The n e w e ng l a n d j o u r na l of m e dic i n e

H e a l t h L a w, E t h i c s , a n d H u m a n R i g h t s

MaryBeth Hamel, M.D., M.P.H., Editor

Forbidden and Permitted Statements about Medications

Loosening the Rules
Jerry Avorn, M.D., Ameet Sarpatwari, J.D., Ph.D., and AaronS. Kesselheim, M.D., J.D., M.P.H.

In May 2015, Amarin, a small Irish pharmaceuti-
cal company, brought a preemptive suit against
the Food and Drug Administration (FDA), argu-
ing that if the agency were to refuse to allow it
to distribute information about the usefulness of
its product (a prescription fish oil) for an unap-
proved indication, that refusal would violate its
First Amendment right to free speech.1 Supported
by the pharmaceutical industry and libertarian
advocacy organizations such as the Washington
Legal Foundation,2 this action represented the
most recent assault on a long-standing legal and
regulatory tradition prohibiting drug manufac-
turers from making claims that differ from FDA
determinations about a drugs efficacy and ad-
verse effects. On June 5, the FDA responded to
the company with a conciliatory letter, noting
that most of the promotional materials the com-
pany planned to distribute were acceptable and
that the agency was reassessing its policies in
this area.3 In any case, the FDA noted, the com-
pany could simply reposition its product as a
dietary supplement. This would give it great
latitude about its promotional claims and would
essentially remove the medication from the FDAs
oversight.
Many observers thought this would be the
end of the matter, since the FDA letter provided
Amarin with several pathways for promoting the
unapproved use of its product. Others felt the
case was not only about fish oil; this view was
vindicated when the company persisted in its
litigation, arguing that it should not be within
the FDAs purview to determine what a drug
manufacturer can and cannot say about the effec
tiveness of its products if such statements were
not outright fraudulent. On August 7, the case
took on a dramatically more important role when
a federal judge ruled on the Amarin suit by cit-
ing the First Amendment, presenting his courts
considered and firm view that the FDA could
not prevent promotion of a drug for an unap-
proved use if a manufacturers promotional state-
ments are truthful.4 The FDA has the right to
appeal this decision.
In justifying his conclusion, the judge built
on an earlier case in which a federal court of
appeals had overturned the conviction of a phar-
maceutical sales representative for promoting
unproven (and in some cases untested) uses of
his companys product on the grounds that this
violated his First Amendment rights.4 The FDA
itself has appeared increasingly willing to limit
its own authority in this regard. In February
2014, the agency issued a draft guidance that
would make it easier for drug manufacturers to
disseminate information on the use of their
products for indications the FDA had not ap-
proved. In June of that year, the FDA similarly
declared its willingness to allow pharmaceutical
companies to make statements about the risks
of their products that differ from the agencys
own determination of side effects.
At the center of this growing controversy is
the First Amendment to the Constitution, which
provides that Congress shall make no law . . .
abridging the freedom of speech. This language
has been interpreted as protecting to varying
degrees nearly all speech, with very few excep-
tions (e.g., speech inciting . . . imminent law-
less action the kind of speech that could
directly lead to violent overthrow of the govern-
ment).5 However, communication about medica-
tions has traditionally been held aside for special
legal treatment, particularly in the context of
commercial speech communication from a
business entity that proposes a commercial trans-
action. Since the middle of the 20th century,

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 The n e w e ng l a n d j o u r na l
legislators and regulators have imposed much
tighter communication restrictions on FDA-reg-
ulated manufacturers than on other companies.
Such measures have been based on the concepts
that interpreting statements about medical prod-
ucts such as prescription drugs requires highly
specialized knowledge and that the consequences
of misleading statements in this domain could
have important effects on health or even life it-
self. This debate relates only to promotional
statements manufacturers can make, not to the
ability of physicians to prescribe any approved
drug for any purpose they choose, which would
not be affected by these issues.
Much of the evolution of the FDA the first
federal consumer protection agency has been
rooted in its statutory authority to prohibit drug
manufacturers from making promotional state-
ments about their products that differ from the
agencys evaluations. These powers were origi-
nally granted and have been augmented over
time to enable the FDA to control often poorly
substantiated claims of effectiveness and safety
made by some manufacturers about their prod-
ucts, from the early days of patent medicines
to the present.6 The rationale for limiting such
communication was that physicians and patients
could not be expected to determine whether a
given drug was safe and effective without having
the benefit of the lengthy and complex evalua-
tion process conducted by FDA scientists and its
outside advisors, who assess reams of complex
data on pharmacology and clinical trial results,
not all of which are publicly available.
Much of the recent opposition to these re-
strictions has been based on the concept that
individual decision making in an open market-
place offers a better way to inform choices about
all products, including medications, than the de-
terminations of a government agency. One land-
mark in the ascendancy of this ideology outside
health care was the 2010 Citizens United case. The
Supreme Court determined that because corpo-
rations are personlike entities, corporate finan-
cial contributions to political campaigns (which
it considered a form of speech) deserve the same
protections accorded to political statements made
by individuals.7 The following year, the Supreme
Court expanded the concept of speech even
further, ruling that the right of a company (IMS
Health) to sell pharmacy-derived data to drug
companies describing the prescribing patterns
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of m e dic i n e
of physicians also constituted a form of pro-
tected commercial speech.8 In a legal environ-
ment that endorses the sale of prescribing re-
cords and corporate contributions to political
campaigns as forms of protected speech, it is
not surprising that the right of the FDA to regu-
late what companies can say about their prod-
ucts efficacy and safety is also coming under
increasing attack on First Amendment grounds.
Commer cial Speech
by Manufac t urer s
The Pure Food and Drug Act of 1906 established
the FDAs authority to require that manufactur-
ers of medicines accurately depict the contents
of a product on its label.9 Initially, the term
label included only information affixed to the
container itself. But with the federal Food, Drug,
and Cosmetic Act of 1938, the law expanded to
include all associated promotional materials, a
view endorsed by the Supreme Court in 1948.10
Until 1962, manufacturers were not required
to demonstrate whether a new drug worked, and
as a result the FDA had only limited authority
over manufacturers statements about efficacy.
In that year, Congress amended the law to re-
quire that manufacturers demonstrate efficacy
before a drug could be marketed.11 Before that
reform, medications were commonly advertised
as being helpful for diseases on which they had
no documented effect, and risks were neither
systematically assessed nor thoroughly reported
to prescribers.12,13 The 1962 legislation gave the
FDA the authority to consider any labeling
including promotional materials that adver-
tised uses of a drug not approved by the agency
as false or misleading.14 Although some off-
label use may be for a purpose that is solidly
based on evidence, much of it is not.15,16 An in-
crease in investigations and enforcement actions
starting in the early 2000s and continuing to the
present has led to a levying of more than $15 bil-
lion in civil and criminal fines and settlements
against nearly all major drug manufacturers for
illegal off-label promotion.17,18 One of the most
commonly cited instances of off-label promotion
in these lawsuits was the marketing of antipsy-
chotic medications to control behavioral symp-
toms in elderly patients with dementia, a use
that is not only generally ineffective but that also
increases the risk of death by 60 to 70%.19
 Health Law, Ethics, and Human Rights
E xpansion of Right s
to Commer cial Speech
Opponents of the FDAs right to regulate com-
panies statements about their products have
sought to diminish that authority on practical as
well as Constitutional grounds.20 One main argu-
ment has been that FDA restrictions on manu-
facturers statements about their products can
limit the ability of physicians and patients to
learn of potentially useful new properties of
drugs.21 For example, by 1999 it was demon-
strated that thalidomide could be helpful in the
treatment of advanced myeloma.22 However, the
ability of its manufacturer to convey this infor-
mation was limited until the manufacturer sub-
mitted and the FDA approved a supplementary
indication for multiple myeloma in 2006 that
was based on the results of a well-controlled
clinical trial that confirmed its efficacy in the
treatment of this condition.23 Similar arguments
are made regarding the promotion of other drugs
for evidence-based indications for which they
have not been approved.
An economic objection has also been made to
the FDAs capacity to restrict the promotion and
distribution of drugs for uses it has not ap-
proved. Since such additional use would generate
revenue for the manufacturer, the FDA restric-
tions are seen as unfairly limiting a companys
ability to receive revenues for its products.24 In
some ways, this can be seen as analogous to an
argument an airline might make objecting to gov-
ernmental rules about permitted routes or limits
on pilot work hours on the grounds that such
regulation reduces their capacity to profit from
their investment in airplanes.
In terms of Constitutional jurisprudence,
courts have tended in recent years to agree with
such antiregulatory sentiment and have favored
expanding interpretations of rights to commer-
cial speech under the First Amendment. In Thomp-
son v. Western States Medical Center,25 the Supreme
Court reviewed a law that allowed drug com-
pounders makers of individualized formula-
tions of prescription drugs to avoid FDA
oversight provided that they refrained from ad-
vertising. Compounding pharmacies claimed that
this restriction violated their right to dissemi-
nate information about their products. The Court
applied the traditional test for evaluating restric-
tions on commercial speech, which it first stated
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in 1980. This test requires the assessment of
several factors: whether the speech is lawful and
not misleading, whether the governments inter-
est in restricting the speech is substantial, wheth-
er the restriction advances that interest, and
whether it is no more limiting than necessary.26
In a 5-to-4 decision, the Court found that the
government had a substantial interest in pro-
moting public health by ensuring rigorous drug
testing but that it also had an interest in facili-
tating patients access to compounded products.
Ultimately, it ruled to allow advertising by the
compounding pharmacies on the grounds 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.25 A majority of the justices believed societys
interests could be protected by measures that
did not restrict commercial speech, such as lim-
iting the sales of compounded drugs or adding
disclaimers that the products were not approved
by the FDA. Subsequent events have raised the
question as to whether the Courts decision
achieved an adequate balance between concerns
for public health and free speech. A recent re-
view of the proliferation of commercial com-
pounding pharmacies evaluated 11 infectious
outbreaks caused by contaminated compounded
medications that affected 207 patients and caused
17 deaths, nearly all of which occurred after the
Supreme Court decision. The review identified
inadequate regulatory controls as the major un-
derlying cause.27 Not included in this total was a
subsequent 2012 epidemic caused by the fungal
contamination of an injectable steroid prepared
by a compounding pharmacy, which resulted in
749 serious infections in 20 states, including 229
cases of meningitis and 61 deaths.28
The expansion of companies rights to com-
mercial speech related to prescription drugs was
augmented with the 2011 case of Sorrell v. IMS
Health,8 which dealt with a Vermont law that
prohibited the sale of prescribing records to drug
companies for marketing purposes without a
prescribers consent.29 In a 6-to-3 decision, the
Court found that restricting the sale of such
prescription data would impermissibly limit the
right of drug companies to promote their prod-
ucts to physicians. It argued that sophisticated
physicians should simply scrutinize drug manu-
facturers claims and that the state could present
doctors with marketing materials of its own.
969
 The n e w e ng l a n d j o u r na l
This argument was subsequently applied by
the Court of Appeals for the Second Circuit in a
decision that undercut the FDAs restrictions on
off-label promotion. The court reviewed the
conviction of Alfred Caronia, a pharmaceutical
sales representative who had been audiotaped
while promoting the wide use of sodium oxybate
(Xyrem). The drug had been approved only for
the treatment of narcolepsy, but Caronia also
discussed its use in managing Parkinsons dis-
ease, fibromyalgia, insomnia, and other condi-
tions for which there was little evidence of ef-
ficacy. In a 2-to-1 decision, the circuit court
overturned Caronias conviction on the grounds
that it infringed on his right to free speech.
(Subsequently, legal analysts theorized that the
court might have ruled differently if the govern-
ment had argued more precisely that Caronias
speech was evidence of an intent to market the
drug impermissibly.) Although the court acknowl-
edged the governments interest in promoting
drug safety and public health, it held that alter-
native policies, such as disclaimers and limits on
physicians ability to write off-label prescriptions,
could more directly and narrowly achieve the
governments goal of reducing the publics expo-
sure to unsafe drugs.30 The FDA chose not to
appeal the decision to the Supreme Court. Ob-
servers have suggested that the agency was con-
cerned that if it lost the case on appeal to a court
known for its advocacy of commercial speech,
its entire regulatory infrastructure would have
been undermined.31
Not all major decisions have exonerated com-
panies making claims that run counter to the
FDAs regulatory decisions. One such case relat-
ed to interferon gamma-1b (Actimmune), which
the FDA had approved for treatment of the rare
condition of chronic granulomatous disease.32
The company, led by physician W. Scott Har-
konen, issued a press release claiming that a
clinical trial in which the efficacy of the drug
was tested for the treatment of a different and
more common condition, idiopathic pulmonary
fibrosis, demonstrated a reduction in mortality
of 70% in patients with a mild-to-moderate form
of this disease. However, this contention was
based solely on post hoc analyses of data from
the larger trial, in which patients with all levels
of severity of idiopathic pulmonary fibrosis had
been enrolled and in which it had been shown
that the drug did not confer a statistically sig-
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of m e dic i n e
nificant survival advantage.33 At trial, nearly
everybody agreed that the press release misrep-
resented the trial results, and a court of appeals
ruled that the press release was fraudulent even
if not literally false and upheld Harkonens con-
viction, primarily on the basis of Harkonen hav-
ing deceived investors in his role as chief execu-
tive officer.32 The Supreme Court chose not to
review the case.34 Harkonen served 6 months of
home detention, and his company, in a separate
case, paid $37 million to settle charges of off-
label promotion. A subsequent prospective clini-
cal trial showed no evidence that the drug was
effective in patients with mild-to-moderate pul-
monary fibrosis; the study was stopped early
owing to the drugs lack of benefit as compared
with placebo.35
Lo osening of FDA Marke ting
Re s tric tions on Manufac t urer s
Although the FDA currently prohibits manufac-
turers from engaging directly in off-label mar-
keting, it has become increasingly permissive in
providing numerous avenues to convey such in-
formation to prescribers safe harbors that
make it possible to communicate off-label claims
without risking government sanction. Thus far,
companies have been permitted to respond to
unsolicited questions from physicians concern-
ing off-label uses, to support independent and
nonpromotional continuing medical education
programs that discuss off-label drug uses, and
to disseminate reprints of peer-reviewed journal
articles that evaluate off-label indications.36-38
Most recently, the FDA has signaled a willing-
ness to further loosen its marketing restrictions
in two 2014 draft guidance documents. In Febru-
ary of that year, in response to a petition from
11 manufacturers arguing that current restrictions
on off-label promotion were too onerous,39 the
agency included clinical practice guidelines among
the materials that manufacturers could provide
to clinicians in describing off-label drug uses.40
In June 2014, the FDA also proposed a sharp
departure from its policy for communications
about risk that would allow companies to give
clinicians reprints of peer-reviewed studies that
depict lower estimates of the risks of their prod-
ucts than those determined by the FDA, as long as
the study or analysis and the manner of distribu-
tion meet the [specified] principles of accuracy.41
 Health Law, Ethics, and Human Rights
Such claims must be accompanied by the ap-
proved labeling and by a cover sheet stating that
the FDA has not reviewed the data, and they
must be distributed separately from promotional
materials. The draft guidance would not require
companies to submit this evidence to the FDA to
request a labeling change; rather, they would
be permitted to directly market the materials on
lower risk to physicians without FDA review.42
However, for both claims of efficacy and
statements about side effects, the results of indi-
vidual studies can be incomplete or misleading
while not being outright fraudulent; publication
in a peer-reviewed journal does not in itself pro-
tect against this. Poorly designed or conducted
clinical trials or observational studies can readily
overstate benefits or minimize risks; unorthodox
or inept statistical analyses can create the im-
pression of efficacy or of safety even when more
rigorous assessments would come to a different
conclusion.
Implic ations for Fu t ure
Regul ation
These recent FDA draft guidances suggest that
the agency is becoming increasingly open to al-
lowing companies to disseminate their own posi-
tions about the effectiveness and safety of their
products, although it has noted, for example,
that safety-related claims must be based on ac-
cepted design and other methodological stan-
dards and that the studies must be sufficiently
well-designed and informative.41 However, these
new standards are inherently ambiguous. For
example, arguments for efficacy that are based
on poorly controlled trials or surrogate measures,
even if reported in medical journals, may not
translate to actual clinical benefit for patients.
Similarly, inadequately powered trials or flawed
observational studies may substantially under-
state important risks associated with a drug. Yet
each of these approaches can be claimed to use
accepted standards and thus become permissi-
ble for communication to prescribers (and, plau-
sibly, in the future to patients as well, in direct-
to-consumer advertisements). At present, the FDA
carefully makes assessments of benefit and risk
based on the totality of an enormous body of
available evidence. Some of that evidence, in-
cluding most of its details, may not be available
for clinicians to assess, even if they had the time
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and expertise to do so. If a manufacturer can
select from a wide variety of analyses of varying
quality some of which the manufacturer may
have funded or directed the benefits and risks
of drugs can readily be misstated.
The proposed new categories of information
that companies could disseminate as recommen-
dations for medication use also include clinical
practice guidelines, which are often fair and
comprehensive syntheses of all rigorous evi-
dence.43 But these guidelines can also reflect a
paucity of available data or be subject to bias
arising from conflicts of interest on the part of
guideline writers.44,45 In a review of 16 guidelines
released jointly by the American College of Car-
diology and the American Heart Association, ap-
proximately half (1246 of 2711) the recommen-
dations were found to be level C expert
opinions lacking rigorous evidentiary support.46
Similar evidentiary problems have been noted in
gastroenterology,47 infectious disease,48 and pedi-
atrics,49 among other specialties. Much of clinical
medicine requires physicians to make decisions
in the face of incomplete data, and expert-based
guidelines can be helpful in this regard. But in
the absence of definitive experimental findings,
opinion-based guidelines can be particularly vul-
nerable if their authors opinions are influenced
by their personal academic biases or financial
interests, including ties to companies that could
benefit or be harmed by the recommendations
of those guidelines.50
In an extreme declaration of the view that the
government should back away from regulating
statements that pharmaceutical companies can
make about their products, former FDA Com-
missioner Andrew von Eschenbach argued in the
Wall Street Journal that FDA evaluation should be
limited to proof of concept and safety testing
and that the marketplace should then be allowed
to sort out which products work and have an
acceptable risk-to-benefit profile.51 We believe
that it is unlikely that the marketplace itself will
be able to adequately take the place of the FDA
in determining whether medications are effec-
tive and safe and appropriate to use in specific
clinical situations. On the contrary: weaker re-
strictions on drug promotion could create an in-
centive for manufacturers to obtain initial approval
for a narrow indication that is the easiest to
support and then aggressively market a prod-
ucts off-label uses. Considerable research shows
971
 The n e w e ng l a n d j o u r na l of m e dic i n e

that marketing can drive prescribing practices, in terms of Constitutional rights, will have to be
which in turn can lead to adverse patient outcomes taken into account as the debate over these
if those decisions are not evidence-based.52,53 regulatory standards intensifies.
The prospect of effective regulatory oversight Disclosure forms provided by the authors are available with
of promotional statements for herbal remedies the full text of this article at NEJM.org.
and dietary supplements was eliminated more From the Program on Regulation, Therapeutics, and Law
than 20 years ago in the Dietary Supplement (PORTAL), Division of Pharmacoepidemiology and Pharmaco-
Health and Education Act of 1994.54 The result economics, Department of Medicine, Brigham and Womens
Hospital, and Harvard Medical School, Boston.
has been the proliferation of untested, ineffective,
and frequently unsafe products that fill store 1. Complaint, Amarin Pharma, Inc. v. U.S. Food and Drug Ad-
shelves and patients medicine cabinets and con- ministration (S.D.N.Y. 2015) (http://www.aboutlawsuits.com/
wp-content/uploads/2015-5-8-Amarin-offlabel-lawsuit.pdf).
sume about $32 billion of health care resources 2. Washington Legal Foundation. Brief for Amarin Pharma v.
in the United States, often with no demonstrable U.S. FDA as Amicus Curiae Supporting Plaintiffs. June 12, 2015
benefit.55 Many of these products advertise (http://www.wlf.org/upload/litigation/briefs/AmarinvFDA-WLFA
micus.pdf).
health-enhancing effects and bear disclaimers 3. Letter from Janet Woodcock, Director of the FDA Center for
that the FDA has not evaluated the promotional Drug Evaluation and Research, to Stephen Ketchum, Amarin
claims, but there is evidence that such disclaimers President of Research and Development. June 5, 2015 (http://
freepdfhosting.com/702316334b.pdf).
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behavior. We believe disclaimers will not work filed August 7, 2016).
56

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 Health Law, Ethics, and Human Rights
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