ingredients have been used in manufacture;
(c) approved ingredients have failed some quality
control that is specified in the NDA; or (d) the
Sponsor has violated some previous agreement
with FDA about how the drug should be marketed.
Almost any infraction perceived by FDA will be
termed misbranding. Comparative statements
(‘Drug X was better than Drug Y’), and active-
comparator clinical trials data in a proposed pack-
age insert, are especially likely to meet with dis-
approval by FDA.
FDA enforcement actions may be listed in esca-
lating order of severity:
- Warning letter from FDA to the manufacturer,
requiring a specified corrective action within a
reasonable time frame. - Mandatory issuance of a ‘Dear Doctor’ letter to
the medical profession. - Black boxing of drug product (usually with
agreement not to promote). - Product recall (although, in practice, most of
these are voluntary on the part of the Sponsor). - NDA withdrawal.
- Product seizure and establishment closure.
FDA can take these actions independently. For
example, although a product seizure can be
appealed against in Federal Court, the product
remains seized, and sales remain halted while the
legal process takes place, usually over at least
several months. This prolonged periodper seis
often sufficient to kill the product in the market-
place, even if agreement for its reintroduction is
eventually reached. The more serious enforcement
actions are also punishable with prison terms and
fines under the FD&C Act. A large, decentralized
inspectorate is distributed throughout the United
States and around the world as part of FDA’s
enforcement arm.
Typically, FDA requires that post-marketing
surveillance of new drugs is reported at less than
annual intervals. Usually, after three- or four-year
market experience, annual reports can then be
agreed. A review of the labeling is made on each
of these occasions, which, for nonurgent matters, is
when a Sponsor or FDA might suggest amend-
ments to it. All advertising materials that have
been used during the year must be filed with
these annual reports, even though they were sent
to DDMAC at the time of their introduction.
It is surprising that these strict regulations and
their energetic enforcement apply only to approved
drugs. The United States currently has a vigorous
market in so-called ‘natural products’. Thus, oral
proteoglycans ‘to repair joint cartilage’,Gingko
bilobaextracts ‘to improve memory’ or the ‘anti-
aging effect’ of oral, powdered shark cartilage may
yet be advertised to the general public with impu-
nity, and purchased by the general public without
prescription. Legally, this creates a paradox
because manufacturers want people to believe
that these drugs are effective, and yet therapeutic
effectiveness is tantamount to one criterion for
bringing drugs within the jurisdiction of the Food
Drugs & Cosmetic Act. However, at present, there
is strong political support against extending FDA
jurisdiction over such products.
FDA has just announced a new rule for label
format, to be implemented in June 2006 for all
NDAs, and a longer timetable for revisions of
older products. The principal innovation is a
summary section, intended to draw attention to
important ‘highlights’ such as important con-
traindications, likely adverse drug interactions.
The overall aim is to improve patient safety when
prescribing. There is a set of four guidances that
accompany the new rule. This move is not without
controversy: at the time of writing, several States
have mounted legal challenges to the new rule, and
some patient advocacy groups are also vocal
critics.38.4 European labeling
There is reasonable similarity across the coun-
tries of the European Union, and these labels are
collated into national compendia such as the
Rotte Listein Germany or theData Sheet Com-
pendiumin the United Kingdom, to which the532 CH38 DRUG LABELING