per capita is twice as great in the United States
compared to the United Kingdom, and four times
more than in Germany. Caesarian section is 25% of
all births in the US but only 8% in Britain. Defen-
sive medicine is only part of the story; the need for
an aggressive approach, with the need to cure as
opposed to treatment, is a major factor in the Uni-
ted States. Less litigation may reduce this pressure,
but this is unlikely to occur. Conversely, fear of
litigation alsoincreases drugattributionand report-
ing of adverse events.
In Japan, concurrent prescribing of different
drugs of the same class in small doses is not unu-
sual.Disclosure ofcancer diagnosis to the patient is
frowned upon in Japan, and reporting of GI side
effects by the patient may be discouraged by the
culture.
Differences in preferred dose form, availability
of suppositories in France, injections in Italy, pills
in the United Kingdom and polypharmacy in
Japan, reflect medical practice, education and prac-
tice conditions. There is great emphasis and con-
cern in Germany over the heart and diet; in France
over the liver; in the United Kingdom over viruses;
and in the United States over hypertension and
obesity. Only in 1999 were oral contraceptives
approved in Japan, a brave action, for it may
increase the falling rate of Japanese population
replacement, shared with Italy and Western nations
(excluding the United States). All reflect a different
but small emphases on drug development.
In the different regions, the physicians and
investigators are held in varying degrees of esteem
by their patients. In Japan, the ability to depend on
others, to lean and to be leaned on, is considered
healthy (Doi, 1973). The doctor is held in great
respect by the patient, and both the doctor and
patient regard the chief investigator with even
greater respect. This can interfere with adverse
event reporting (AER) (avoidance of offense) by
the patient, and perhaps lack of critical observation
by their sub-investigators. These factors can influ-
ence the use of placebo, and ‘informed consent
format’ in clinical studies. However, great strides
are being made in Japan to share the responsibility
with the patient for mutual benefit.
Physicians in the three regions deal differently
with failure to achieve the desired clinical effect. In
the United States, the tendency is to change medi-
cations. In other countries, dose titrations of the
same medication may be used more frequently.
The different approaches reflect both medical
school teaching and expectation of the results of
therapy. In many areas of Europe, the physicians
and investigators are free, to a certain extent, from
suspicion of monetary influence because of exten-
sive socialized or government-backed health
schemes. This has its pitfalls, but allows a degree
of benevolent, autocratic meritocracy to emerge,
which resulted in the evolution of the ‘expert sys-
tem’ for regulation in Europe andthe ‘doctor knows
best’ for the patient in Japan, which works quite
well in those cultures. Again, the reporting, antici-
pation or recognition of adverse effects may be
diminished. This contrasts with the United States,
where frequently almost twice the number of
adverse events are reported compared to European
studies (except Sweden) and, not infrequently, pla-
cebo response rates are also increased. It has been
postulated that these increased effects spring from
both the aggression of American medical practice
in search ofcureand from the higher doses used. In
addition, US physicians often focus on extensive
data gathering in an attempt to achieve diagnostic
certainty. This leads to increased search for, and
investigation of, adverse reactions and their caus-
ality. This may also be due to the litigious nature of
the US system. The diagnostic approach ‘blitz’ has
been heavily impacted by the inroads of managed
care to reduce costs.Ethnic effects on European AER
As part of an ongoing effort by the EC’s General
Directorate for Scientific Research, the European
‘concertation’ procedure’s impact on the ability to
monitor and detect changes in clinical safety was
studied. Some of the information gathered on spon-
taneous ADRs was made available to the ICH EC
Working Party by Dr M. Papaluca, Amanti.
The nature and incidence of serious spontaneous
ADRs on three different new agents approved by
the 11 EEC, at that time member states (1989–
1991) were examined. As expected, the reporting
rate varied between regions, according to the18.4 SUBJECTIVE FACTORS 239