(Davitz and Davits, 1981), that Jews, Hispanics
and Italians appear to suffer more than Germans,
Anglo-Saxons and Asians, but such difference
may simply appear to be the socially acceptable
level of expression of pain versus the actual pain
severity itself.
In many African animist cultures, Western med-
icine may cure the disease but not the patient, who
continues to languish. Western medicine is
regarded in Africa in the sameway that the Western
world regards naturopathy – as ineffective, and this
can cause the reverse placebo effect. This can be
seen to the extreme in the severe mental function
and physiologic systemic shutdown produced by a
witch doctor’s curses, which seem totally unre-
sponsive to antidepressant medication (Cannon,
1957), and the first author of this chapter has wit-
nessed and successfully treated such an episode but
had to use unconventional methods.
In addition, Third World patients who report
seeing spirits and ghosts may not be equated to
‘hallucinating patients’, as in a Western culture, for
they may be experiencing the prevailing expecta-
tions of their culture (Hartog and Hartog, 1983).
Even within the United States, 70–90% of self-
recognized episodes of sickness are managed out-
side the formal healthcare system (Zola, 1972).
Thus, the incorporation of clinical social sciences
is essential if physicians are to understand, respond
to and help patients (Eisenberg, 1973); this is also
applicable to the interpretation of clinical results.
18.5 The evolution of ICH topic E5
Background
In November 1991, in Brussels, the International
Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals
for Human Use (ICH) was held. A new topic was
proposed to, and accepted by, the ICH Steering
Committee. This was the thorny issue of tripartite
mutual acceptance of ‘foreign’ data. It was
assigned the prefix E5 (efficacy, fifth topic
approved) but was to be one of the slowest to be
resolved – as the reader by now will appreciate,
slowly resolved because of its complexity, not
because of ill-will. It is true that initially, mutual
suspicion reigned, with regional rights and pride.
This was quickly replaced by mutual respect, first
amongst the regulators and then between the reg-
ulators and the pharmaceutical industry represen-
tatives. At a meeting in Washington in 1992,
Professor Chikayuki Naito from Teikyo Univer-
sity, Japan, was handed perhaps the toughest job
of ICH. He was appointed chairman of the E5
working party. He selected his working party mem-
bers from the three regions, including this chapter’s
first author. He then immediately set to work. One
of the most interesting discussions was the topic’s
title; should it be ‘ethnic’ or ‘racial?’ – so inter-
woven were these descriptors with cultural, reli-
gious and language differences. Eventually,
‘ethnic’ was selected, for it allowed more regional
incursion than ‘racial’, which was too restrictive.
Then tasks were assigned on a regional basis; the
United States representative (the first author) to a
literature search, review and compilation; Japanese
members were to research the dosing differences
between the three regions on the 80 common drugs,
backed up where available by matching PK data;
Europe was assigned two tasks, first to review of
the European adverse event database (national
variations) and second, through an independent
third party (Center for Medical Research), review
of dosage, efficacy and safety differences. The
reports were issued in October 1993 at the ICH 2
Orlando meeting. Professor Naito reported for the
Japanese delegation that, amongst 42 drugs exam-
ined, daily doses ofb-blockers and ACE inhibitors
in the United States and Europe were twice as high
as in Japan. Hypolipidemic drugs were similar in
all the regions but, surprisingly, the highest doses
were in the EC. Similarly with antibiotics: higher
maximum doses were prescribed in EC and also in
the United States, than in Japan.
H 2 blockers, a protein pump inhibitor and
NSAIDs showed no difference in daily doses in
the three regions, but again, maximum and lowest
doses allowed were all lower in Japan. They had
also reviewed the PK factors in 80 drugs approved
in the three regions but largely concluded that
intra-ethnic variation in drug metabolism was as
large or larger than interethnic differences; how-
ever, this variability was greater in the Japanese18.5 THE EVOLUTION OF ICH TOPIC E5 241