31.9 Developments during 2005
The year 2005 was tumultuous at the FDA for
numerous reasons. However, there was one event
that is likely to have a particularly long-lasting
impact on researching investigational drugs and
the approval of NDAs. This was the recognition
by FDA that certain cyclo-oxygenase-2 specific
(‘COX-2s’), nonsteroidal anti-inflammatory agents
(NSAIDs) carried an excess risk of cardiovascular
adverse events in patients. In the case of rofecoxib
(Vioxx), this led to its voluntary withdrawal from
the market by its manufacturer.
Stereotypical behaviors resulted. Medical jour-
nal editors were prolix. Professional pharmaceu-
tical industry bashers were given yet more cause
for their wrath. Congress and the newspapers
severely criticized the FDA. Plaintiffs’ lawyers
salivated.
This adverse event potential had been known for
2–3 years at least, judging by the publications in
medical journals. But lost in the cacophony was
that the underlying reason for this problem was the
disappearance of an appropriate risk–benefit bal-
ance when prescribing such drugs. Undoubtedly,
there are many patients with arthritis and other
inflammatory conditions for whom other NSAIDs
are either ineffective or intolerable. However, the
volume ofsales of the‘COX-2s’would suggest that
indiscriminate use of these agents as all-purpose
analgesics had been taking place; famous, direct-
to-consumer television and newspaper advertise-
ments of these drugs by trade name undoubtedly
increased this product demand.
The regulatory and industry responses to this
crisis have been numerous, and are probably not
complete at the time of writing (January 2006).
These include
a voluntary embargo by several pharmaceutical
companies on advertising newly approved drugs
(probably to be followed by regulations none-
theless);a vigorous debate on making risk management
plans an intrinsic part of all NDA approvals and
their continuing status;reorganization and bolstering of FDA pharma-
covigilance departments;in the opinion of some, an inordinate new imbal-
ance in regulators’ practices, leading to evidence
of intolerability excessively outweighing effi-
cacy when making both IND study and NDA
approval decisions.Direct-to-consumer advertising of prescribed
drugs by trade name now exists only in the United
States (it was banned in May 2005 in its only other
locale, New Zealand). Congressman Waxman,
among others, is publicly opposed to this practice
in the United States. This debate will play out
before the next edition of this textbook appears.31.10 Summary
No apology is made for the extensive historical
narrative that opened this chapter. Dealing success-
fully with the FDA requires an understanding of
how the institution thinks, and how the individuals
within it are constrained. The way the FDA thinks
is predicated on its legislation, and how and why
that legislation has evolved, mostly in reaction to
crisis, but, at last, recently, in progressive negotia-
tions with the industry and patient groups to
bring about change that is of mutual benefit. The
FDA has a complicated structure, and remains the
most stringent regulatory authority in the World.
We are likely to see further changes in the years to
come.406 CH31 UNITED STATES REGULATIONS