F.R. § 202.1(e)(6)-(7) (2008) (delineating ways in which an advertisement for a prescription drug is or can be "false, lacking in fair balance, or otherwise misleading").

117 Howard Brody, The Company We Keep: Why Physicians Should Refuse to See Pharmaceutical Representatives, 3 Annals Fam. Med. 82, 83 (2005) (noting that "almost all [physicians] agree that we are extremely busy and work under tremendous time pressure").

118 Michael A. Steinman & Dean Schillinger, Drug Detailing in Academic Medical Centers: Regulating for the Right Reasons, with the Right Evidence, at the Right Time, Am. J. Bioethics, Jan. 2010, at 22.

119 Daniel Stryer & Lisa A. Bero, Characteristics of Materials Distributed by Drug Companies: An Evaluation of Appropriateness, 11 J. Gen. Internal Med. 575, 578 (1996); see also Othman et al., supra note 110, at 7-8 (surveying seven studies of journal advertisements which found that the references included in advertisements were typically of low methodological quality); Macarena Gonzalez Santiago et al., Accuracy of Drug Advertisements in Medical Journals Under New Law Regufating the Marketing of Pharmaceutical Products in Switzerland, 8 BioMed Cent. Informatics & Decision Making, Dec. 2008, at 4 (finding that twenty-one percent of the seventy-eight claims in twenty-nine advertisements studied were not supported by the cited studies); Roberto Cardarelli et al., A Cross-Sectional EvidenceBased Review of Pharmaceutical Promotional Marketing Brochures and Their Underlying Studies: Is What They Tell Us Important and True?, BioMed Cent. Fam. Practice, Mar. 2006, at 2-3 (finding that twenty-five percent of the twenty advertisements studied cited invalid studies), available at http://www.biomedcentral.com/content/pdf/l471-2296-7-13.pdf.

Footnote

120 See Daylian M. Cain & Allan S. Detsky, Everyone's a Little Bit Biased (Even Physicians), 299 JAMA 2893, 2894-95 (2008).

121 Waxman, supra note 18, at 303.

122Zd.

123 Susan Heavey & Lisa Richwine, Special Report: Outgunned FDA Tries to Get Tough with Drug Ads, Reuters, Sept. 3, 2010, available at http://www.reuters.com/article/idUSTRE682lPN20100903.

124 Ben Comer, DDMAC Regulatory Letters Could Double in 2010, Med. Marketing & Media (July 22, 2010), http://www.mmm-online.com/ddmac-regulatory-letters-coulddouble-in-20lO/article/175154/ # .

125 See, e.g., Warning Letter from Thomas W. Abrams, Dir., Div. of Drug Marketing, Advertising, and Commc'ns, Office of Med. Policy, Ctr. for Drug Evaluation and Research, Food & Drug Admin., to Robert S. Whitehead, Chief Exec. Officer, Slate Pharm. (Mar. 24, 2010) (describing a sales aid "for Testopel presenting] the headline claim, "RECLAIM YOUR LIFE(TM)," in conjunction with three graphic images of a man jogging, a man playing with a child, and a man kissing a woman" and noting that "FDA is not aware of any studies that measured" "the ability for patients to resume their 'normal' activities and lifestyle (i.e., to reclaim their lives)" "or any other evidence to support such effects of Testopel treatment").

126 See, e.g., Warning Letter from Thomas W. Abrams, Dir., Div. of Drug Marketing, Advertising, and Commc'ns, Office of Med. Policy, Ctr. for Drug Evaluation and Research, Food & Drug Admin., to Andrew Witty, Chief Exec. Officer, GlaxoSmithKline (Apr. 19, 2010) (describing a slim jim "containing] multiple claims regarding the superior potency of Altabax over mupirocin" that were unsupported by "a head-to-head clinical comparison" of the two products).

127 See, e.g., Warning Letter from Thomas W. Abrams, Dir., Div. of Drug Marketing, Advertising, and Commc'ns, Office of Med. Policy, Ctr. for Drug Evaluation and Research, Food & Drug Admin., to Brian Dickson, Chief Med. Officer, Cornerstone Therapeutics, Inc. (June 22, 2010) (describing a visual aid that relegated important risk information to the back of the piece where it was "not visible or even accessible to the viewer since the back of the visual aid contains an adhesive strip at the top of the page designed to be adhered to a flat surface").

Footnote

128 Comer, supra note 124.

129 Id.

130 Id. (reporting that as of July 22, 2010 DDMAC had "sent out 40 enforcement letters . . . in 2010, compared with a total of 41 enforcement letters ... in all of 2009"); Covington & Burling, Trends in DDMAC Enforcement Activity During the Bush Administration, Food & Drug ?-Alert (Covington & Burling, D.C.), Mar. 30, 2009, at 2 (noting that "[a]fter a sharp drop (greater than 50%) in the total number of DDMAC letters between the first and second years of the Bush administration, the total number of letters remained relatively constant for the duration, averaging approximately 24 letters per year").

131 Heavey & Richwine, supra note 123.

132 Michael Sernyak & Robert Rosenheck, Experience of VA Psychiatrists with Pharmaceutical Detailing of Antipsychotic Medications, 58 Psychiatric Services 1292, 1294 (2007) (reporting that the over five-hundred salaried Veterans Administration psychiatrists surveyed estimated that they met with "pharmaceutical representatives an average of 14 26 times (range of 1-300)" in the previous year); Ashley Wazana, Physicians and the Pharmaceutical Industry: Is a Gift Ever Just a Gift?, 283 JAMA 373, 373, 376 (2000) (summarizing twenty-nine studies and concluding that "[p]hysician interactions with pharmaceutical representatives were generally endorsed, began in medical school, and continued at a rate of about 4 times per month"); Amy C. Brodkey, The Role of the Pharmaceutical Industry in Teaching Psychopharmacology: A Growing Problem, 29 Acad. Psychiatry 222, 223 (2005) (reporting that there were an estimated sixty million pharmaceutical representative-physician visits in the year 2000).

133 The challenges confronting corporate compliance officers are in part a function of resource and technology limits. For example, as more and more sales representatives are provided with tablet personal computers, the doctor's office may become less and less of a black box, facilitating efforts of regulators and compliance professionals to ensure that marketing messages are accurate and consistent. See Pfizer Equips Sales Reps with Tablet PCs, iHealthBeat (Dec. 16, 2009), http://www.ihealthbeat.org/articles/2009/l2/l6/pfizerequips-sales-reps-with-tablet-pcs-for-physician-visits.aspx. Moreover, problems with the quality of off-label promotion stem in part from the fact of prohibition. Under the current legal regime, off-label promotion frequently amounts to claims made by sales representatives in the field that are not vetted by companies' compliance or legal departments or even by headquarters sales and marketing personnel.

Footnote

134 Michelle M. Mello et al., Shifling Terrain in the Regulation of Off-Label Promotion of Pharmaceuticals, 360 New Eng. J. Med. 1557, 1561 (2009).

135 Allison D. Burroughs et al., Off-Label Promotion: Government Theories of Prosecution and Facts that Drive Them, 65 Food & Drug L.J. 555, 565-66 (2010).

136 Tushnet, supra note 53, at 227-28.

137 Id. at 228.

138 Note that this would not necessarily be a net positive for the pharmaceutical industry. See, e.g., Ariel Katz, Pharmaceutical Lemons: Innovation and Regulation in the Drug Industry, 14 Mich. Telecomm. & Tech. L. Rev. 1, 7 (2007) ("[T]he regulatory framework is not solely a burden imposed on the industry, but also a valuable service of drug quality certification .... [T]his aspect of the regulation, which may not be easily substituted by private market-based mechanisms, contributes to the value of new drugs"); Michael K. Loucks, Pros and Cons of OffLabel Promotion Investigations and Prosecutions, 61 Food & Drug L.J. 577, 580 (2006) ("[T]he core victims of the crimes of off-label promotion include those companies that have invested time and money to gain the benefit of the regulatory barrier to entry to the marketplace.").

AuthorAffiliation

Kate Greenwood[dagger]

AuthorAffiliation

[dagger] Research Fellow and Lecturer in Law, Center for Health & Pharmaceutical Law & Policy, Seton Hall University School of Law. I dedicate this Article to the memory of my beloved cousin, Lydia Poole Barker. I thank Margaret Gilhooley, Simone Handler-Hutchinson, John Jacobi, Kevin Outterson, Jordan Paradise, Tara Adams Ragone, and all of the participants at the American Journal of Law and Medicine Symposium "Marketing Health: The Growing Role of Commercial Speech Doctrine in FDA Regulation" for sharing their ideas with me. Kathleen Trawinski provided valuable research assistance. Mistakes remain my own.

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