findings among ‘selected secondary end points’).
A sound interpretation, of course, is based upon
only those end points that were selected before the
experiment began, and comparing these with those
for which no such statistical differences were
found.
9.4 Historical clinical trials
Any general work must include these classic bits of
history. Perhaps unusually, clinical trials appear to
be a European scientific invention. There is no
evidence that either the ancient world or the med-
iaeval Arabs carried out prospective studies
(although there are some anachronisms in recent
fiction). Sir John Elwes of Marcham Manor
(Berkshire, now Denman College of the Womens’
Institute) was a famous miser. After injuring both
legs, Elwes gambled with his apothecary that the
latter’s treatment of one leg would result in slower
healing than the other leg which would be left
untreated. The apothecary duly lost his fee with a
wound that took an extra two weeks (Milledge,
2004). The precise date of thisn¼1 clinical trial
is uncertain, but it must have been close to what is
generally accepted as the earliest clinical trial,
conducted by Lt. James Lind, RN.
Thomas (1997) has pointed out that sailing
men-of-war frequently went many months
without docking (for example, Nelson spent 24
unbroken months on HMSVictorywhile blockad-
ing French ports, and it is said that Collingwood
once went 22 months without even dropping
anchor). Scurvy was rampant in the Royal Navy,
often literally decimating ships’ crews. Sailors
survived on the poor diets carried aboard for long
months, with water-weevils and biscuit-maggots
constituting important dietary protein! Before
Lind’s time, the Dutch had already learned to
treat scurvy by replenishing their ships at sea
with fresh fruit and vegetables. This was also
known by Cook; when in command of H.M.
BarqueEndeavour, men were flogged for not eat-
ing their vegetables.
Lind had been pressed into the Royal Navy as a
Surgeon’s Mate in 1739 and with some experience
as an apprentice surgeon in Edinburgh. It is a nice
irony that the first prospective clinical study with
n>1 was actually conducted by a surgeon!
The clinical trial was held at a single site, H.M.S.
Salisbury, a frigate in the English Channel during
the early summer of 1747 (Lind, 1753; Frey, 1969;
Thomas, 1997). The experimental controls
included that all 12 patients met the same inclusion
criteria (putrid gums, spots on the skin, lassitude
and weakness of the knees). All patients received
the same diet except for the test materials. All
treatments were administered simultaneously (par-
allel group). Compliance with therapy was con-
firmed by direct observation in all cases. The trial
had six groups, withn¼2 patients per group.
The test medications were (daily doses): (a) cider
(1 quart), (b) elixir of vitriol (25 drops), (c) vinegar
(two spoonfuls plus vinegar added to the diet and
used as a gargle), (d) sea water (‘a course’),
(e) citrus fruit (two oranges, plus one lemon
when it could be spared) and (f) nutmeg (a ‘big-
ness’). Lind noted, with some disdain, that this last
treatment was tested only because it was recom-
mended by a surgeon on land. The famous result
was that within six days, only 2 of the 12 patients
had improved, both in the citrus fruit group, one of
whom became fit for duty and the other at least fit
enough to nurse the remaining 10 patients.
We should note the absence of dose standardi-
zation and probably of randomization because
Lind’s two seawater patients were noted to have
‘tendons in the ham rigid’, unlike the others.
However, the result had been crudely replicated
by usingn¼2 in each group. If we accept that the
hypothesis was that the citrus-treated patients
alone would improve (Lind was certainly skeptical
of the anecdotal support for the other five alter-
native treatments), then, using a binomial prob-
ability distribution, the result hasp¼ 0 :0075. But
statistics had hardly been invented, and Lind had
no need of them to interpret the clinical signifi-
cance of this brilliant clinical trial.
Lind was not quick to publish his most famous
treatise reporting this clinical trial (Lind, 1753).
Indeed, in 1748, his Edinburgh MD thesis was on
an entirely unrelated subject. Subsequently, Lind
was Treasurer of the Royal College of Surgeons of
Edinburgh, and then appointed physician to the
Royal Naval Hospital, Haslar (a fifth of his first104 CH9 PHASE II AND PHASE III CLINICAL STUDIES