required a big disaster to get things done. To be
precise, thalidomide.
Dr Frances Kelsey had the thalidomide applica-
tion on her desk. She was busy and had simply
not got around to it. Then from Europe she heard
about a question of peripheral neuropathy, and
possibly thyrotoxicity; at that point she made an
active decision to hold up the approval. It was
an Australian dermatologist who identified drug-
induced phocomelia, and the rest is well known.
Only nine cases of phocomelia were reported
in the United States, from an exposure of about
4000 women of childbearing potential, most of
whom were pregnant. Kelsey received a medal
from President Kennedy.
Amazingly enough, the 1962 amendments
would still not have kept thalidomide off the mar-
ketin theUnited States. The precise strain of rodent
that would have been required to identify the lesion
was not in common use, and the adverse event
frequency in neonates, in the average-sized NDA
of the day, might not detect adverse events of such
low frequency. However, the 1962 amendments
required, in the general case, that drugs should be
demonstrated to be effective prior to approval, for
the first time.
The 1962 Kefauver-Harris amendments pro-
vided further capability to FDA. They set forth
the requirements of the IND process. The FDA
was empowered, for the first time, to seize a drug
and cause it to bewithdrawn. Adverse event report-
ing to FDA became mandatory. Labeling and
advertising requirements were clarified, and trans-
ferred that responsibility to FDA from the Federal
Trade Commission. Inspections of manufacturing
sites were also facilitated by these far-reaching
amendments.
In 1966, it was estimated that there were about
4000 drugs available which had been approved on
pre-1962 criteria. FDA commissioned the National
Academy of Sciences/National Research Council
(NAS/NRC) to review these ‘grandfathered drugs’
against the modern standards. Some of the reviews
lasted 15 years, and were contentious, while other
drugs felt to be important had to be transferred to
new manufacturing sites. The abbreviated NDA
(ANDA; mostly thought of today in connection
with generic drug approvals) was invented in
1970 for the latter purpose. The NAS review was
extended to OTC drugs in 1972. Meanwhile,
devices came under the FDA aegis in 1972, and
biologics and vaccines were subsumed under the
FDA umbrella in 1972.
As regulations increased, so did the risk of drug
development. Complaints were loud that rare dis-
eases, offering small potential markets, were
increasingly ignored because the costs of drug
development to address those markets had become
so high as to deter research and development by the
pharmaceutical manufacturers. After much debate,
a compromise was reached in the Orphan Drug Act
(1983). If it could be demonstrated that the inci-
dence of the disease in question was fewer than
200 000 persons per year in the United States, then
Orphan Drug designation would be allowed. This
provided tax credits and exclusivity guarantees,
should an eventual NDA succeed. Currently,
there is criticism that this absolute number of
200 000 patients has not been raised with time, as
the US population is now greatly increased since
1983, and, unless amended, this legislation will
eventually become moot. Meanwhile, there is
also often debate with FDA on borderline cases
of calculation of incidence. Several drugs that are
in the market in Europe are denied to Americans by
reason of FDA not granting Orphan Drug designa-
tion, and there being no other method for gaining
exclusivity for at least the seven years that the
Orphan Drug Act provides.
The Waxman-Hatch Amendment (1984) traded
off patent term restoration for innovative drug
development with generic drug ANDA approval.
The contents of the ANDA were clearly stated for
the first time. Furthermore, FDA review times
could be added to the patent-awarded period of
exclusivity. Currently, FDA compares these review
periodsin ahighlyconservativemanner:the review
period is compared to the period that the drug
company has been conducting IND research, and
the public is led to the view that FDA review is a
trivial component of total development time.
Furthermore, FDA stops this artificial clock every
time they send a question about the NDA back
to the sponsor, even though review activities at
the Agency continue. In one case, in the 1990s,
when these procedures had been well established,31.1 THE FOOD AND DRUG ADMINISTRATION: HOW WE GOT TO WHERE WE ARE 399