The FDA’s long-standing authority
to prohibit off-label promotion of pharmaceuticals has recently been questioned
under free speech challenges, one of which has already succeeded in a United
States District Court. Oftentimes, drugs
that receive FDA approval for treating specific medical conditions are found to
be effective in treating additional ailments. Such “off-label use” can be quite effective and its practice is fairly
prevalent. In fact, over
half of all cancer drugs are used off-label. Furthermore, physicians are allowed to
prescribe drugs for off-label use and in some cases such methods would be
considered best practices. However,
issues arise when pharmaceutical manufacturers market or promote their products
for off-label uses, i.e. those that may be safe and beneficial, but have not
yet received FDA approval.
The FDA prohibits companies from advertising
or promoting drugs for off-label uses, regardless of the drug’s efficacy or safety. If manufacturers market or promote off-label uses,
they risk liability under 21
U.S.C. § 331(a), which prohibits “[t]he introduction or delivery for
introduction into interstate commerce of any food, drug, device, tobacco
product, or cosmetic that is adulterated or misbranded”,
and under 21
U.S.C. § 333(a) the FDA may impose up to one year in prison and up $1,000
in fines per occurrence. Penalties may
be increased to up to three years and $10,000 in fines if there was “intent to
defraud or mislead” or if the manufacturer is a repeat offender.
Under 21
U.S.C § 352, a drug is “misbranded” if labeling “does not contain adequate
directions for use.” The FDA defines “adequate
directions for use” in 21
C.F.R. § 201.5 as “directions under which the lay[person] can use a drug
safely and for the purposes for which it is intended”. “Intended use” is defined as “the objective intent of
the persons legally responsible for the labeling of drugs”, which may be shown
by “oral or written statements” and “the circumstances that the article is. . .
. offered and used for a purpose for which it is neither labeled nor
advertised.” Accordingly, manufacturers
may not promote previously approved drugs for non-approved use until they have
undergone the clinical testing required by the FDA.
On August 7, 2015 the United
States District Court of the Southern District of New York granted a
preliminary injunction in favor of Amarin Corporation plc, a pharmaceutical
manufacturer. The Court held that Amarin
“may engage in truthful and non-misleading speech promoting the off-label use
of Vascepa. . . . and such speech may not form the basis of a prosecution for
misbranding”. It further held that Amarin’s
promotion was sufficiently truthful and non-misleading.
Vas
cepa is a heart medication
derived from fish oil that was originally approved by the FDA for treating
adult patients with “very high triglyceride” levels (i.e. those whose
triglycerides exceed 500 mg/dL of blood). Amarin also sought approval to treat adults with triglyceride levels
between 200 and 499 mg/dL who are also taking statins (“persistently high
triglycerides”). An FDA-approved study
showed that Vascepa was effective in reducing triglycerides these levels, and
according to the Court is “undisputed[ly]” safe relying on Vascepa’s current
application in very high triglyceride patients and the FDA’s approval for
public use of a chemically similar dietary supplement.
After
the FDA refused to approve Vascepa’s “secondary use” in persistently high
triglyceride patients, and had warned Amarin from using the results of an FDA
approved study in promoting Vascepa’s secondary use to doctors, Amarin and four
doctors filed a complaint to enjoin the FDA under the First Amendment. Amarin and the doctors argued that
prohibiting manufacturers from releasing the results of reliable studies to
doctors violated free speech principles. The Court agreed with Amarin, citing United
States v. Caronia, a Second Circuit case, which held that free speech principles
prevented FDA from criminalizing the truthful promotion of off-label uses. The main thrust of the Court’s holding is that
manufacturers are able to provide this information of off-label use to doctors
when it is truthful, from reliable studies, and non-misleading.
In
response to Amarin’s victory, another manufacturer, Pacira, filed a complaint in
the same District Court as Amarin. Pacira’s
drug EXPAREL is FDA-approved for post-surgery pain relief after bunionectomies
and hemorrhoidectomies. However, the
drug has been shown to be an effective pain reliever in other surgeries. Pacira’s primary argument is that the
promotion is not off-label because it was approved for general post-surgical
use, while the FDA contends such approved use is limited to those situations
that were studied, i.e. bunionectomies and hemorrhoidectomies. Alternatively, Pacira argues that providing
information to physicians from other studies falls under the Amarin exception in that it is truthful
and non-misleading.
Going forward, it is unclear
whether the FDA will appeal the Amarin decision. Given that the case would be appealed to the Second
Circuit Court of Appeals, which decided Caronia,
the case used to support the Amarin
decision, the FDA may be apprehensive about their chances. However, the FDA has a lot to lose because its
ability to prohibit off-label promotion has been a major tool in regulating
manufacturers abilities to promote drugs for wider uses, and accordingly
increase their profits.
Further
implications of the decision are also unclear. While the decision is a temporary victory for pharmaceutical companies,
it is doubtful that manufacturers in other jurisdictions will start testing the
waters of off-label promotion. It seems
unlikely that manufactures in other jurisdictions will begin promoting truthful
off-label uses before favorable decisions are made in their own jurisdictions. One objection to the Amarin decision is that it practically allows courts, rather than
the FDA, to decide whether certain uses of a drug are objectively safe. Further, it remains unclear whether
manufacturers will be able to use successful studies to market off-label use to
the public.
Joe Gregorio is a
third year law student at DePaul University College of Law. Joe is a
managing editor of the E-Pulse; editor
of articles, notes, and comments for The DePaul Law Review; and co-chair of Outreach and
Recruitment for the Jaharis Health Law Institute. His current interests
are in health care regulation, specifically in drugs and devices, fraud and
abuse, and health care delivery.