Dockets Management Branch

Food and Drug Administration

5630 Fishers Lane

Rockville, MD 20852

> Re: Request for Comments on First Amendment Issues
>
> [Docket No. 02N-0209]{.underline}

Dear Sir or Madam:

In response to the request by the Food and Drug Administration (FDA) for
public comment on the First Amendment issues raised by its regulations,
guidances, policies, and practices,[^1] this letter provides the
comments of the Washington Legal Foundation (WLF).

FDA's initiative to conform its regulatory activities to First Amendment
standards represents an important step that can produce substantial
benefits from both a legal and public health perspective, for which FDA
must be commended. As a non-profit public interest law and policy center
with many members and supporters who wish to disseminate or receive
truthful information about FDA-regulated products, WLF has a
long-standing interest in the intersection of public health and First
Amendment issues, and in the many specific questions FDA raised in its
request for comments. While we have confined our comments here to a
limited number of salient points, we look forward to addressing a
broader range of these questions in response to the information
submitted by other interested parties. In this initial submission, WLF
has focused on certain of the core principles enunciated by First
Amendment caselaw that must provide the framework for all of FDA's
efforts to scrutinize and revamp its regulatory practices, and on a key
area where WLF has worked for reform since 1993: promoting the free flow
of truthful scientific and medical information about off-label uses of
FDA-approved drugs and devices.[^2]

# [FRAMEWORK PRINCIPLES]{.underline}

## Speech Restrictions Cannot Survive First Amendment Scrutiny [Unless They Are A Last Resort]{.underline} 

Perhaps the most fundamental principle that must guide FDA's review of
its existing speech restrictions is that FDA must seek
[alternative]{.underline} methods for achieving its objectives (or, if
some speech restriction is unavoidable, alternatives that restrict less
speech rather than more). This is true whether the speech is commercial
or non-commercial.[^3]

In its recent decision in [Thompson v. Western States Medical
Center]{.underline}, 535 U.S. \_\_\_, 122 S. Ct. 1497 (2002), the
Supreme Court struck down a ban on advertising unapproved compounded
drugs in the FDA Modernization Act of 1997 (FDAMA). The Court applied
the commercial speech test of [Central Hudson Gas & Electric Corp. v.
Public Serv. Comm'n]{.underline}, 447 U.S. 557 (1980). Thus, the Court
asked: (1) whether the speech was untruthful or misleading, or concerned
unlawful activity (characteristics that would strip the speech of First
Amendment protection and end the analysis); (2) whether the Government
had asserted a "substantial" interest in restricting the speech;
(3) whether the Government had demonstrated that the restriction
"directly advanced" such a substantial interest; and (4) whether the
Government had established that the restriction was "not more extensive
than is necessary to serve that interest." [Western States]{.underline},
122 S. Ct. at 1504.

Importantly, the Court also clarified some ambiguities in past cases
concerning the "final prong" of the commercial speech analysis, holding
that "[if the Government could achieve its interests in a manner that
does not restrict speech, or that restricts less speech, the Government
must do so.]{.underline}" [Id.]{.underline} at 1506 (emphasis added). In
so holding, the Court implicitly rejected earlier statements that a
"reasonable fit" between a speech restriction and the direct advancement
of a substantial interest could suffice to uphold the restriction.[^4]
Underscoring this point, the Court emphasized that "\[i\]f the First
Amendment means anything, it means that regulating speech must be a last
- - not first - - resort."[^5] [Id.]{.underline} at 1507. While the
Court noted a number of concerns with FDAMA's advertising ban
- - including the amount of beneficial speech it suppressed - - the
Government's failure to treat speech restrictions as a last resort was
the key defect. Instead of seeking alternatives, banning speech "seems
to have been the first strategy the Government thought to try."
[Id.]{.underline}

At present, the FDA regulatory landscape is littered with speech
restrictions. Some of these restrictions may comply with the First
Amendment. But the task of determining whether they do requires a
rigorous effort to identify and evaluate alternatives - - a genuine
commitment to eliminating or trimming down speech restrictions whenever
possible. Without making speech restrictions a last resort, FDA will
find itself in the same situation it faces now, in which First Amendment
caselaw "threaten\[s\] to diminish the overall legal credibility
necessary for FDA to sustain its authority to accomplish its important
public health duties."[^6]

## The First Amendment Does Not Permit Restrictions Designed To Keep [Truthful Information from Citizens]{.underline} 

Government agencies may seek to regulate speech for a number of
legitimate purposes - - perhaps most importantly in the FDA context, to
prevent the serious harms that can result from untruthful or misleading
speech. While a purpose consistent with the First Amendment will not
necessarily suffice to uphold a restriction on speech, it is a threshold
requirement. Whether speech is categorized as commercial or
non-commercial, a restriction designed to prevent citizens from using
truthful information to make choices about lawful activities does not
satisfy this requirement. The First Amendment "directs us to be
especially skeptical of regulations that seek to keep people in the dark
for what the government perceives to be their own good."[^7]

This principle has been recognized repeatedly in cases involving
restrictions on information about drugs and devices, including the first
Supreme Court decision to extend First Amendment protection to
commercial speech. In that case, [Virginia State Bd. of Pharmacy v.
Virginia Citizens Consumer Council, Inc.]{.underline}, 425 U.S. 748, 769
(1976), the State of Virginia argued that a ban on advertising
prescription drug prices was justified by the fear "that if the
pharmacist who wishes to provide low cost, and assertedly low quality,
services is permitted to advertise, he will be taken up on his offer by
too many unwitting customers." The Supreme Court disagreed, holding at
770 that:

> Virginia is free to require whatever professional standards it wishes
> of its pharmacists . . . . But it may not do so by keeping the public
> in ignorance of the entirely lawful terms that competing pharmacists
> are offering . . . . \[T\]he justifications Virginia has offered for
> suppressing the flow of prescription drug price information, far from
> persuading us that the flow is not protected by the First Amendment,
> have reinforced our view that it is. We so hold.

Similarly, the court in [WLF I]{.underline} rejected paternalism as a
valid basis for restricting the dissemination of truthful information
about off-label uses of drugs and devices, holding that "\[t\]o the
extent that the FDA is endeavoring to keep information from physicians
out of concern that they will misuse that information, the regulation is
wholly and completely insupportable." [WLF I]{.underline}, 13 F. Supp.2d
at 69. "If there is one fixed principle in the commercial speech arena,"
the court observed, "it is that 'a State's paternalistic assumption that
the public will use truthful, nonmisleading commercial information
unwisely cannot justify a decision to suppress it.'" [Id.]{.underline}
at 69-70 (quoting [44 Liquormart, Inc. v. Rhode Island]{.underline}, 517
U.S. at 497).

Most recently, the Supreme Court's [Western States]{.underline} decision
rejected the theory that an interest in "protecting" patients from
truthful information could justify its suppression. There, the Court
addressed the argument (put forward by the dissent) that FDAMA's ban on
advertising compounded drugs could be sustained by an interest in
preventing patients who do not need compounded drugs from seeking them,
holding that:

> Even if . . . FDAMA's speech-related restrictions were motivated by a
> fear that advertising compounded drugs would put people who do not
> need such drugs at risk by causing them to convince their doctors to
> prescribe the drugs anyway, that fear would fail to justify the
> restrictions. Aside from the fact that this concern rests on the
> questionable assumption that doctors would prescribe unnecessary
> medications . . . \[it\] amounts to a fear that people would make bad
> decisions if given truthful information about compounded drugs. . . .
> [We have previously rejected the notion that the Government has an
> interest in preventing the dissemination of truthful commercial
> information in order to prevent members of the public from making bad
> decisions with the information.]{.underline}
>
> [Western States]{.underline}, 122 S. Ct. at 1507 (emphasis added).

Given the nature of its mission, FDA has legitimate interests that will
sometimes warrant carefully-crafted limitations on speech (for example,
preventing untruthful or inherently misleading claims about the products
it regulates, or preserving the integrity of the approval process for
drugs and devices set out in the Food, Drug and Cosmetic Act
(FDCA)).[^8] But preventing freely-made decisions based on truthful,
non-misleading information is not one of those interests. Adherence to
this principle is crucial to any successful effort by FDA to conform its
policies and practices to First Amendment mandates.

For example, FDA's Federal Register notice asks whether its current
approach to regulating advertising "lead\[s\] to overprescription of
drugs."[^9] Whether FDA's regulations could lead to "overprescription"
by some definition may be an interesting question, but it has no
relevance to the task at hand. Preventing "overprescription" is not a
goal that can justify restrictions on truthful, non-misleading speech.
And pursuing that goal would only derail FDA's effort to develop lawful
policies capable of surviving First Amendment scrutiny.[^10]

Similarly, FDA's Federal Register notice states that "if advertising of
prescription drugs results in the inappropriate prescription of
pharmaceuticals, the effect on public health will be negative."[^11] If
"inappropriate" prescriptions means prescriptions that result from the
doctor or patient receiving false or misleading information, FDA's
statement amounts to the proposition that drug advertisements should not
be false or misleading. This proposition is obviously correct, but FDA
already prohibits false or misleading advertisements. If "inappropriate"
prescriptions means prescription that a doctor writes based on a
judgment with which FDA disagrees, FDA has no power to suppress speech
to alter the doctor's prescribing habits - - or to keep patients from
asking their doctor about a drug they have seen advertised. This is
precisely the sort of paternalistic speech ban the First Amendment does
not permit.

## Commercial Speech Cannot Lose First Amendment Protection[ ]{.underline}Because It Fails To Satisfy FDA Requirements: Truthful and[ Non-Misleading Speech Goes Beyond FDA-Approved Speech]{.underline} 

Because Government agencies can properly prohibit commercial speech that
is false or "inherently" misleading, the conclusion that speech is false
or inherently misleading brings an end to First Amendment scrutiny.[^12]
The critical issue is whether the Government itself can dictate that
conclusion and short-circuit review of its commercial speech
restrictions.

In its Federal Register notice, FDA has asked whether it could sustain a
position "that certain promotional speech about drugs is inherently
misleading, unless it complies with FDA requirements."[^13] What is
meant by this question is not entirely clear. FDA plainly has the
authority to adopt requirements that proscribe inherently misleading
drug promotions generally, or to adopt requirements that proscribe
specific types of promotional claims that actually are inherently
misleading.[^14] But like any communication, a drug promotion is either
inherently misleading or it is not ‑ ‑ it cannot become so [merely
because it fails to comply with FDA requirements]{.underline}.
Inherently misleading speech may overlap with speech that violates
Government requirements, but the two are logically distinct categories.
Were it permissible to jettison logic and conflate these two categories,
the many cases testing the validity of Government requirements that
purport to ban "inherently misleading" speech would not exist.

In fact, numerous cases have explicitly rejected the proposition that
speech is "inherently misleading" because it does not satisfy Government
requirements, even where the speech in question is potentially
misleading. In [Pearson v. Shalala]{.underline}, 164 F.3d 650, 655 (D.C.
Cir.), [reh'g denied]{.underline}, 172 F.3d 72 (D.C. Cir. 1999), the FDA
contended that the health claims appellants wished to include on dietary
supplements were inherently misleading because they did not meet FDA's
requirement that there be "significant scientific agreement" about such
claims before they could be included in the labeling for dietary
supplements. The court disagreed, finding the argument that health
claims were inherently misleading unless they satisfied FDA's
significant scientific agreement requirement "almost frivolous." 164
F.3d at 655. The court further concluded that the claims at issue had
the potential to mislead, but that FDA failed to prove that the problem
could not be cured through disclosures and therefore justified an
outright ban on the claims.[^15] [Id.]{.underline} at 655-60.

In the context of drugs and devices, the theory that statements lacking
FDA approval were inherently misleading was considered and rejected in
[WLF I]{.underline}. There, FDA argued that manufacturer-funded or
manufacturer-disseminated speech about off-label uses is inherently
misleading because the FDCA "prescribes a specific system for
determining the 'truth' of claims about drugs and devices." [WLF
I]{.underline}, 13 F. Supp.2d at 67. The court concluded that FDA had no
power to impose a "specific system for determining truth," holding that:

> In asserting that any and all scientific claims . . . regarding
> prescription drugs are presumptively untruthful or misleading until
> the FDA has had the opportunity to evaluate them, FDA exaggerates its
> overall place in the universe.
>
> [Id.]{.underline}

Cases decided outside the FDA context have reached the same conclusions
about the Government's power to dictate truth. In [Bioganic Safety
Brands, Inc. v. Ament]{.underline}, 174 F. Supp.2d 1168 (D. Colo. 2001),
for example, the State of Colorado argued that safety claims about
pesticides were inherently misleading because a Colorado statute banned
such claims. The court found otherwise, rejecting the theory that the
State could properly determine that safety claims on pesticide labels
were inherently misleading "as a matter of law":

> Whether speech is "inherently misleading" . . . is a determination for
> the court, not the legislature, to make. If a legislature could place
> speech outside First Amendment protection by simply declaring the
> speech "inherently misleading," the First Amendment . . . would be
> subject to [de]{.underline} [facto]{.underline} modification by state
> legislatures.

[Id.]{.underline} at 1180.[^16]

In short, FDA cannot sustain a position that certain promotional speech
about drugs is inherently misleading unless it complies with FDA
requirements. Whether asserted in connection with drugs or any other
products, such a position would nullify the constitutional protections
accorded to commercial speech, and the cases have squarely rejected this
sort of "[de]{.underline} [facto]{.underline} modification" of the First
Amendment. Government-mandated systems for determining truth are not a
part of our First Amendment jurisprudence.

# THE DISSEMINATION OF INFORMATION ON OFF-LABEL USES

# [UNDER THE FIRST AMENDMENT]{.underline}  {#under-the-first-amendment .unnumbered}

## The Importance Of Promoting The Free Exchange Of Accurate Scientific [And Medical Information Concerning Off-Label Uses]{.underline} 

Advances in medical care often stem from the discovery that new uses of
FDA-approved drugs and devices can benefit patients otherwise lacking
satisfactory treatment options. The medical community's knowledge
regarding the safety and efficacy of FDA-approved drugs and devices
inevitably outpaces FDA-approved labeling. Physicians who regularly work
with these drugs and devices, and researchers who study their utility in
treating diseases or patient populations that are not included in the
existing labeling, often learn that they can be used safely and
effectively for purposes outside the labeling.

The diffusion of this knowledge can have important benefits for
patients ‑ ‑ particularly patients faced with serious illnesses and few
treatment options, or a range of treatment options that have already
failed or proved unsatisfactory due to low effectiveness or side effects
that are hard to tolerate. In fields such as oncology, for example, a
substantial number of medically-accepted treatments involve off-label
uses of FDA-approved drugs.[^17] Similarly, physicians have long relied
extensively on off-label treatments in caring for patients with
AIDS.[^18] Were doctors limited to using FDA-approved products only as
labeled ‑ ‑ or deprived of information on scientific and medical
developments permitting them to learn about and evaluate new treatment
alternatives ‑ ‑ in many cases their patients would receive sub-optimal
care.

These points are important because off-label use is an area where
removing barriers to the free flow of truthful and non-misleading
information can help to advance FDA's public health mission in a
substantial way, as well as fulfilling its legal obligations. But we
need not belabor these points, because they are recognized by FDA. In
its reply brief in the [Western States]{.underline} case, for example,
the Government drew an analogy between compounded drugs that may benefit
individual patients and off-label uses of FDA-approved drugs and
devices, explaining that:

> Congress . . . has generally refrained from providing . . .for the FDA
> to limit a physician, as part of the practice of medicine, from
> prescribing any legally available product for a particular patient.
> [See]{.underline} 37 Fed. Reg. 16,503 (1972) (noting repeated
> references in the legislative history of the 1938 Act and the 1962
> amendments that Congress did not intend the FDA to interfere with a
> physician's ability to prescribe legally approved products for
> unapproved uses) . . . . Consistent with that background, the FDA has
> permitted physicians to prescribe approved drugs for uses that are not
> identified in approved labeling. . . . That policy reflects the FDA's
> recognition that certain off-label uses perform an important
> therapeutic role in certain areas of medical practice, and that undue
> restrictions on such uses could have adverse health consequences.[^19]

Likewise, FDA has long understood that completely suppressing the
exchange of accurate scientific and medical information on off-label
uses between physicians and the manufacturers of drugs and devices does
not serve its public health objectives. For example, the FDA stated in
1994 that "because the agency recognizes the importance of dissemination
of reliable scientific information on . . . unapproved uses, it has
developed a number of policies related to dissemination of such
information."[^20] These include, for example, FDA's Final Guidance on
Industry-Supported Scientific and Educational Activities;[^21] FDA's
policy permitting manufacturers to provide information on off-label uses
in response to an unsolicited request;[^22] and FDA's decision to
"refrain from regulating the dissemination of information on unapproved
uses \[by manufacturers\] if the dissemination involves submission of
original research to peer-reviewed journals," recognizing "the need
among health care professionals for peer review and dissemination of the
latest significant scientific data and information on drugs and devices
in scientific journals."[^23]

Like FDA, Congress has also recognized the benefits of allowing
manufacturers to disseminate scientific and medical information on
off-label uses to health care professionals. In enacting Section 401 of
FDAMA,[^24] Congress sought to ensure "that health care practitioners
can obtain important scientific information about uses that are not
included in the approved labeling of drugs, biological products, and
devices" while also "encourag\[ing\] that these new uses be included on
the product label."[^25]

As of 1994, FDA stated that "\[s\]triking the proper balance between the
need to regulate the promotion of unapproved uses for drugs and devices
and the need for reliable scientific data and information on unapproved
uses of approved products has long been a difficult and controversial
challenge for the agency."[^26] Today, the challenge remains. Neither
the FDA's policies nor the FDAMA's provisions on dissemination of
off-label information have struck a balance that serves scientific and
public health needs and respects First Amendment freedoms. Balancing
might be necessary - - FDA has a legitimate interest in encouraging
manufacturers to seek new indications for their products, and in some
circumstances curtailing truthful speech might prove to be the only
possible mechanism for directly advancing that goal[^27] - - but FDA's
current speech restrictions go well beyond any measures that would
comport with its constitutional obligations. We do not attempt to
address here all of the restrictions on speech about off-label uses that
appear legally unsound; instead, we have focused on extremely modest
changes that are plainly required to bring FDA's policies into line with
well-established First Amendment precepts.

## The Standard for Analyzing FDA's Prohibitions on Speech Concerning [Off-Label Uses]{.underline} 

In evaluating its current policies, FDA must be attentive to the
[content]{.underline} of the speech in question, and the First Amendment
standards necessary to justify restrictions on that specific type of
speech. It cannot presume that the standard of review follows naturally
from the identity of the speaker. As noted earlier, FDA's Federal
Register notice appears to assume that a commercial speech analysis
would apply to all of its existing speech restrictions.[^28] Given the
breadth and pervasiveness of these restrictions, any such assumption is
not well-founded.

When FDA's restrictions go beyond advertisements and similar promotional
communications and curb the exchange of scientific information by
FDA-regulated companies, they should be judged by the same strict
scrutiny standard that would apply when any other party engaged in the
same communication. In fact, even when a manufacturer's involvement
introduces some commercial element into fully-protected speech, the
strict scrutiny standard applies when the commercial and non-commercial
speech is "inexplicably intertwined."[^29]

One example of a scenario calling for application of the strict scrutiny
standard is FDA policies limiting manufacturers' dissemination of
peer-reviewed journal articles or their involvement in CME programs. In
the [WLF I]{.underline} decision, the court declined to apply strict
scrutiny to these policies, although they were found deficient anyway
under the commercial speech analysis. The reasons the court should have
applied a more stringent standard have been persuasively stated by
commentators, and we need not elaborate further on the issue:

> . . . . Where science and medical practice information is involved,
> the most exacting test is appropriate. In this case, the potential
> harm of censoring speech is huge because it would limit information
> that doctors could receive about the beneficial uses of drugs.
> Meanwhile, the potential harm of allowing the speech is minimal. The
> information has been vetted already in the scientific community, and
> it is offered only to people with the expertise to evaluate it.
>
> Speech with scientific or academic value is at the core of the
> communications protected by the First Amendment. . . . The otherwise
> fully protected speech at issue \[in the [WLF]{.underline} decisions\]
> should not be treated as "only" commercial speech by virtue of the
> fact that a manufacturer paying to disseminate the speech has an
> economic interest in the product under discussion. . . . \[T\]he fact
> that a manufacturer "has an economic motivation" to support
> distribution of the information "would clearly be insufficient by
> itself to turn the materials into commercial speech."
>
> Moreover, aside from the case law establishing that scientific speech
> is protected fully, the speech in these cases exhibits none of the
> characteristics that would make it commercial speech. The Supreme
> Court has "characteriz\[ed\] the proposal of a commercial transaction
> as the test for identifying commercial speech." The activities at
> issue---[e.g.]{.underline}, mailing a textbook or an article reprint,
> or presenting data at a symposium---do not propose a commercial
> transaction. Thus . . . the speech should not be commercial.
>
> Additionally, the speech here does not reflect any of the related
> characteristics . . . used in identifying commercial speech.  . . . .
> The textbooks, article reprints, and symposia support are not
> "advertisements" in the common understanding of the term; even if they
> were, that would be insufficient to "compel the conclusion that they
> are commercial speech." Nor does the reference to a specific product
> in textbooks, article reprints, or symposia presentations "by itself
> render \[the communication\] commercial speech." Thus, the speech at
> issue here is not commercial.
>
> Even if the speech here could be deemed a hybrid, including commercial
> and noncommercial aspects, whatever elements of the latter may exist
> are intertwined inextricably with the fully protected non-commercial
> elements which require application of the strictest standard of First
> Amendment scrutiny. . . .

John Kamp, Daniel E. Troy, and Elizabeth Alexander, [FDA Marketing v.
First Amendment: Washington Legal Foundation Legal Challenges To
Off-Label Policies May Force Unprecedented Changes At FDA]{.underline},
54 Food and Drug L.J. 555, 563-64 (1999) (footnotes omitted).

## Under Any First Amendment Standard, FDA Cannot Prohibit Dissemination of Peer-Reviewed Journal Articles or Reference Textbooks, or Prevent Manufacturers From Suggesting Content [or Speakers For Independent CME Programs]{.underline} 

In its [WLF I -- WLF III]{.underline} decisions, the district court held
that under the First Amendment standards applicable to commercial
speech, FDA could not properly prohibit manufacturers from disseminating
peer-reviewed journal articles or reference textbooks on off-label uses
to medical professionals, nor could it prohibit manufacturers from
suggesting content or speakers to independent CME providers for programs
discussing off-label uses.[^30] In addition, the court held that (while
FDA could require disclosures regarding manufacturers' financial
interests, and the fact that the uses in question were not FDA-approved)
it could not condition manufacturers' exercise of their First Amendment
rights on compliance with any of the additional requirements in Section
401 of FDAMA or its implementing regulations[^31] - - requirements the
court characterized as "a kind of constitutional blackmail."[^32]

The court's opinions concluding that FDA could not constitutionally
prohibit the speech in question are thorough and plainly correct, and we
will not repeat here all of the various considerations underlying the
court's conclusions. However, two points bear particular emphasis:

> \(1\) The FDA has [only one legitimate interest]{.underline} in
> restricting the dissemination of truthful off-label information, which
> is encouraging manufacturers to submit supplemental applications for
> off-label uses (more precisely, FDA's interest is in "encourag\[ing\]
> that these new uses be included on the product label" while
> [also]{.underline} ensuring that "health care practitioners can obtain
> important scientific information about \[off-label\] uses");[^33] and
>
> \(2\) This interest cannot justify FDA's broad speech
> restrictions - - they are clearly not a last resort for getting new
> uses on-label, or even consistently helpful in that regard.

There are numerous incentives for manufacturers to submit supplemental
applications for off-label uses whenever it is rational and appropriate
to do so, without adding speech prohibitions into the calculus.[^34]
Some of these incentives stem from sources wholly independent of the
FDA. For example, getting the use on-label can reduce product liability
risks, and it can increase sales by expanding insurance coverage for the
use.

The most obvious incentive for submitting supplemental applications is
that [FDA approval means something in the marketplace]{.underline}.
Physicians know that an FDA-approved indication results from a rigorous
process for testing safety and effectiveness, and physicians and
patients alike place confidence in FDA's "seal of approval." To the
extent that FDA's speech restrictions reflect a fear that its seal of
approval is not valued by the public, such a fear is unwarranted. And
FDA itself [can]{.underline} speak freely about off-label uses - - if it
fears that the rigorous evidence requirements necessary for an approved
indication are undervalued, [it has the power to educate physicians and
patients about the safety and effectiveness benefits accompanying an
approved indication]{.underline}.[^35] A ban on truthful speech by
manufacturers can hardly be necessary when FDA can use speech to combat
any perceived undervaluation of its seal of approval.

Moreover, the FDAMA contains several provisions to facilitate both
supplemental and new applications. Section 403, for example, is designed
specifically to encourage supplemental applications for off-label uses;
it specifies various mechanisms for FDA to work cooperatively with
manufacturers to facilitate the approval process, to clarify the
requirements for approval, to specify data requirements that avoid
duplication of data from studies supporting the original application,
and to work collaboratively with NIH and other groups to identify
existing studies that would wholly or partly support supplemental
applications for off-label uses.

Given all of these considerations, there is no logical reason to
conclude that the current restrictions on disseminating truthful
information from peer-reviewed journal articles and medical reference
texts (or on suggesting content or speakers for an independent CME
program) are a necessary underpinning of FDA's supplemental application
process. Nor is there any empirical evidence supporting the theory that
censorship is necessary to preserve manufacturers' incentives to seek
FDA approval for off-label uses. In fact, FDA has previously predicted
that the mildly-liberalizing FDAMA provisions on disseminating off-label
information could potentially produce [more]{.underline} supplemental
applications by expanding the market for the product and justifying the
cost of clinical trials.[^36]

In short, FDA's existing speech prohibitions plainly are not a "last
resort" necessary to prop up the FDCA's approval regime for drugs and
devices. At the same time, they undermine FDA's interest in promoting
physicians' access to reliable scientific and medical information and
thereby deprive some patients of the most appropriate therapy. Under the
First Amendment, these prohibitions are unlawful.

## FDA's Speech Prohibitions Cannot Be Enforced as "Non-prohibitions" [Under a New Legal Theory]{.underline} 

FDA's current position (which resulted in the [WLF IV]{.underline}
decision dismissing the Government's appeal for lack of a constitutional
case or controversy and vacating a portion of the district court's
injunctions) is that FDAMA and its CME Guidance do not prohibit speech.
More specifically, they are "safe harbors" that do not "independently"
prohibit speech. The only catch is that, if a manufacturer's truthful
speech concerning off-label uses does not conform to the applicable safe
harbor, it can be used as evidence that the product is intended for a
"new use" and subject the manufacturer to prosecution under an "intended
use" or "misbranding" theory.[^37]

In short, there is no "prohibition" on speech that does not conform to
Section 401 of FDAMA or the CME Guidance, but engaging in the
"non-prohibited" speech can still result in prosecution. No doubt these
subtleties are intriguing to scholars of FDA law. But they are
irrelevant for First Amendment purposes.

As the [WLF I -- WLF III]{.underline} decisions demonstrate, the First
Amendment does not permit FDA to prohibit the speech at issue there.
Since the speech cannot be prohibited directly, it cannot be prohibited
indirectly by forming the predicate for prosecution under a different
legal theory. Were it otherwise, "\[t\]his would allow the government to
'produce a result which \[it\] could not command directly.'"[^38]

In fact, in [Western States]{.underline}, the Supreme Court had no
difficulty striking down a speech prohibition that was "not a
prohibition." The FDAMA provisions at issue there created a safe harbor
permitting pharmacies to sell compounded drugs without complying with
the FDCA's new drug approval requirements (and certain other
requirements) provided that they refrained from advertising specific
compounded drugs.[^39] Predictably, the Government argued that:

> \[FDAMA's compounding provisions\] do\[ \] not absolutely prohibit any
> speech. A pharmacy that wishes to mass-produce a particular drug and
> promote that product by advertising may do so . . . if it complies
> with the FDCA's new drug approval . . . requirements. It is only if
> the pharmacy wishes to avail itself of the exemption from those
> otherwise generally applicable requirements that it must limit its
> promotional activities.[^40]

This subtlety apparently escaped the Supreme Court entirely. It never
even addressed the "non-prohibition" theory, and concluded that "the
prohibition is unconstitutional." [Western States]{.underline}, 122
S.Ct. at 1509.

Here too, the relevant "non-prohibitions" amount to unconstitutional
prohibitions on speech. Under the First Amendment, the Government cannot
directly prohibit this speech, nor can it indirectly produce the same
result.

The time has come for FDA to adopt guidance on the dissemination of
enduring materials concerning off-label uses (and on CME programs) that
adheres to the First Amendment. At a minimum, such a guidance document
should assure manufacturers that they will not be penalized (directly or
indirectly, under any legal theory) for engaging in the speech protected
by the [WLF I -- WLF III]{.underline} decisions.

\* \* \*

In embarking on this review of its existing speech restrictions and
their legal validity under the First Amendment, FDA has undertaken a
critical and long-needed initiative. We hope that FDA will find these
comments useful, and look forward to submitting further comments on
these important issues.

Sincerely,

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Daniel J. Popeo

Chairman and General Counsel

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Richard A. Samp

Chief Counsel

[^1]: 67 Fed. Reg. 34942 (May 16, 2002).

[^2]: [See]{.underline} [Washington Legal Found. v.
    Friedman]{.underline}, 13 F. Supp.2d 51 (D.D.C. 1998)("[WLF
    I]{.underline}"); [Washington Legal Found. v. Friedman]{.underline},
    36 F. Supp.2d 16 (D.D.C. 1999)("[WLF II]{.underline}"); [Washington
    Legal Found. v. Henney]{.underline}, 56 F. Supp.2d 81 (D.D.C.
    1999)("[WLF III]{.underline}"); [Washington Legal Found. v.
    Henney]{.underline}, 202 F.3d 2000 (D.C. Cir. 2000)("[WLF
    IV]{.underline}"); [Washington Legal Found. v. Henney]{.underline},
    128 F. Supp. 11 (D.D.C. 2000)("[WLF V]{.underline}").

[^3]: We note that FDA's Federal Register notice appears to presume that
    all of the speech prohibitions FDA currently imposes are subject to
    a "commercial speech" analysis, rather than the strict scrutiny
    standard applied to fully-protected speech. As discussed further
    below, this presumption appears unfounded.

[^4]: [See]{.underline}, [e.g.]{.underline}, [Board of Trustees of the
    State University of New York v. Fox]{.underline}, 492 U.S. 469, 480
    (1989).

[^5]: Similarly, the Court observed that "\[n\]owhere in the legislative
    history of the FDAMA or petitioners' briefs is there any explanation
    of why the Government believed forbidding advertising was a
    necessary as opposed to merely convenient means of achieving its
    interests," even though it was "well-established that the party
    seeking to uphold a restriction on commercial speech carries the
    burden of justifying it." [Western States]{.underline}, 122 S. Ct.
    at 1507 (quoting [Edenfield v. Fane]{.underline}, 507 U.S. 761, 770
    (1993) and [Bolger v. Youngs Drug Products Corp.]{.underline}, 463
    U.S. 60, 71, n. 20 (1983)).

[^6]: 67 Fed. Reg. at 34943.

[^7]: [44 Liquormart, Inc. v. Rhode Island]{.underline}, 517 U.S. 484,
    503 (1996).

[^8]: [See]{.underline} [Western States]{.underline}, 122 S. Ct. at 1505
    ("\[p\]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"); [WLF
    I]{.underline}, 13 F. Supp.2d at 70-71 (concluding that FDA has a
    substantial interest in maintaining incentives for manufacturers of
    approved drugs and devices to apply for approval of off-label uses).

[^9]: 67 Fed. Reg. at 34943.

[^10]: This is not to suggest that the Government has no power to curb
    perceived "overprescription" of drugs (or perceived overutilization
    of any healthcare products or services); it can do so for
    appropriate reasons and through appropriate methods. For example,
    Government agencies that pay for healthcare services use a variety
    of tools to combat overutilization, including measures such as
    co-payment requirements, utilization reviews, and coverage
    restrictions.

[^11]: 67 Fed. Reg. at 34943.

[^12]: [See]{.underline}, [e.g.]{.underline}, [In re
    R.M.J.]{.underline}, 455 U.S. 191, 203 (1982). By contrast, when
    commercial speech is potentially misleading, the Government must
    explore alternatives (such as requiring disclaimers) that could
    eliminate the potential for deception without prohibiting the speech
    altogether. [See]{.underline}, [e.g.]{.underline}, [Western
    States]{.underline}, 122 S. Ct. at 1508 (even if the Government had
    argued that FDAMA's ban on advertising compounded drugs were
    necessary to prevent patients from being misled about their risks,
    "this interest could be satisfied by 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").

[^13]: 67 Fed. Reg. at 34943.

[^14]: For example, FDA's regulations prohibit advertisements that
    "\[p\]resent\[ \] information from a study in a way that implies
    that the study represents larger or more general experience with the
    drug than it actually does." 21 CFR 202.1(e)(6)(v). Because an
    advertisement falling within this category would actually be
    inherently misleading, there is no question about the regulation's
    validity.

[^15]: Ironically, while [Pearson]{.underline} curtly dismissed the
    theory that the claims at issue were inherently misleading unless
    they complied with FDA requirements, the case might be the basis for
    FDA's inquiry about whether it can successfully characterize
    [drug]{.underline} claims as inherently misleading unless they
    comply with FDA requirements. Noting that "the government does not
    assert that appellants' dietary supplements in any fashion
    [threaten]{.underline} consumers' health and safety," the court
    included a footnote stating that "\[d\]rugs, on the other hand,
    appear to be in an entirely different category - - the potential
    harm is presumably much greater." [Pearson]{.underline}, 164 F.3d at
    656 & n.6 (emphasis in original). One cannot quibble with the
    observation that drugs have greater risks than dietary supplements
    - - but the point has no bearing on whether FDA can make a drug
    promotion "inherently misleading" by fiat, nor was the court
    suggesting such a possibility.

[^16]: For additional cases, [see]{.underline}, [e.g.]{.underline},
    [Peel v. Attorney Reg. & Disciplinary Commission]{.underline}, 496
    U.S. 91, 108 (1990) ("\[w\]hether the inherent character of a
    statement places it beyond the protection of the First Amendment is
    a question of law over which Members of this Court should exercise
    [de]{.underline} [novo]{.underline} review"); [Nutritional Health
    Alliance v. Shalala]{.underline}, 953 F. Supp. 526, 529 (S.D.N.Y.
    1997), [aff'd in part, vacated and dismissed in part on other
    grounds]{.underline}, 144 F.3d 220 (2d Cir. 1998) ("\[a\]lthough the
    Government argues that health claims that have not been FDA approved
    are inherently misleading, not all potential health claims are
    misleading; at least some can be presented in a non-misleading
    fashion"); [Ass'n of Nat'l Advertisers, Inc. v.
    Lungren]{.underline}, 809 F. Supp. 747, 756 (N.D. Cal. 1992),
    [aff'd]{.underline}, 44 F.3d 726 (9^th^ Cir. 1994) ("\[i\]f First
    Amendment scrutiny in the commercial speech arena is to have any
    bite at all, a legislative body cannot justify its restrictions on
    commercial speech simply by declaring that marketing claims are
    misleading").

[^17]: [See]{.underline}, [e.g.]{.underline}, U.S. General Accounting
    Office, [Off-Label Drugs, Reimbursement Policies Constrain
    Physicians in Their Choice of Cancer Therapies]{.underline},
    GAO/PEMD-91-14 (Sept. 1991) (finding that 25% of cancer drugs were
    used off-label and that 56% of cancer patients were given at least
    one drug off-label).

[^18]: [See]{.underline}, [e.g.]{.underline}, Testimony of Sarah F.
    Jagger, General Accounting Office Director of Health Services
    Quality and Public Health Issues, before the House Government Reform
    Committee Subcommittee on Human Resources, 1996 WL 520197 (F.D.C.H.)
    (Sept. 12, 1996) (citing research finding that more than 80% of AIDS
    patients received at least one drug off-label and that 40% of all
    drugs that were given were prescribed off-label).

[^19]: Reply Brief for the Petitioners in [Thompson v. Western States
    Medical Center]{.underline}, 2002 WL 243584, \*28.

[^20]: 59 Fed. Reg. 59820, 59822 (Nov. 18, 1994). [See]{.underline}
    [also]{.underline} 21 CFR 312.7(a) (providing that manufacturers may
    not represent in a promotional context that a drug under
    investigation is safe and effective for the purposes for which it is
    under investigation, and that "\[t\]his provision is not intended to
    restrict the full exchange of scientific information concerning the
    drug, including dissemination of scientific findings in scientific
    or lay media").

[^21]: 62 Fed. Reg. 64074 (Dec. 3, 1997).

[^22]: 59 Fed. Reg. at 59824.

[^23]: 59 Fed. Reg. at 59823.

[^24]: 21 U.S.C. §§ 360aaa - 360aaa-6.

[^25]: H.R. Conf. Rep. No. 105-399 (Nov. 9, 1997), 1997 WL 703162 (Leg.
    Hist.), \*99.

[^26]: 59 Fed. Reg. at 59825.

[^27]: It is important to note that there are two circumstances where
    balancing is [not]{.underline} called for. First, balancing is not
    required in connection with false or inherently misleading speech
    about off-label uses (which the First Amendment permits FDA to ban
    completely). Second, for reasons discussed above in Section I.B.,
    the presumption in favor of free speech cannot be balanced against a
    perceived need to keep truthful information from people to preclude
    them from making informed decisions with which FDA might disagree.

[^28]: [See]{.underline} 67 Fed. Reg. at 34943 ("FDA seeks comment
    on . . . issues related to the FDA's regulation of commercial
    speech").

[^29]: [Riley v. Nat'l Federation of the Blind]{.underline}, 487 U.S.
    781, 796 (1988).

[^30]: The court also made clear that FDA could require manufacturers
    that disseminated enduring materials or sponsored CME programs to
    disclose their financial interest in the products discussed and the
    fact that the uses discussed were not FDA-approved, and that FDA
    retained full authority to apply and enforce any of its rules or
    guidance documents sanctioning manufacturers for disseminating false
    or misleading information. [See]{.underline} [WLF I]{.underline}, 13
    F. Supp.2d at 74.

[^31]: Under Section 401 of FDAMA, manufacturers must satisfy a variety
    of conditions (beyond straightforward disclosure requirements
    similar to those authorized in the [WLF I]{.underline} opinion)
    before they can disseminate those journal articles and reference
    texts that FDAMA permits. If they satisfy all of these conditions,
    their dissemination of these materials shall not be construed "as
    evidence of a new intended use of the drug or device that is
    different from the intended use . . . set forth in the official
    labeling" or construed "as labeling, adulteration or misbranding of
    the drug or device." The most important of FDAMA's conditions is
    that the manufacturer must submit a supplemental application for the
    off-label use (or certify that it will submit such an application
    within the statutory deadline), unless FDA exempts the manufacturer
    from this requirement because a supplemental application would be
    prohibitively expensive or it would be unethical to conduct the
    studies necessary to support the application. Additional conditions
    include, [inter]{.underline} [alia]{.underline}: (1) that the
    manufacturer submit an advance copy of the information to be
    disseminated to FDA, along with any clinical trial information and
    reports of clinical experience; (2) that the disseminated
    information be accompanied by a bibliography of other scientific
    articles concerning the off-label use; and (3) that the manufacturer
    prepare and submit semi-annually to FDA lists of the materials
    disseminated and the categories of recipients.

    It should be noted that (notwithstanding FDAMA's infirmities) FDA's
    implementing regulations are more burdensome. For example, the
    regulations significantly restrict manufacturers' ability to qualify
    for an exemption to FDAMA's requirement for a supplemental
    application for the off-label use. By contrast, Congress envisioned
    that FDA would make exemption decisions that could take into account
    a broad range of factors bearing on whether the off-label use
    already represented accepted medical practice or whether the cost of
    the studies necessary for a supplemental application were justified
    by the likely return ([e.g.]{.underline}, whether the off-label use
    was recognized by specified compendia or medical societies, whether
    the use was recommended by a Federal agency, the patent status of
    the product, and the size of the patient population).
    [See]{.underline} H.R. Conf. Rep. No. 105-399, 1997 WL 703162 (Leg.
    Hist.), \*100.

[^32]: [WLF III]{.underline}, 56 F. Supp.2d at 87.

[^33]: H.R. Conf. Rep. No. 105-399, 1997 WL 703162, \*99.

[^34]: And of course, in a circumstance where it is [not]{.underline}
    rational and appropriate to submit a supplemental application (for
    example, where the necessary clinical trials cannot ethically be
    conducted, or where the patent status of the product or size of the
    relevant patient population makes a supplemental application
    economically prohibitive), the application will not be
    submitted - - burdening the manufacturer's speech will not change
    that outcome, and consequently it will not advance FDA's interests
    in any way. Similarly, restricting truthful speech cannot
    incentivize a manufacturer to submit a supplemental application for
    an off-label use in a case where it has already done so.

[^35]: [See]{.underline}, [e.g.]{.underline}, [44
    Liquormart]{.underline}, 517 U.S. at 507 ("\[e\]ven educational
    campaigns focused on the problems of excessive . . . drinking might
    prove to be more effective \[than the State's advertising ban\]");
    [Linmark Associates, Inc. v. Willingboro]{.underline}, 431 U.S. 85,
    97 (1977)(a ban on "for sale" signs was not justified to assure that
    a town remained racially integrated where "\[t\]he township
    obviously remains free to continue the 'process of education' it has
    already begun" and "can give widespread publicity through 'Not for
    Sale' signs or other methods to the number of whites remaining in
    Willingboro").

[^36]: [See]{.underline} 63 Fed. Reg. 64556, 64579 (Nov. 20, 1998),
    explaining that:

    > A firm would typically conduct clinical studies in support of a
    > supplemental application for a new use only if the firm believed
    > that the added revenues associated with the new indication would
    > exceed the costs of the supporting studies. Because this rule
    > \[implementing section 401 of FDAMA\] will accelerate the receipt
    > of these revenues, it is possible that some new use supplemental
    > applications that would not \[otherwise\] have been economically
    > justified . . . will now be submitted.

[^37]: [See]{.underline} 65 Fed. Reg. 14286 (March 16, 2000) (notice
    concerning Decision in [Washington Legal Foundation v.
    Henney]{.underline}); FDA Response to Citizen Petition of Washington
    Legal Foundation, Docket No. OIP-0250 (Jan. 28, 2002).

[^38]: [Perry v. Sinderman]{.underline}, 408 U.S. 593, 597 (1972)
    (quoting [Speiser v. Randall]{.underline}, 357 U.S. 513, 526
    (1958)).

[^39]: Thus, a prosecution against a pharmacy that advertised compounded
    drugs would not have been based on an alleged violation of FDAMA's
    compounding provisions, since they only represented a safe harbor
    that technically did not prohibit advertising; instead, the pharmacy
    would be prosecuted for selling unapproved and misbranded drugs
    under the same theories FDA would use against a manufacturer that
    disseminated off-label information without conforming to the safe
    harbor in Section 401 of FDAMA or the CME Guidance.

[^40]: Reply Brief for the Petitioners in [Thompson v. Western States
    Medical Center]{.underline}, 2002 WL 243584, \*18-19.