6000-odd admissions were for scurvy). He subse-
quently developed a large private practice, but
little fame amongst his peers, and was buried at
Gosport in 1794. The Royal Navy was even slower
to act on his findings, not instituting citrus juice in
sailors’ diets, until the year after Lind’s death,
following much administrative resistance but no
scientific controversy (Bardolph and Taylor, 1997).
The British, especially those in the Royal Navy, are
still known as ‘limeys’, which is the unique exam-
ple of a national nickname based on a therapy
proven by clinical trial.
Thus, Lind illustrates some other aspects of
clinical trials: first, he had little academic kudos,
although he was clearly qualified by experience
and training (a requirement of trialists by law
in the United States). Second, he did not publish
his results rapidly. Third, his results were not
implemented promptly in the interests of the
public health. It is important to realize that these
undesirable aspects of clinical trials persist to
this day.
9.5 Limitations of controlled
clinical trialsProgress in therapeutics has not always arisen from
controlled clinical trials. Chance observations have
historically led to huge advances. Today’s three
most commonly used cardiovascular drugs are
good examples: digoxin is a component of digitalis
(famously reported by Withering after observing
the treatment of a dropsical lady by a gypsy),
aspirin is derived from the willow tree bark first
reported by the Revd. Edmund Brown to treat his
own malarious fevers, and warfarin is the result of a
University of Wisconsin investigation into a
hemorrhagic disease of cattle. Lest we forget,
Jenner’s experiments would be ethically impossi-
ble today: they included deliberate exposure to
small pox, and aspirin is a drug that would probably
fail in a modern preclinical toxicology program
due to chromosomal breaks and gastrointestinal
adverse effects due to systemic exposures in
rodents. Modern clinical trials are therefore not
necessarily the holy grail of therapeutic progress.
Statistical theory must also be held not only
with respect but also with healthy skepticism. It
should be remembered that the development of
statistics, as they have come to be applied to clin-
ical trials, has arisen from a variety of
nonmammalian biological sources. Experimental
agriculture stimulated the early giants (Drs. Fisher
and Yates) to explore probability density functions.
While epidemiological studies have confirmed
much that is similar in human populations, it is
unknown whether these probability density func-
tions apply uniformly to all disease states. Any
statistical test that we employ makes assumptions
that are usually not stated.9.6 The clinical development plan
It is impossible to consider clinical trial protocol
design in isolation. All clinical protocols should be
written after a clinical development plan has been
agreed by the diverse membership of the clinical
development team. The clinical development plan
should itself follow the construction of a hypo-
thetical drug label. The goals of such a plan
might be as limited as to provide for the start of
phase II, or as complex as mapping an entire route
from first-in-man studies to product registration.
The path from the present status to the overall goal
can then be understood. It may be added that,
within a large company, this is also a good way
for clinical and marketing departments to commu-
nicate.9.7 Protocols, case report forms,
and investigators’ brochuresOther chapters describe the regulatory governance
of clinical trials, and little needs to be added here.
These clinical trial documents are central to these
processes. Equally, the regulatory requirements
(which still vary from country to country), and
the documents needed to support them, must be
taken into account when constructing the clinical
development plan.9.7 PROTOCOLS, CASE REPORT FORMS, AND INVESTIGATORS’ BROCHURES 105