Comments on FDA Enforcement of Drug Advertising Regulations
October 28, 2002
Docket No. 02N-0209
Public Citizen submits these comments to address some of the issues raised in comments submitted in response to the FDA Notice dated May 16, 2002 and to discuss the broader issues concerning the critical importance of rapidly diminishing FDA enforcement of drug advertising laws and regulations. We begin with a brief discussion of the nature of advertising and FDA enforcement actions with regard to advertising. We then address promotion of products for unapproved uses, including promotion of products never approved for any use.
Of course, the purpose of advertising and promotion is to sell products. And maximizing the positive aspects of drugs and medical devices and minimizing the negative in advertisements is the best way to convey to the public and to health professionals that the benefits outweigh the risks, even if the balance is exaggerated. Thus, the FDA’s failure to regulate the accuracy of statements about benefits, risks, and the balance between them can skew decisions to use (OTC drugs, devices or dietary supplements) or prescribe (prescription drugs or devices), and thereby injure patients.
We agree with former FDA Commissioner Dr. David Kessler’s statement that “enormous potential exists for misleading advertising to reach the physician and influence prescribing decisions .... Misleading advertisements can result in significant adverse consequences ... needless injury and even death may occur because physicians have been persuaded to prescribe products for uses for which they have not been adequately tested or to substitute therapies that may be less safe or less effective than the alternatives.”
If there is any serious problem concerning current FDA attitudes toward commercial speech, it does not lie in the nine questions posed in the Federal Register notice — which raise the possibility of less FDA enforcement — but in a deepening crisis of non-enforcement of existing laws and regulations concerning advertising, particularly, as seen below, of prescription drugs.
The table below shows that, from a high of 157 drug advertising enforcement actions (warning letters and notice of violation letters) in 1998, the number of FDA enforcement actions has severely declined (85%) to a projected 24 enforcement actions in 2002. The most drastic one-year percentage decrease has been the 67% decrease (from 73 to a projected 24) from 2001 to 2002. This decline is coincident with the new policy that the FDA Office of Chief Counsel “review” of all such letters, which was put in place in approximately March, 2002.
FDA Advertising Enforcement 1997-2002: Warning and Notice of Violation Letters to Drug Companies
FDA Ad Enforcement per year
Data from FDA web site FDA.gov/cder/warn/index.htm (2002 data extrapolated from the first 9 months)
Studies from 1992 and 1996 on the degree of false or misleading information in prescription drug ads demonstrates that the number of FDA enforcement actions, even in 1997 and 1998, address only the tip of the iceberg. The 1992 study found that 40 percent of reviewed drug ads (all ads in 10 leading medical journals during one month) did not present fair balance between effectiveness and adverse effects and that 47 percent of ads did not appropriately highlight risks and contraindications in special patient populations such as the elderly. The 1996 study found that 42 percent of materials distributed by drug companies failed to comply with FDA regulations, including 35 percent that lacked fair balance between the benefits and risks of drugs.
The decrease in FDA enforcement actions cannot be explained as the result of a cleaner marketplace. As discussed in the September 13, 2002 comments of Blue Cross and Blue Shield, the FDA has only five full-time employees to review DTC ads, a grossly insufficient number in light of the great number of advertisements. EMC167 at 6. Thus, it is not surprising that a 1998 survey of 3,000 doctors found that more than half of physicians disagreed with the statement, “DTC advertising is a reliable source of information,” and more than 60 percent disagreed with the statement, “DTC advertising is an objective source of information.” Id.
PROMOTION OF UNAPPROVED USES AND UNAPPROVED DRUGS
Several industry comments argue that the FDA’s restrictions on promotion of unapproved uses are inconsistent with First Amendment jurisprudence. The industry seeks room to promote and market uses of drugs and medical devices that have not been approved, including uses that have explicitly been denied, by the FDA. Without arguing that the new drug application (“NDA”) approval process or medical device premarket approval (“PMA”) process should be abolished altogether, these comments argue that once a drug or device is approved for one use, the manufacturer should be permitted to market it for any use, possibly subject to a disclaimer requirement to state that the promoted use was not one approved by the FDA. This position, if adopted, would not encourage scientific discourse and debate about the merits of new therapies and treatments. Rather, it would deal a body blow to the NDA and PMA processes, which are the public’s first and most important line of defense against unproven treatments and license the dissemination of information that, by definition, has not been proven to be truthful. Such an approach would permit manufacturers to make unverified claims of safety and efficacy to sell their products, subject only to after-the-fact FDA enforcement actions. In short, the industry proposals would increase industry profits at the expense of the public health mandate of the Food, Drug, & Cosmetic Act (“FDCA”), which Congress enacted to prevent deaths and injuries from drugs and medical devices.
The FDCA and the FDA’s current regulation of off-label promotion further both the core values of the First Amendment and the public health and safety. The FDA does not stifle truthful speech in educational and professional settings, but rather ensures a measure of objectivity and balance in scientific and educational programs concerning unapproved uses. Although the FDA does not allow promotion of unapproved uses to consumers, the substantial interest in protecting the public from unsafe or ineffective drugs and devices more than justifies the restriction. If the product manufacturer can substantiate claims of safety and effectiveness for an additional use, it can obtain the right to promote its product for that use by submitting a supplemental NDA. If the data cannot withstand FDA scrutiny, then the claims are not true for purposes of the FDCA. Nothing in the First Amendment prohibits the suppression of false or misleading commercial speech.
One problem with permitting promotion of unapproved uses is that the manufacturer never has to prove that the claims made are true. Accordingly, the constitutional debate is largely a disagreement about whether the First Amendment requires that the FDA permit manufacturers to make any health claim that is not provably false, or whether it permits the FDA to bar any health claim that is not demonstrably true. As discussed in the September 13, 2002 comments of Public Citizen Health Research Group, in the public health context, where the truth about safety and efficacy is rarely an absolute, the First Amendment bars only restricting speech that has been proved to be true. And proof does not consist of a single study or a few journal articles supportive of a claim. Too often, those “proofs” are later discredited because the researchers published data prematurely, because they engaged in scientific corner cutting, because their sample was too small, or for other reasons. The FDA should thus have no hesitancy in maintaining the position, taken by Congress in the FDCA, that a health claim is not true for First Amendment purposes until it has been shown to be adequately supported by replicable health and safety data. If that data exists, an off-label indication need not be off-label, as a supplemental NDA will pass FDA scrutiny. Thus, the line drawn by FDAMA — a manufacturer may make off-label claims based on studies if, but only if, it is willing within 6 months to submit its data to the FDA so that the FDA can decide whether the statement is in fact supported by evidence of sufficient quantity and quality to say with a reasonable assurance that the claim is true — poses no First Amendment problem.
I. PRELIMINARY COMMENT
A. Congress established the statutory scheme at issue here. The FDA’s function is to implement that scheme. Because the industry suggestions discussed herein (like some of the implications of the FDA Notice) are at odds with the direction of Congress, the FDA does not have discretion to implement those suggestions.
B. Fundamentally mischaracterizing the nature of the NDA and PMA processes, some comments suggest that the FDA’s restrictions on off-label promotion suppress discussion of off-label uses of approved products. See, e.g., C32 at 155 (Pfizer comments); C46 (PhRMA comments). That suggestion is incorrect.
First, to talk about products being “FDA-approved” is misleading. To begin with, the vast majority of medical devices enter the market without any safety and effectiveness approval. See House Rep. No. 101-808 at 14 (Oct. 5, 1990), reprinted in 1990 U.S. Code Cong. & Admin. News 6305, 6307; Less than the Sum of its Parts, Reforms Needed in the Organization, Management, and Resources of the Food and Drug Administration’s Center for Devices and Radiological Health, Report by the Subcommittee on Oversight and Investigations of the House Committee on Energy and Commerce, 103d Cong., 1st Sess. 13 (Committee Print 103-N, GPO 1993).
Second, when the FDA does grant marketing approval, the approval is not for products but for specific uses of devices and drugs, as opposed to the devices or drugs in a general sense. That is, the PMA process and the NDA process do not determine the safety and effectiveness of a product in general; they determine the safety and effectiveness of a product for the uses specified in the application.
Third, the FDA does not suppress discussion — as opposed to promotion — of off-label uses. Scientists, doctors and scholars are free to discuss off label uses to their heart’s content, without any interference from the FDA. Rather, the FDA attempts to ensure that self-interested manufacturers, seeking to expand the market for their products, do not taint that discussion by tipping the scales of reasoned scholarly debate by heavily funding one side of the debate — the side favoring off-label uses — and drowning out any dissenting voices. Permitting manufacturers to use their economic muscle to monopolize what should be an objective scientific debate serves no legitimate public policy goal.
C. Some comments suggest that a manufacturer’s dissemination of articles discussing unapproved uses of their products or discussion of unapproved uses at manufacturer-sponsored conferences does not propose a commercial transaction and thus is outside the realm of commercial speech. See C46 at 20 (PhRMA comments). To suggest that the company would sponsor a program on its own product without any intent that the audience then use the product as discussed in the program is either flatly dishonest or unbelievably naive. A company-sponsored program that discusses use of a company product carries with it, at the least, an implicit solicitation, and in many cases an explicit one. The discussion at pages 9-12 of the September 13, 2002 comments of Public Citizen Health Research Group (C41) offers but one example illustrating this fact.
The Supreme Court has broadly defined “commercial speech” to embrace “expression related solely to the economic interests of the speaker and its audience,” Central Hudson Gas & Electric Corp. v. Public Service Commission, 447 U.S. 557, 561 (1980), and speech that “propose[s] a commercial transaction.” Board of Trustees v. Fox, 492 U.S. 469, 473-74 (1989). As stated above, a company-sponsored program regarding how to use a company product proposes a commercial transaction, in that the company surely hopes and intends that the audience will then use the product based on the program. Cf. National Commission on Egg Nutrition v. FTC, 570 F.2d 157 (7th Cir. 1977) (advertisement regarding relationship between eggs and cholesterol constitutes commercial speech for purpose of persuading public to buy eggs). In addition, the speech at issue refers to specific products and is economically motivated. Together, these characteristics refute in claim that the speech at issue is non-commercial. See Bolger v. Youngs Drug Products Corp., 463 U.S. 60, 66-67 (1983). Moreover, including scientific and educational content in programs cannot transform the commercial speech aspect of those programs into non-commercial speech. See id. at 67-68.
II. THE FDCA AND FDA REGULATIONS ON OFF-LABEL PROMOTION COMPLY FULLY WITH THE FIRST AMENDMENT.
Public Citizen recognizes that commercial speech is entitled to a fair measure of protection under the First Amendment. Indeed, Public Citizen has worked hard to extend First Amendment protection to truthful commercial speech. The FDCA and FDA policy regarding off-label promotion, however, do not raise significant First Amendment questions.
In Central Hudson, 447 U.S. at 563-64, the Supreme Court laid down the now familiar four-part test for assessing the constitutionality of a restriction on commercial speech. That test inquires: (1) whether the advertised activity is unlawful, and whether the speech about it is misleading; (2) whether the government’s asserted interest in regulating speech is substantial; (3) whether the restraint directly advances the government’s interest; and (4) whether the legislation is no more extensive than necessary to serve the government’s interest. Id. at 566.
A. The Speech At Issue Is Misleading.
If the proposed speech is misleading, the government may suppress it in its entirety, without further inquiry, because only truthful commercial speech is protected under the First Amendment. Ibanez v. Board of Accountancy, 512 U.S. 136, 142 (1994). The Supreme Court has emphasized:
Obviously, much commercial speech is not provably false, or even wholly false, but only deceptive or misleading. We foresee no obstacle to a State’s dealing effectively with this problem. The First Amendment, as we construe it today, does not prohibit the State from insuring that the stream of commercial information flows cleanly as well as freely.
Friedman v. Rogers, 440 U.S. 1, 9-10 (1979) (citations omitted); accord Zauderer, 471 U.S. at 638 (“The States and the Federal Government are free to prevent the dissemination of commercial speech that is false, deceptive, or misleading . . .”); In Re R.M.J., 455 U.S. 191, 203 (1982) (commercial speech may be restricted “when the particular content or method of the advertising suggests that it is inherently misleading or when experience has proved that in fact such advertising is subject to abuse;” “Misleading advertising may be prohibited entirely.”); Central Hudson, 447 U.S. at 563 (“The government may ban forms of communication more likely to deceive the public than to inform it.”).
Promoting drugs and devices for unapproved uses is misleading because it implies a level of scientific certainty — a reasonable assurance of safety and effectiveness — that does not exist. It is no answer to suggest that members of the public and physicians can evaluate health claims on their own. Lay consumers cannot conceivably evaluate such claims independently. Further, physicians are not trained to do so and, to the extent that they are able, they should not be expected to wade through volumes of preliminary and often conflicting and inconclusive scientific literature — such as clinical trials and epidemiologic studies — to assess whether a particular health claim is well-founded each time they hear of a possible unapproved use. In fact, Congress considered evidence on exactly this point when, in 1962, it added an efficacy requirement as a prerequisite to marketing. See C65, and citations therein (comments of Sen. Kennedy, Cong. Waxman, and others). Congress has reasonably decided that this scientific review is the FDA’s function, not the job of every consumer and physician in the United States. See, e.g., American Home Products Corp v. FTC, 695 F.2d 681, 695 (3d Cir. 1982) (“unrealistic” to expect consumers to assess the validity of complex scientific claims). In this way, promotion of products for unapproved uses is “misleading” and therefore not entitled to First Amendment protection.
B. Substantial Governmental Interests Are Served By Restricting Off-Label Promotion.
Because the speech at issue is misleading, it can be suppressed without running afoul of the First Amendment. Yet even if the off-label promotion could survive the first prong of Central Hudson, the restrictions would be permissible because the FDA’s implementation of Congress’ statutory scheme furthers substantial governmental interests. Consideration of the interests at stake reveals why industry-sponsored promotion of off-label uses is proscribed and demonstrates that Congress and the FDA have regulated in this area with sensitivity to First Amendment values.
First, “[p]reserving 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.” Thompson v. Western States Medical Center, 535 U.S. __, 122 S. Ct. 1497, 1505 (2002). This interest is a corollary of the government’s substantial interest in protecting the health, safety, and welfare of its citizens. See, e.g., Rubin v. Coors Brewing Co., 514 U.S. 476, 485 (1995). This interest is plainly served by limiting the dissemination of information that could lead doctors and their patients to choose unproven remedies in lieu of more reliable therapeutic treatments; for when information disseminated by or on behalf of manufacturers about their drugs and medical devices proves to be unfounded, individual patients pay with their health and their lives. See 59 Fed. Reg. 59824-25 (listing examples).
Moreover, restricting promotion of unapproved uses does not stifle legitimate scientific discourse. Neither the FDCA nor FDA regulations restrict the ability of independent scientists or researchers to publish — orally or in writing — anything they see fit relating to the safety and effectiveness of unapproved uses. Likewise, they do not restrict the ability of activity providers (such as universities, medical societies, professional organizations, and the like) to organize programs on any topics they choose. The only restraint is on the commercial actor; the entity whose conduct is ultimately aimed at selling its product.
In addition, the FDA has a compelling interest in protecting consumers from the economic injury that flows from paying premium prices for products that promise a health benefit but do not deliver. If patients are prescribed drugs or medical devices on the basis of inaccurate representations or preliminary scientific findings that prove unwarranted, they will have paid for products that they did not need to purchase. And, too often, when the health claims prove unwarranted, consumers will pay again for additional treatment, either to correct injury caused by the use of the product for an off-label indication or to treat the original problem, which persists and may even have worsened in the meantime. See, e.g., Is the FDA Protecting Consumers from Dangerous Off‑Label Uses of Medical Drugs and Devices?, H.R. Rep. No. 102‑1064, 102d Cong., 2d Sess. (1992) (discussing manufacturers’ promotion of three specific products for off-label uses).
C. The Limited Restraint Imposed By The FDA’s Proposed Policy Statement And Approval Regulations Is Narrowly Tailored To Further The Government’s Substantial Interests.
In assessing the last two components of the Central Hudson test, the courts give substantial deference to the agency’s judgment. As the Court stated in Fox:
What our decisions require is a ‘fit’ between the legislature’s ends and the means chosen to accomplish those ends,” [citation omitted] — a fit that is not necessarily perfect, but reasonable; that represents not necessarily the single best disposition but one whose scope is in “proportion to the interest served,” [citation omitted]; that employs not necessarily the least restrictive means but, as we have put it in other contexts discussed above, a means narrowly tailored to achieve the desired objective. Within those bounds we leave it to governmental decision makers to judge what manner of regulation may best be employed.
492 U.S. at 480. Accord Lorillard Tobacco Co. v. Reilly, 533 U.S. 525, 556 (2001); United States v. Edge Broadcasting Co., 509 U.S. 418, 434 (1993). The “‘least restrictive means’ is not the standard.” Lorillard, 533 U.S. at 556.
In the case of promotion for unapproved uses, the FDA has not sought to suppress altogether the dissemination of claims in connection with unapproved uses. Instead, the FDA has crafted a system that simultaneously protects the ability of those who market drugs and devices to tout uses that have been proven safe and effective, allows a full discourse on any use (approved or unapproved), and protects the interest of the public in not being misled by unproven claims. Moreover, the safe harbor provisions of FDAMA allow a manufacturer to promote off-label uses by disseminating peer-reviewed articles and references publications to physicians as long as the company has submitted a supplement NDA or certifies that it will submit one within six months thereafter (36 months if the studies have not yet been completed). 21 U.S.C. § 360aaa-3.
The fit between the means and ends at issue here plainly satisfies the standard laid down in Fox. Not only do the FDA regulations not restrain the dissemination of truthful speech, they are further valid because the FDA has selected reasonably tailored means to achieve the plainly compelling goals set forth in the FDCA. Central Hudson, 447 U.S. at 563-64. The limits placed on manufacturers’ ability to promote their products for unapproved uses are entirely reasonable steps to ensure that drugs and devices are used safely. Under the FDCA and FDA regulations, a program provider unaffiliated with the manufacturer may conduct an educational program regarding an unapproved use. The program must be balanced and objective, and the sponsor must disclose that use of the product has not received FDA approval. These requirements are fully consistent with the First Amendment. See generally Zauderer, 471 U.S. 626.
Again, drugs and medical devices are not approved in general. They are approved for specific uses. Approval of a drug or device for treating disease X says no more about its safety and effectiveness for treating disease Y than does no approval at all. For example, the anti-arrhythmics Encainide and Flecainide were widely prescribed off-label to patients after they had heart attacks. When use in post-heart attack patients was eventually studied, the drugs were shown to increase mortality. In the interim, thousands of people had died. Similarly, the drug Duract, approved as a short-term pain reliever, was prescribed off-label for long term use, which caused severe liver injury and resulted in death in some cases. The fact that the FDA had approved these drugs for one use did nothing to alleviate the injury of the patients injured by the off-label uses.
Furthermore, the FDCA recognizes only two categories of uses for drugs and devices: FDA-approved and unapproved. Uses of drugs and devices that have been specifically rejected by the FDA fall into the “unapproved” category. For example, various estrogens and androgens were previously approved by the FDA for use in treating postpartum breast engorgement (“PPBE”) in new mothers who did not breastfeed. Although that use has now been withdrawn due to the increasing evidence of serious injury and death caused by this use, the drugs are still approved for treating other conditions. Under the industry’s view, the manufacturers of these drugs could still sponsor programs to promote their products to treat PPBE, despite the FDA’s specific rejection of this use, because approval of other uses remains in effect. In contrast, under the FDCA and FDA regulations, a program provider — but not a manufacturer — could present a scientific program on use of these drugs to treat PPBE. The program’s content would have to state honestly the unapproved status of the use of the drug for that indication and any financial relationship between the provider or any presenter, and the manufacturer.
In essence, the industry’s position is that the FDA should not regulate company-supported “non-labeling activities” the effect of which is to promote unapproved uses through the dissemination of “truthful” information. Assessing the “truth” of safety and effectiveness, however, is not a simple matter. Thus, to protect our health and safety, Congress has established procedures for making this determination are already in place — the new drug application and medical device premarket approval processes. The “truth” about safety and effectiveness of drugs and devices for specific uses is not established on the basis of one test or study. Claims of safety and effectiveness become “truthful” when a sufficient body of scientific evidence offers reasonable assurance of such claims. Cf. 21 U.S.C. § 360e(d)(2) (premarket approval for medical devices based on “reasonable assurance” of safety and effectiveness). This framework was established in the first instance by Congress and followed by the FDA.
Marketing a product for any given use implies a level of scientific certainty that the product is safe and effective for that use and encourages purchases on the ground that consumer health will be benefited. Safety and effectiveness claims are, in fact, susceptible to objective scientific evaluation. If the claims are valid, there is no reason — other than a monetary one — not to seek FDA approval for the additional unapproved use. The regulatory process does not prevent marketing products for any safe and effective use. It only delays marketing until the claims can be evaluated by the FDA, in the interest of protecting the public health and safety. Thus, unapproved uses worthy of approval are capable of receiving it. Manufacturers may prefer to increase sales by marketing for unapproved uses immediately, but the interest in protecting the public health and safety surely outweighs the parochial economic interests of the pharmaceutical and medical device companies.
Although the industry comments purport not to question the NDA and PMA procedures through which drug and medical device manufacturers receive permission to market products for specified uses, their arguments would effectively gut those statutory procedures. To prohibit written promotion of unapproved — or specifically disapproved — uses on a product label, while allowing free reign to engage in off-label promotion would be to pay mere lip-service to the plain meaning of the statute and the clear congressional intent manifest in the legislative history.
The Supreme Court’s decision in Western States Medical Center, 122 S. Ct. 1497, poses no obstacle to the FDCA and FDA rules regarding off-label promotion. In Western States, the Court struck down restrictions on pharmacies advertising that they compounded specific drugs because the restriction was insufficiently related to the ends it purportedly served. That is, the FDA did not adequately explain the connection between the speech restriction and the stated interest (preserving the NDA process, while making compounded drugs available to patients with special needs). See Docket No. C53 at 2-3 (statement of Center for Constitutional Rights, discussing Western States). In contrast here, one cannot plausibly suggest that the speech restrictions inherent in the approval system established by Congress and implemented by the FDA are not well-tailored to address a compelling state interest. The purpose of the approval processes, like the FDA’s restrictions on promotion of unapproved uses, is to prevent doctors and their patients from being misled by unproven health claims. No system of after-the-fact enforcement (see C46 at 22 (PhRMA comments, suggesting such enforcement would sufficiently protect public interest)) would be adequate to that task. When an unproven assertion of safety and effectiveness is made and relied on, the resulting injury is often irreparable. (Consider, for example, the Dalkon Shield.) Thus, a premarket approval system is essential to the accomplishment of Congress’ goals.
Moreover, affirming the court of appeals’ decision in Western States presented no risk to the public health because the law on pharmacy compounding thus returned to the pre-FDAMA status quo, which did not permit compounding. The practical result of the Supreme Court’s decision was to return the problem to Congress. More importantly, the public health imperative at stake was less compelling than in the off-label context. Compounding, although potentially very dangerous, has to date existed on a small scale. In contrast, and as evidenced by the industry’s sustained efforts to loosen restrictions and its history of aggressive promotion of drugs for unsafe and ineffective uses before 1962, when Congress enacted the requirement of proof that each promoted use be effective, see C65 (giving examples), off-label promotion presents a potentially enormous public health hazard, as unrestricted promotion increases the risk that patients will take drugs that do not work for the promoted use or that are harmful, often in situations where a proven therapy was available.
While they do not directly question the premarket approval systems, several industry comments suggest ways, other than restricting off-label promotion, in which the FDA can achieve the goal of ensuring that promoted uses are safe and effective. To begin with, the government is required to narrowly tailor its speech restriction to achieve the desired objective. As stated above,”[w]ithin those bounds,” the courts “leave it to governmental decision makers to judge what manner of regulation may best be employed.” Fox, 492 U.S. at 480. That is, because Congress and the FDA have chosen a narrowly tailored means of protecting the NDA and PMA processes, and thus of protecting the public from unsafe or ineffective drugs and medical devices, the regulatory scheme passes constitutional muster, even if other means could also satisfy the public health imperative.
In any event, the industry suggestions are all somewhat disingenuous, as they boil down to ways to increase the profits of name brand pharmaceutical manufacturers. For instance, one comment suggests that the FDA change Orange Book requirements so that generics drugs lose their A/B equivalency rating for a three-year period after the name-brand manufacturer receives approval for a supplemental use. See C32 at 164. The A/B rating, however, is the mechanism by which generics get substituted for more expensive name-brand products. If a generic loses its A/B rating, it loses its access to the market. Accordingly, this suggestion is, in essence, an offer from the industry: We will comply with the restrictions on off-label promotion, if you give us three more years of market exclusivity. Not surprisingly, the winner in such a scheme would be not patients — forced to spend millions of more dollars each year on higher-priced pharmaceuticals — but the industry. The value to the industry of the three years of exclusivity would be tremendous. As a point of comparison, the six-months of exclusivity granted under the pediatric exclusivity provision was worth $1.5 billion is sales of Prilosec and $900 million is sales of Prozac. According to the FDA’s report to Congress on the pediatric exclusivity provision, the provision will earn innovator companies an average of $1.5 billion per year for 20 years, while costing consumers approximately $13.9 billion over 20 years, or 695 million per year. Generic companies and pharmacies will also pay a lot for the provision, an estimated $750 million per year. If the Orange Book suggestion were adopted, the cost to patients and the benefit to the industry would be six times that much.
Another comment suggested that the FDA could encourage companies to seek approval of supplemental indications by decreasing the cost and delay of obtaining approval. The time and expense associated with approval is, of course, the time and expense required to control the clinical studies needed to demonstrate safety and effectiveness. Yes, it would be cheaper and faster to do without rigorous proof of safety and efficacy, but it would also endanger people’s lives. Perhaps the authors of this suggestion simply forgot about DES, Phen-Fen, hormone replacement therapy, Encainide, and Flecanide.
D. The Restrictions On Off-Label Promotion Do Not Constitute A Forbidden Prior Restraint.
The restrictions on off-label promotion do not constitute an unconstitutional prior restraint. As the Supreme Court made clear in Central Hudson, the “prior restraint” doctrine has no applicability in the commercial speech context. To the contrary, a government may permissibly require “a system of previewing advertising campaigns to insure that they will not defeat” government-imposed restrictions. 447 U.S. at 571 n.13; see also Zauderer, 471 U.S. at 626, 658 n.13 (1985) (Brennan, J., joined by Marshall, J., concurring in part, concurring in the judgment in part, and dissenting in part) (explaining that “traditional prior restraint principles do not apply to commercial speech”); cf. Nutritional Health Alliance v. Shalala, 244 F.3d 220, 227-28 (2d Cir. 1998) (procedural safeguards against prior restraints analyzed in commercial speech cases under rubric of narrow tailoring).
Moreover, the courts have long approved a broad array of government-imposed preclearance schemes, from permit requirements to use public places for expressive activities, see, e.g., Cox v. New Hampshire, 312 U.S. 569 (1941) (upholding parade permit law), to film censorship, see, e.g., Times Film Corp. v. Chicago, 365 U.S. 43 (1961); Fehlhabner v. North Carolina, 675 F.2d 1365 (4th Cir. 1982) (obscenity nuisance statutes), to commercial advertising, Nutritional Health Alliance, 244 F.3d 220 (nutritional labeling advertising restriction).
E. Disclaimers Would Not Provide A More Narrowly-Tailored Means Of Serving The Compelling Government Interest At Stake Here.
Pfizer’s comments contend that disclaimers are more narrowly-tailored means of achieving the FDA’s goal of protecting the approval processes, and thus protecting the public health. Pfizer suggests that a disclaimer might state that the FDA has not approved the use discussed, that the manufacturer is not recommending the use, and that the information is provided for informational purposes. See C32 at 165; see also C46 at 19 (PhRMA comments); C39 at 3 (Johnson & Johnson comments). However, notwithstanding the appellate court decision in Pearson v. Shalala, 164 F.3d 650 (D.C. Cir. 1999), long-standing Supreme Court precedent suggests that the First Amendment does not require the government to use disclaimers to mitigate the adverse effects of commercial speech. See Friedman, 440 U.S. at 12 n.11, (“there is no First Amendment rule ... requiring a State to allow deceptive or misleading commercial speech whenever the publication of additional information can clarify or offset the effects of the spurious communication”).
Moreover, the cases show why use of disclaimers would be an ineffective course of action in these circumstances. In Zauderer, for example, a lawyer was charged with engaging in deceptive practices by advertising that he accepted cases on a contingent fee basis with “no cost” to the client in the event that the litigation was unsuccessful. The Ohio Supreme Court had found the lawyer’s advertisement misleading because it failed to disclose to clients that they would nonetheless remain liable for costs, as required by Ohio’s disciplinary rules. The United States Supreme Court, upholding the validity of the Ohio disclosure rule, remarked that “warning[s] and disclaimer[s] might be appropriately required . . . to dissipate the possibility of consumer confusion or deception.” That is, the disclaimer provided information relevant to the consumer’s evaluation of which lawyer to hire and the fee that would be assessed, thus correcting any misimpression that the ad might otherwise convey; it was thus permissible to ensure that the public had the necessary information to make its decision.
The rationale supporting the disclaimer requirement in Zauderer does not apply to off-label promotion because nothing in the disclaimers envisioned by the advocates of off-label promotion would contain information to help doctors or patients to appraise a product. Contrary to Pfizer’s suggestion, the key point on which a disclaimer would be needed is not whether the FDA stands behind the product’s safety but whether the product is in fact safe and effective. Off-label promotion necessarily suggests that a product would be a safe and effective treatment for the promoted use, and nothing in Pfizer’s proposed disclaimer would help to cure that misimpression. The virtue of going though the FDA approval process is that it ensures that an objective scientific evaluation can support the self-interested claims of safety and effectiveness. Disclaimers do nothing to fill the informational void when that objective evaluation has not occurred or, indeed, when the use promoted has failed that evaluation. They do not tell the doctor or consumer whether the product is safe for that use, whether it is effective for that use, or whether it is more or less safe or effective than products approved for that indication. There is a vast gulf between providing useful information and disclaiming responsibility. Because the disclaimers envisioned by Pfizer will not assist doctors or patients in distinguishing between proven and unproved claims made in promotional material, disclaimers will not cure the inherently misleading nature of off-label promotion.
III. RESTRICTIONS ON PRE-APPROVAL PROMOTION LIKEWISE COMPORT WITH THE FIRST AMENDMENT.
The considerations discussed above also support that FDA’s rule against promotion of products that have not been approved for any use. Discussion about such products is not commercial when sponsored by independent entities, and in such instances serves the purpose of furthering scientific analysis and development. When sponsored by the product manufacturer, however, the object of the speech is to foster interest in the product in the hope of furthering sales when and if that product reaches the market. For example, Pfizer’s comments describe a purported benefit to doctors from knowing about “soon-to be available products” (that is, products not yet approved for any use). C32 at 98. Yet it is clear from Pfizer’s discussion that the manufacturer’s promotion would be aimed at convincing the doctor to prescribe the new product when it is available. That is, the promotion is not seeking to educate; it is seeking to boost future sales. Accordingly, the suggestion that promotion of products that have not (yet) received FDA approval is not commercial speech, C32 at 100, is disingenuous at best. See also C58 (Medtronic comments, discussing restrictions on promotion of unapproved products).
Furthermore, promotion of products in the NDA or PMA pipeline can exert pressure on the FDA grant approval, thereby threatening the objective scientific analysis (do the benefits outweigh the risks?) at the heart of the NDA and PMA processes established by Congress to protect our health and safety.
In addition, when an NDA is submitted for more than one indication, and the NDA is later approved for only a single indication, pre-approval promotion of the product becomes in effect off-label promotion. For example, earlier this year the FDA approved an NDA for the Pharmacia drug Bextra. The NDA sought approval for four indications, but the FDA approved only three. Pharmacia’s pre-approval touting of the drug for all four uses, however, increases the chances that the product will now be used off-label for an indication (acute pain) expressly rejected by the FDA. Relaxing pre-approval restrictions on promotion, as Pfizer requests and as Chief Counsel Troy has reportedly suggested, would be an open invitation to new product sponsors to manipulate pre-approval promotion to further post-approval off-label usage.
Recent court decisions addressing speech restrictions imposed by the FDCA and FDA regulation thereunder do not call into question that agency’s authority to impose restraints on advertising and promotion of drugs, medical devices, and other FDA-regulated products, where such restrictions advance the vital health and safety concerns at the heart of the FDCA.
Sidney M. Wolfe, M.D.
Larry D. Sasich, Pharm.D., M.P.H.
Public Citizen Health Research Group
Allison M. Zieve
David C. Vladeck
Public Citizen Litigation Group