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GLOBALIZATION OF CLINICAL TRIALS
One particular aspect that applies to most medium- and
low-income developing countries is that participation in a
clinical trial may represent the best therapeutic alternative
for a specifıc patient, as the available standard of care or access
to the health care system may be suboptimal. Although
signing the informed consent can be interpreted as a reasonable
attitude in this situation, the issue is the considerable
difference this represents as we compare this situation with
patients in other parts of the world where the standard of care
is available outside a clinical trial. Recent research suggests
that in a developing country like Brazil, fınancial gains and
therapeutic alternative are the most frequent motivations explaining
subject participation in clinical research. 21 The degree
to which these elements represent nonperceived pressure that
interferes with the consent process must be carefully considered
while conducting research in less developed health care systems.
One particularly and very sensitive aspect of globalization
of clinical research relates to what happens after the long and
extremely expensive process of development, when a drug is
proven as the better treatment alternative for a specifıc indication
and is released into the market. Data presented by the
European Federation of Pharmaceutical Industries and Associations
breaking down sales of new medicines launched
from 2009 through 2013 indicated that 55% were consumed
exclusively in the United States, 23% in Western Europe, and
10% in Japan. This leaves 12% for the 6 billion people living in
the rest of the world. 22 This fantastic heterogeneity in access
has many implications and has not been appropriately addressed.
Although the need to pay back the estimated more
than 1 billion U.S. dollars it costs to develop a new medication
is perfectly understandable, we should discuss how to
make these pharmaceutical advances available to everybody
who can benefıt from it. Many of the institutions that participate
in clinical research and generate data that helped with
drug approval are not able to treat patients with the same
medication after the trial is over and the drug is approved.
These discrepancies in access are particularly striking when
we look at a drug like imatinib that has changed the lives of
patients with chronic myeloid leukemia and unquestionably
can be characterized as the most successful targeted therapy
to date. A recent publication suggests that less than 30% of
the estimated 1.2 to 1.5 million patients with chronic myeloid
leukemia had access to the drug 13 years after it was launched
in 2001. 23 Whereas there are many other issues other than
drug cost to explain this specifıc discrepancy, addressing the
real value of a drug, much more than its price, is an urgent
and inescapable debate.
The perception patients may have of what clinical research
is also varies across different regions and is associated with
educational and cultural characteristics that should be taken
into account. Although the altruistic principles of participating
in a phase I trial exist, data indicate that most patients do
not have a clear understanding of the objective of the trial and
accept entering the trial mainly expecting a therapeutic benefıt.
Analyses of predominantly early-stage cancer trials indicate
that subjects are often motivated to participate in
research by the expectation of a direct medical benefıt, and
when asked, blur the distinction between research and treatment.
This therapeutic misconception has the clear potential
of compromising the consent process. The subject knows it is
research, but has an unrealistic expectation of being helped
by the trial. For example, the investigator may think the
chances of a subject benefıting from a phase I trial are remote
( 2%), but the patient thinks it may be as high as 50%. According
to Kahneman, this may be an example where intuition
(system 1) overwhelms logical thinking (system 2). 24 In
one recently published report, 65 of 95 participants in phase
I oncology trials did not know they were enrolled in a research
study and 93% of them substantially underestimated
their risk while overestimating their chances of benefıt. Although
the concerns of compromising consent have been
heavily directed to developing countries where access to care,
illiteracy, and language issues are substantial barriers, it is
worth noting that these results refer to studies conducted in
the United States. 25,26
Looking from a wider perspective, the globalization of clinical
research is an unavoidable process where the benefıts do
certainly exceed the potential challenges. Recent examples of
trials with global participation have led to the development of
fundamental advances in oncology. Among those, it is worth
mentioning the development of anti-HER2 treatments that
have improved the curability and survival of patients with the
HER2-positive subgroup of breast cancer. 27-31 Another particular
example is the fast development of crizotinib for the
treatment of patients with ALK-positive non-small–cell lung
cancer, in which global participation was instrumental to
screen a large number of patients to identify the specifıc subgroup
that benefıts from crizotinib treatment. 32
CONCLUSION
Globalization of clinical research is vital to speed up availability
of life-saving medicines throughout the world. Challenges
of conducting multiregional clinical trials can be successfully
addressed through strategic and tactical planning as part of a
global drug development program. Implementations of International
Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human
Use guidelines, particularly GCPs, do help standardize procedures
and are instrumental to conduct trials at a global
level.
Although some global initiatives have addressed biomedical
education and suggested strategies to strengthen health
care systems, we still need much more emphasis in the discussion
of improving clinical research capacity with a worldwide
perspective. Clinical trials are needed in low-income
and middle-income countries to answer questions on prevalent
conditions. At the same time, they improve local clinical
research training and infrastructure, as well as facilitate early
access to technology. The positive and lasting effects of global
trials in less developed regions are certainly unquestionable
but unfortunately yet to be realized. As more trials are conducted
in resource-limited settings, good clinical practices
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