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BARRIOS, WERUTSKY, AND MARTINEZ-MESA
extremely successful in making possible the conduct of clinical
research in different countries and health care scenarios.
Although local regulatory standards may still vary, most respect
the basic principles of GCP for clinical trials.
As quality is a fundamental principle in the conduct of clinical
research, we need to address monitoring, auditing, and
inspections as a basic element in the process of globalization.
The mandatory requirement for GCP inspections in different
parts of the world is costly, logistically challenging, and results
in the need for qualifıed human resources. Barriers in
communication (languages, dialects, and translation requirements),
different qualifıcation, interaction with national
regulatory authorities, and confıdentiality agreement
issues are all very important considerations that can be diffıcult
to address. As results are usually used to fıle for registration
of new drugs, foreign data should be in accordance with
FDA regulations. 15 Greater cooperation between national
regulatory bodies and all involved in clinical research, including
patient representatives, ethics committee, sponsors,
and investigators needs to be stimulated to guarantee transparency
in the whole process.
One other important aspect of globalization is the fact that
the inclusion of geographically distinct populations with different
lifestyles, ethnicities, and genetic profıles can influence
the safety and effıcacy of drugs. Global trials need to consider
this genetic diversity, both when designing the study and at
the time of interpreting or reporting the results. Safety concerns
need to be taken into consideration, as several studies
have shown that Asians metabolize drugs differently from
other patients. As an example, for 31.2% of the new drugs
approved in Japan between 2003 and 2005, the recommended
standard doses were different from those in the
Western population. In part as a result of this diversity, some
countries like China and Japan require phase I trials to be
performed in national subjects for all new drugs not already
registered in another country. 16 As a consequence, early
phase trials (usually performed in developed regions) are relatively
more frequent there than in other countries. Another
telling example comes from a study looking at the genetic
makeup of the very heterogeneous Brazilian population, which
demonstrated that well beyond self-characterization as white,
brown or black, a large proportion of the population has substantial
degrees of genetically defıned African, Amerindian,
and European ancestry with obviously important pharmacogenetic
implications. 17 In our opinion, the explanation for
this complex issue should widely link not only the genetic
make-up of a population, but also take into account cultural
and social differences in diet, way of life, education, physical
activity, nutritional status, and religion, as they all could be
contributing factors. Global studies should consider these
important aspects that, in parallel, may represent a great opportunity
to advance the investigation in this area.
Finally, a few words about the methodology and statistics
of multiregional clinical studies. Global studies can answer
global scientifıc questions and address global objectives, but
at the same time they allow us to analyze regional aspects that
could be extremely important. The ability of a study to reach
a correct and robust conclusion depends heavily on a strong
methodologic design and a careful sample size calculation, as
well as planning a sampling strategy that could allow us to
make inferences from specifıc populations. 18 The sample size
calculation in a multiregional trial needs to take into account
not only the overall sample size, but the influence that imbalances
in regional recruitment may have in the interpretation
of the results. In this sense, global trials, by expanding the
population, can have both an extremely positive perspective
of making inferences to a wider population, but at the same
time, the danger of compromising the results because of
problems with estimating the number of patients coming
from a specifıc region.
A number of other issues should be considered when
thinking about study design. The appropriateness of a global
development strategy should be addressed or questioned if
substantial regional variations in the results are to be expected.
Different standards of treatment as well as differences
in available supportive care could potentially have an effect in
the results of a trial. Balancing enrollment or stratifıcation
according to region mitigates some of these potential imbalances;
however, particular attention to these issues during
trial design is mandatory. One issue that has been intensely
discussed is the interpretation of the long-term survival results
of some global trials. Regional variations in access to
medications defıne different standards of care after progression
in a study. This can and does have an important effect in
survival estimations, as in many situations up to two-thirds
or more of the survival of a certain population occurs after
the patient has completed the trial and it can be expected that
available treatments will be different depending on where the
patient is from. 19
Ethical Aspects of the Globalization of Clinical Trials
A number of ethical concerns have been appropriately raised
in the process of globalization of clinical research. One of the
main reasons to expand this debate is the fundamental need
to protect subjects, regardless of where the clinical experiment
is being conducted. Harmonization of ethical principles
governing research, although different from the more
standard and operational national regulatory legislation, still
remains a challenge. Requirements for very specifıc, consistent,
and clear documentation of the informed consent process
are essential. Issues of language, cultural differences,
illiteracy, and education should be constantly address.
The epidemiologic transition theory has focused in developing
countries. 20 In low- and middle-income countries, less
people are dying from avoidable infectious diseases as
chronic noncommunicable illnesses are playing an increasing
role in the mortality patterns. At the same time, we can
identify changes in lifestyle behaviors and nutritional status
with less nutrient deprivation and more obesity among the
poorest populations. In addition, increases in life expectancy result
in a higher proportion of older patients in these developing
countries. All these epidemiologic conditions explain cancer as a
global health care problem and justify the inclusion of patients
from developing regions in global cancer studies.
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