October 28, 2002

Comments of Public Citizen

Docket No. 02N-0209

## INTRODUCTION

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.

## ADVERTISING OVERVIEW

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.[^1]

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."[^2]

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.

![](media/image1.png){width="6.0in" height="4.0in"}

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.[^3] 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.[^4]

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*.[^5]

## 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]{.underline}.

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.").[^6]

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]{.underline}.

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]{.underline}.

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]{.underline}.

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]{.underline}.

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.[^7]

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.

## CONCLUSION

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.

Sincerely,

Sidney M. Wolfe, MD

Larry D. Sasich, Pharm. D., MPH

Public Citizen Health Research Group

Allison M. Zieve

David C. Vladeck

Public Citizen Litigation Group

[^1]: The Canadian economist Stephen Leacock has defined advertising as
    "the science of arresting the human intelligence long enough to get
    money from it." Leacock also thought that, for the purpose of
    selling, advertising "is superior to reality." Leacock, *The garden
    of folly* 122-31 (1924). An executive of a direct-to-consumer drug
    advertising company commented that "consumers react emotionally, so
    you want to know how they feel about your message and what emotional
    triggers will get them to act. . . . We want to identify the
    emotions we can tap into to get that customer to take the desired
    course of action." *Why Rubin-Ehrenthal sticks exclusively to DTC
    accounts*, Medical Marketing & Media 136-46 (Sept. 1999). Another
    article, describing problems the drug industry has had in adapting
    to direct-to-consumer marketing, said that companies "are overly
    focused on communicating rational attributes to customers. But
    consumers often choose a product on \[the basis of\] emotional
    attributes. . . . Liebman*, Return on TV Advertising isn't a Clear
    Picture*, Medical Marketing & Media 81-84 (Nov. 2001).

[^2]: Kessler, *Addressing the problem of misleading advertising*, 116
    Ann. Intern. Med. 950-951 (1992).

[^3]: Wilkes, Doblin & Shapiro, *Pharmaceutical advertisements in
    leading medical journals: experts' assessments,* 116 Ann. Intern.
    Med. 912-19 (1992).

[^4]: Stryer & Bero, *Characteristics of materials distributed by drug
    companies: an evaluation of appropriateness*, 11 J. Gen. Intern.
    Med. 575-83 (1996).

[^5]: One of the questions about which the FDA has sought input is
    whether the FDA's position on direct-to-consumer (DTC) drug
    advertising is consistent with relevant legal authority. Currently,
    although in 1997 the FDA issued guidance on television advertising,
    the FDA has no regulations written specifically for DTC ads. For
    more than a decade, Public Citizen has have been urging the FDA to
    promulgate regulations specific to DTC ads.

[^6]: Courts have repeatedly upheld government prohibitions on deceptive
    advertising and labeling of foods and drugs against First Amendment
    challenges. *See*, *e.g.*, *Kraft, Inc. v. FTC*, 970 F.2d 311,
    324-26 (7th Cir. 1992) (upholding Federal Trade Commission ban on
    deceptive calcium claims for processed cheese products);
    *Bristol-Myers Company v. FTC*, 738 F.2d 554, 762 (2d Cir. 1984)
    (sustaining FTC prohibition against certain advertising claims for
    analgesics); *United States v. General Nutrition, Inc*., 638 F.
    Supp. 556, 562 (W.D.N.Y. 1986) (upholding FDA prohibition of certain
    nutritional claims on the product label); *FTC v. Pharmtech
    Research*, 576 F. Supp. 294, 303 (D. D.C. 1983) (granting
    preliminary injunction against deceptive advertisements for dietary
    supplements); *United States v. Articles of Food, Etc*., 67 F.R.D.
    419, 424 (D. Idaho 1975) (sustaining FDA prohibition on certain
    language on labeling of potato chip package); *United States v.
    Articles of Drug*, 32 F.R.D. 32, 35 (S.D. Ill. 1963) (affirming FDA
    ban on false and misleading medical guidance in pamphlets and other
    literature sold with supplements).

[^7]: Moreover, although in *Pearson* the court of appeals held that the
    FDA was required to use disclaimers to mitigate the adverse effect
    of misleading commercial speech, no other court has imposed such a
    requirement on the government. Indeed, all of the Supreme Court
    cases concerning disclaimers involve efforts by regulatory
    authorities to require them, not efforts by the judiciary to impose
    them. Thus, notwithstanding *Pearson*, the FDA need not anticipate
    the imposition of court-imposed disclaimer requirements in future
    cases, as the determination of how best to cure misleading speech
    lies with the legislative branch in the first instance.