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Marketplace & Business

Outsourcing Clinical Trials

For some the outsourcing of clinical trials is an exercise in rational economics, for others it is
a misguided false economy with the potential for harm. Paul Wathall of HCA International Ltd investigates

This article focuses on the role of emerging and developing countries in commercially
sponsored pharmaceutical research, while highlighting two schools of thought that
in general are either supportive or critical of this trend. It will discuss the impact of
proportional over-representation of participants from developing countries and more
specifically to address the likely impact of regional variation on the external validity of
study results to dominant markets with superior purchasing power. The article cites
numerous examples of trials, which produce parameter estimates of questionable
value to Western European decision makers and highlights differences between
emerging regions and Western Europeans, which suggest the two are mutually
incomparable. It is proposed that these differences may confound study outcomes,
decision-making parameter estimates and data pertaining to the incidence of adverse
drug interactions. Further research should therefore be undertaken in order to explore
the relationship between geographical variance and external validity, particularly where
safety data derived from relatively drug-nave regions are assumed to pertain to
maximally treated populations elsewhere in the world.
ARGUMENTS FOR AND AGAINST
OUTSOURCING CLINICAL TRIALS
Rapid patient recruitment and cost
containment are just two of the factors
leading industry and US Government
sponsors to view non-traditional regions
as preferred locations for pharmaceutical
research (see Table 1 for a comprehensive
list of pros and cons) (1,2). Correspondingly,
a decline in recruitment in the West has
generated two schools of thought which,
in general, appear to either welcome
globalisation unreservedly, or imply that
investigators in developing countries
are somehow less capable of conducting
research to the same ethical and quality
standards as those in the West (3,4).
Today, such ad hominem arguments have
generally diminished, albeit in response to
a limited number of audits and anecdotal
reports which, though occasionally
contradictory, suggest that Eastern European
data and ethical standards are comparable, if
not superior to our own (5,6). Nevertheless,
it is possible to conclude that such criticism
was not only misguided, but as much fuelled
by prejudice and misconception as by any
benevolent concern for society as a whole. In
this regard, surely the commercial benefits

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Table 1: The advantages and disadvantages of off-shoring clinical trials

Advantages

Disadvantages

G Rapid recruitment consistently higher

than the global average

G Poorly-developed transport and communications

systems

G Excellent data quality

G Inter- and intra-country language differences

may sometimes lead to problems in
protocol adherence

G Participants described as well-educated with

a good understanding of the risks and benefits
of trials
G Large patient population and centralised
health facilities
G Patients tend to be less mobile facilitating
easier follow-up
G Relatively drug-nave population
G Greater trust evident between patients
and investigators
G Promotes continued political and commercial
integration of the former communist bloc into
the European community
G All countries in the region are now
considered GCP compliant (although there
is some variability)
G EE sites query generation rates
comparatively lower
G CEE costs will tend to be lower than
in Western Europe

G Monitoring frequency and set-up time may be

higher than in the West
G Mechanisms for coordinating the function
of ethic committees in Eastern Europe are
poor and the ethical supervision of trials
varies considerably
G Customs regulations often incredibly complex.
The wording of CEE law and contracts may
be unfamiliar
G Lack of screening facilities may mean patients
in developing countries are recruited later in the
natural history of their disease process making
treatments appear less effective
G Tax costs and set-up costs can some times be
greater than in the West
G The differential in costs is depleting particularly
as emerging markets strive to harmonise
regulatory frameworks

G Highly-trained, enthusiastic investigators

motivated to conform to GCP

G Patients frequently hospitalised in the East for

treatments typically conducted as an outpatient
in the West

G High incidence of pathologies otherwise

infrequent in other parts of the world

G Limited access to specialised equipment

required in some trials

G Up to 30 per cent of all expenditure

of all oncological treatments delivered
in Poland covered by clinical
trial programmes

G An application for a new trial takes twice

as long in Poland as it would in the UK
G Source data verification is difficult in some
hospitals especially in the outpatient setting

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derived from developing nations

should be encouraged, particularly
where the outcome is the
attenuation of drug development
timelines coincidental with
increased provision of medicines
in regions where comparable care
would otherwise be lacking (7).
THE MARKET AND
BIOETHICAL CONCERNS

Figure 1: Modified recruitment progress chart

Patient recruitment
Region

Selected/planned (%)

Recruitment target

Other
East
East
West
East
East
East
West
East
East
East
East
East
East
Other
West
West
West
West
West
West
East
West
West
West
West
West
West
West
West
West
West
Other

92.50
80.70
75.40
74.80
70.60
69.80
66.30
59.50
55.90
52.60
51.60
48.40
37.90
36.80
31.60
29.10
28.00
25.40
23.80
18.20
16.40
15.30
12.80
12.50
9.90
9.60
8.90
7.10
3.60
3.10
2.90
1.00
0

280
500
285
500
800
150
80
380
170
500
215
980
1,500
500
580
55
600
130
600
55
500
150
400
120
1,000
250
450
85
900
150
105
100
120

One could argue, however, that

the end is not solely concerned
with speed, cost or efficiency,
or even with rectifying apparent
inequalities of care, but with the
introduction of safe and effective
drugs to the pharmaceutical
market; a market predominantly
located in developed regions,
where treatment diffusion and
penetration rates are typically faster
than in developing regions (8). Of
course, this raises the ethical issue
of what happens to these patients when the study is completed
and trial medications are withdrawn. Arguably, one could question
the ethics of recruiting participants from one society solely for
the benefit of another, particularly where such participants could
never afford these costly treatments otherwise (9,10).
GEOGRAPHICAL DIVERSITY AND PROPORTIONAL
OVERREPRESENTATION OF EMERGENT SUBGROUPS
When one considers that some trials recruit between 50 to
80 per cent of participants from Eastern Europe, it might be
appropriate to question the generalisability of these studies to
other populations (3). This largely depends on the geographical
location of the majority end-user; whether the study populations,
characteristics and circumstances differ significantly from those
of the target population; and whether the primary objective is
concerned with questions of efficacy, effectiveness, or both. In
essence, the concern here relates to issues of external validity,
which refers to the confidence with which we can infer that
the presumed relationship can be generalised across different
populations, locations and times (11).
Within cardiological care, practice certainly varies considerably
between physicians in the East and West, particularly with regard
to prescribing and revascularisation practices, a point which may
be particularly important given that both of these factors explain
a significant amount of variance in event rates and mortality
(12-15). As such, a trial conducted predominantly in Eastern
Europe may positively bias baseline risks and event rates, thereby
making treatment appear either more or less effective than it
otherwise would in the West. This fact was aptly demonstrated in
a recent oncology trial in which a subgroup analysis highlighted a
significant effect of sorafenib amongst renal cell cancer patients
from developed nations, which was not apparent in their Eastern
European counterparts (16).
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REGIONAL VARIATION IN MORTALITY, MORBIDITY AND

SOCIOECONOMIC RISK FACTORS
There is a growing body of evidence suggesting that morbidity
and socioeconomic factors may produce different patient
outcomes between Eastern and Western Europeans treated
with identical investigational medicinal products (12,18).
In order to explore these differences, the author performed a
small exploratory study using site performance data derived
from a recently conducted Phase III placebo-controlled trial.
In this trial, several thousand patients were recruited to explore
the impact of an established cardiovascular drug for a new
indication. Figure 1 displays a modified recruitment chart
for this study in which recruitment targets are shown against
actual recruitment.
Figure 1 highlights a number of interesting points. Firstly, there
are marked differences in performance between Eastern and
Western Europe. Notably, the Eastern European nations are
nearing completion of their recruitment targets, whereas many of
the Western countries are barely off the starting block. Secondly,
although out of 33 countries only 12 were Eastern European; it
was proposed that these countries would recruit 60 per cent of
the total population (numbering 10,000). In reality, the sponsors
competitive recruitment policy would ensure that ultimately the
CEE countries were likely to recruit in excess of 80 per cent of
the study participants required before the study was completed.
REGIONAL VARIATION IN SOCIOECONOMIC RISK FACTORS
The author explored potentially confounding differences in
socioeconomic risk factors between regions using country-level
WHO epidemiological data (19). Variables examined in the
analysis included the percentage of GDP spent on healthcare; the
total health expenditure per capita; mortality rates; healthy years

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Figure 2: Box plot highlighting differences in life expectancy between Eastern and Western Europeans
80

70

33
1
26

60

population as a whole (P<0.0001). There

were also significant differences between
East and West in the remaining variables
examined including, but not limited to,
health expenditure per capita (p<0.001);
smoking prevalence per 100 (P<0.004);
and DALYs lost through CHD (p<0.001)
and stroke per 1,000 (P<0.001). From these
data, we can conclude that the biological
age and socioeconomic risk factors
associated with an Eastern European
are not the same as those of a Western
European of the same age. When combined
with differences in treatment practice and
medication use, it seems likely that data
predominantly collected in the East may
yield results of questionable applicability
to the West.

50
N=

12

21

Eastern Europe

Western Europe and others

of life; smoking and diabetes prevalence; days lost to CHD

and stroke per 1,000. Using SPSS version 14, differences
between Eastern and Western Europe were examined using an
independent sample t-test for continuous variables, or a chi
square or Fishers exact test where parametric assumptions
were not met. Where appropriate, distribution correcting
transformations were employed.
Figure 2 depicts a box plot highlighting the differences in life
expectancy between Eastern and Western Europe and other
developing countries. The plot illustrates that, on average, Eastern
European males die eight years younger than their Western
European counterparts (P< 0.0001). The table also shows three
outliers, each of which relates to one of the three developing
countries (including China) designated other in Figure 1. More
notably, however, is that this Figure highlights two heterogeneous
populations, who could in all likelihood respond differently to
identical treatments.
The analysis also revealed that Eastern European males had,
on average, eight fewer years of healthy life than their Western
European counterparts, suggesting a markedly less healthy

REGIONAL VARIATION, DECISIONMAKING PARAMETER ESTIMATES

AND ADVERSE DRUG INTERACTIONS

There are potentially many other

confounding differences between the East and West which
could have an impact on the trial in question. For example,
sicker patients on fewer drugs would probably derive greater
benefit from experimental treatments. This, in turn, could
influence decision-making parameter estimates such as
baseline risk, absolute risk reduction (ARR) and the number
needed to treat (NNT). That is to say the absolute risk
reduction from this trial might be higher, and the number
needed to treat might be lower than expected within a
Western European or US population.
Moreover, a major attraction of conducting trials in Eastern
Europe is unlimited access to a willing pool of drug-nave
patients. While on the one hand this could confer a significant
recruitment advantage, it may also limit the value of the safety
data acquired, in this context, to the West. Ultimately, these data
may underestimate the potential for adverse drug interactions
when prescribing additional medications to maximally-treated
Western Europeans. This issue seems all the more relevant when
one considers recent concerns over treatments which were initially
deemed safe, prescribed widely and only later associated with
increased risk of cardiac complications (Vioxx & rosiglitazone)

There are potentially many other confounding differences between the East
and West which could have an impact on the trial in question. For example,
sicker patients on fewer drugs would probably derive greater benefit from
experimental treatments. This, in turn, could influence decision-making
parameter estimates such as baseline risk, absolute risk reduction (ARR) and
the number needed to treat (NNT). That is to say the absolute risk reduction
from this trial might be higher, and the number needed to treat might be lower
than expected within a Western European or US population.
20

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(20). Notably, at least one of these drugs was heavily researched

in Eastern Europe from the mid 1990s (21).
SELECTION BIAS AND THE POTENTIAL FOR HARM
Such outcomes, though unfortunate and deeply regrettable, attract
unwanted criticism and suspicion from medical practitioners. This
situation is further exacerbated by examples such as a recently
published ethnographic study, which cited a senior industry
official openly admitting that companies pick and choose study
populations in order to produce the most pronounced drug benefit
signal possible whilst attenuating signals indicative of harm (21).
Perhaps even more disturbing was the fact that this informant
openly admitted that this behaviour significantly increased the
likelihood of ineffective and unsafe drugs gaining FDA approval.
These informants cast serious doubts upon the suitability of
generalising results derived from drug-nave patients to those in
treatment-saturated markets? Why invest in a foreign site if one is
uncertain whether the data collected there will even be usable in
the US or Western European drug approval processes? Clearly the
usefulness of these data to Western policy-makers and prescribing
physicians is dubious at best, or potentially injurious or lifethreatening at worst. But despite this possibility many companies
neglect external validity, funding agencies, ethics committees, the
pharmaceutical industry, medical journals and licensing bodies
alike. Conversely, there is concern among physicians that external
validity is often poor, particularly for pharmaceutical industry
trials, a perception leading to under-use of treatments that are
potentially effective (22). In the recently-published Scottish
Consortium Guidelines (No 390/07), for example, clopidogrel
was granted only limited license post MI. To an extent this was
due to concerns about extrapolating data from the large (45,852)
Chinese mega-trial alluded to earlier, which was marginalised in
deference to a smaller pivotal trial (3,491) conducted within
traditional regions (23). This represents clear evidence that
choosing to conduct trials exclusively in non-traditional regions,
in an attempt to reduce cost, may ultimately prove to be a
false economy.

over 90 per cent of patients taking medicines for chronic

obstructive airways disease in the community were treated on the
basis of guidelines underpinned by randomised controlled trials
for which they would otherwise be ineligible (24).
It is important to acknowledge, however, that despite an annual
growth rate of 30 per cent, the share of trials conducted in nontraditional sites, compared to developed regions, is particularly
modest (12). One estimate suggests that as little as six per cent of
the global research portfolio is presently conducted within middle
and low income countries (25). Arguably, there is little reason for
this to change appreciably and, in fact, more research could be
undertaken in countries which are in economic transition, just as
long as tighter controls are imposed on the proportion of patients
recruited from developing countries in a single trial.
CONCLUSION
There is little evidence to support initial concerns related to the
quality or reliability of data derived from investigators recruiting
in developing countries. There is, however, evidence to suggest
that regional variations in socioeconomic conditions and
healthcare provision can have a significant impact on patient
outcomes and the likelihood of detecting potentially lifethreatening drug interactions.
Despite this, the involvement of investigators in developing
countries is not only desirable but could be increased. This also
applies given the caveat that there are tighter controls on the
proportion of patients from developing countries recruited to a
single trial. The argument that responsibility for assessing the
generalisability of study results rests with physicians is flawed,
given that evidence suggests patients are frequently exposed to
treatments evaluated in trials for which they would otherwise be
ineligible. Also, attempts to conduct trials predominantly within
emerging markets may prove to be a false economy in the long
run, particularly if policy-makers choose to disregard the results.

Further research should therefore be undertaken in order to

explore the impact of regional variability on external validity,
particularly where safety data derived from relatively drug-nave
Although it could be argued that responsibility for assessing
regions are applied to maximally-treated populations located
transferability of study outcomes rests with the prescribing
elsewhere in the world. It is also proposed that grant-holders,
physician, there is evidence to suggest that this does not always
regulatory agencies and policy-makers pay increasing attention to
occur in practice. For example, Travers et al demonstrated that
the possible impact of sampling bias in the design
Table 2: Factors driving demand for more human subjects
and approval stages of clinical trials. At the very
 Increased number of trials undertaken
least, clinical trial sponsors should endeavor to
 More trials of generic drugs
report and justify the proportional geographic
 Regulators demanding larger trials to prove long-term safety and efficacy. Ironically this
make-up of study participants, particularly
is driving trials into populations yielding safety data of questionable validity
when submitting data to the licensing authorities.
 Competition to get drugs approved and marketed within the industry
Although at present sponsors are required to
 In the US patients frequently move from one insurance plan and physician to another
provide data on ethnic background, this does not
making tracking patients difficult
address the influence of geographic variation in
 Growth in the number of new chemical entities
healthcare provision and socioeconomic factors
 Treatment saturation is making Americans and Western Europeans unusable
which may be equally, if not more, influential on
 Drug to drug interactions in treatment saturated participants make outcomes less
outcome than ethnicity (26). This would enable
statistically significant
licensing authorities, policy-makers and prescribing
 Genomics and proteomics increasing drug development time
physicians to evaluate the applicability of study
 Mega trials have grown in number since the early 1980s
outcomes and safety data to local populations.
 80 per cent of trials fail to meet their recruitment deadlines
Perhaps it is time that external validity should be
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more explicitly addressed in the CONSORT guidelines. This is

clearly an issue of patient safety as well as rational economics,
and not just of academic curiosity.
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22

About the author

Dr Paul Wathall is Senior Clinical
Trials Manager for HCA International.
HCA are an American healthcare
company currently establishing a
UK-based research network across
six private hospitals in London,
including the prestigious Harley
Street Clinic. The unit will specialise
in all phases of oncology and
cardiovascular research, providing unparalleled access to
key medical opinion-leaders and a vast array of technology
platforms. Paul has over 10 years experience in clinical
research, was a former NHS research fellow, completed his
PhD in Health Services Research at the University of York
and is currently Director and Treasurer for the Institute of
Clinical Research. Email: paul.wathall@hcahealthcare.co.uk

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