often include not only the reviewing Division
Director but also his or her superior, the Office or
Center Director. The relevant parts of the Code of
Federal Regulations (CFR) are authorized by the
Food, Drugs and Cosmetics (FD&C) Act (21 Uni-
ted States Code 321). Although the licensing of
drug products (21CFR310 and 314) and biologi-
cals (21CFR601) are different, their labels are
governed in a similar manner. It should be noted
that promotional materials are considered to be a
form of labeling in the United States, and the FDA
regulates these as stringently as the package insert
(21CFR201.1). All magazine advertisements and
so on, have to be accompanied by a complete copy
of the approved package insert adjacent to the
published promotional materials. The package
insert in the United States is usually much longer
than in any other country. A recent label for an
injectable treatment for rheumatoid arthritis (eta-
nercept; Enbrel^1 , Amgen and Wyeth) can only be
described as a poster, being 58 cm63 cm, and
filled withprintonthewhole ofboth sidesin mostly
10- and 11-point font!
The general principles that apply to all US drug
labeling (whether a package insert or an advertise-
ment) are as follows:
Consistency with approved package insert
Absence of misleading information
Fair balance
Absence of relevant omissions
Defensibility from the clinical trials database
A specific division of FDA (the Division of Drug
Marketing, Advertising and Communications;
DDMAC) reviews all promotional materials prior
to product launch and must be provided with all
subsequent advertising. Companies can (and fre-
quently are) ordered to recall promotional materi-
als, as well as being required to take corrective
measures after promulgating advertising that the
Agency views as misleading.
The FDA uses black boxes around the text in
labeling to indicate major hazards associated with
marketed products. Most drugs that are ‘black-
boxed’ in the United States usually remain on the
market pending the Sponsor’s compliance not to
engage in any further promotion of the product.
However, this does not apply to certain opioids,
muscle relaxants and cytotoxic drugs, all of which
are black boxed, when these are promoted to spe-
cialist physicians (in these cases, anesthesiologists/
anaesthetists and oncologists, respectively).
Drugs that are extemporaneously compounded
from legally obtained starting materials, by in-
dividual pharmacists per physician’s prescription,
are not subject to the same regulations (see
21CFR216).Among other things, these regulations
nonetheless contain a list of drugs which are
prohibited from compounding, usually in response
to corresponding product withdrawals under the
orthodox regulations (e.g. dexfenfluramine,
chlorhexidine, tetracycline, for any, topical and
pediatric uses, respectively). However, this rela-
tively anachronistic part of pharmacy practice is
also prohibited from engaging in widespread pro-
motion.
The components of United States package
inserts are provided in 21CFR201–202. Related
matters (e.g. imprinting of tablets, labeling of con-
trolled drugs, use of official and trade names, etc.)
are governed by regulations scattered between
21CFR206–299. Spanish translations of drug
labels are permitted (especially for products sold
in California, Florida, New York and Puerto Rico),
and some mandatory, equivalent Spanish vocabu-
lary appears in the regulations (e.g. 21CFR201.16).
The various sections of a US drug label will not
be reprinted here: the reader is advised to look
in the current edition of thePhysician’s Desk
Referencefor models to follow. Most European
physicians comment on the greater technical
detail and length of US labels, in comparison to
those in Europe.
A central legal term in the United States is
‘misbranding’ of an approved drug, meaning that
the provisions of the NDA (as it might have been
amended) have been breached. Such breaches may
include the following: (a) when FDA has deter-
mined that the drug is being promoted for indica-
tions, dose sizes or routes of administration that are
outside the approved labeling; (b) unapproved38.3 DRUG LABELING IN THE UNITED STATES 531