EPC - Paul Wathall

7/26/2019 EPC - Paul Wathall

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Marketplace & Business

18 www.samedanltd.com

Outsourcing Clinical Trials

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

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 mutuallyincomparable. 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-naïve regions are assumed to pertain to

maximally treated populations elsewhere in the world.

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

Disadvantages

Poorly-developed transport and communications

systems

Inter- and intra-country language differences

may sometimes lead to problems in

protocol adherence

Monitoring frequency and set-up time may be

higher than in the West

Mechanisms for coordinating the function

of ethic committees in Eastern Europe are

poor and the ethical supervision of trials

varies considerably

Customs regulations often incredibly complex.

The wording of CEE law and contracts may

be unfamiliar

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

Tax costs and set-up costs can some times be

greater than in the West

The differential in costs is depleting particularly

as emerging markets strive to harmonise

regulatory frameworks

Patients frequently hospitalised in the East for

treatments typically conducted as an outpatient

in the West

Limited access to specialised equipment

required in some trials

An application for a new trial takes twiceas long in Poland as it would in the UK

Source data verification is difficult in some

hospitals especially in the outpatient setting

Advantages

Rapid recruitment consistently higher

than the global average

Excellent data quality

Participants described as well-educated with

a good understanding of the risks and benefits

of trials

Large patient population and centralised

health facilities

Patients tend to be less mobile facilitating

easier follow-up

Relatively drug-naïve population

Greater trust evident between patients

and investigators

Promotes continued political and commercialintegration of the former communist bloc into

the European community

All countries in the region are now

considered GCP compliant (although there

is some variability)

EE sites query generation rates

comparatively lower

CEE costs will tend to be lower than

in Western Europe

Highly-trained, enthusiastic investigators

motivated to conform to GCP

High incidence of pathologies otherwise

infrequent in other parts of the world

Up to 30 per cent of all expenditure

of all oncological treatments delivered

in Poland covered by clinical

trial programmes



19www.samedanltd.com

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 carewould otherwise be lacking (7).

THE MARKET AND

BIOETHICAL CONCERNS

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 PROPORTIONALOVERREPRESENTATION 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 asignificant effect of sorafenib amongst renal cell cancer patients

from developed nations, which was not apparent in their Eastern

European counterparts (16).

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 t reated

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 sponsor’s

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-levelWHO 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

Selected/planned (%)

92.5080.7075.4074.80

70.6069.8066.3059.5055.9052.6051.6048.4037.9036.8031.6029.1028.0025.4023.8018.2016.4015.3012.8012.509.90

9.608.907.103.603.102.901.00

0

Patient recruitment

Region

OtherEastEastWest

EastEastEastWestEastEastEastEastEastEastOtherWestWestWestWestWestWestEastWestWestWest

WestWestWestWestWestWestWestOther

Recruitment target

280500285500

80015080380170500215980

1,5005005805560013060055500150400120

1,000

25045085900150105100120

Figure 1: Modified recruitment progress chart




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

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.

REGIONAL VARIATION, DECISION-

MAKING 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-naïve

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 reductionfrom this trial might be higher, and the number needed to treat might be lower

than expected within a Western European or US population.

Eastern Europe Western Europe and others

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

80

70

60

50

331

26

N= 12 21



21www.samedanltd.com

(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. Thissituation 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-naïve 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 life-

threatening 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 wasdue 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.

Although it could be argued that responsibility for assessing

transferability of study outcomes rests with the prescribing

physician, there is evidence to suggest that this does not always

occur in practice. For example, Travers et al demonstrated that

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 non-traditional 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 life-

threatening 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-naïve

regions are applied to maximally-treated populations located

elsewhere in the world. It is also proposed that grant-holders,

regulatory agencies and policy-makers pay increasing attention to

the possible impact of sampling bias in the design

and approval stages of clinical trials. At the very

least, clinical trial sponsors should endeavor to

report and justify the proportional geographic

make-up of study participants, particularly

when submitting data to the licensing authorities.

Although at present sponsors are required to

provide data on ethnic background, this does not

address the influence of geographic variation in

healthcare provision and socioeconomic factors

which may be equally, if not more, influential on

outcome than ethnicity (26). This would enable

licensing authorities, policy-makers and prescribing physicians to evaluate the applicability of study

outcomes and safety data to local populations.

Perhaps it is time that external validity should be

Increased number of trials undertaken

More trials of generic drugs

Regulators demanding larger trials to prove long-term safety and efficacy. Ironically this

is driving trials into populations yielding safety data of questionable validity

Competition to get drugs approved and marketed within the industry

In the US patients frequently move from one insurance plan and physician to another

making tracking patients difficult

Growth in the number of new chemical entities

Treatment saturation is making Americans and Western Europeans unusable

Drug to drug interactions in treatment saturated participants make outcomes less

statistically significant

Genomics and proteomics increasing drug development time

Mega trials have grown in number since the early 1980s

80 per cent of trials fail to meet their recruitment deadlines

Table 2: Factors driving demand for more human subjects




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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Dr Paul Wathall is Senior Clinical

Trials Manager for HCA International.

HCA are an American healthcare

company currently establishing a

UK-based research network acrosssix 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: [email protected]

About the author

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EPC - Paul Wathall