Global migration of clinical research during the era of trial registration
Global migration of clinical research during the era of trial registration
Paul K. Drain 0 1 2
Robert A. Parker 1
Marion Robine 1
King K. Holmes 0 1 2
0 Department of Medicine, School of Medicine, University of Washington , Seattle, WA , United States of America, 3 Department of Epidemiology, School of Public Health, University of Washington , Seattle, WA , United States of America, 4 Medical Practice Evaluation Center, Department of Medicine, Massachusetts General Hospital , Boston, MA , United States of America, 5 Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School , Boston, MA , United States of America, 6 Biostatistics Center, Department of Medicine, Massachusetts General Hospital , Boston, MA , United States of America
1 Editor: Srinivas Murthy, University of British Columbia , CANADA
2 Department of Global Health, University of Washington , Seattle, WA , United States of America
and Non-Member of the OECD", "Upper-Middle Income", "Lower-Middle Income", or "Low
Income"] and United Nations Populations Division data for country-specific population
estimates. We analyzed data from calendar year 2006 through 2012 by number of clinical trial
sites, cumulative trial site-years, trial density (trial site-years/106 population), and annual
growth rate (%) for each country, and by development category, funding source, and clinical
Data Availability Statement: The third-party data
underlying this study are publicly available. Others
can access the same data through the
ClinicalTrials.gov (https://clinicaltrials.gov/) website
or by contacting the curators of the dataset and
submitting a data request, which was our pathway
to obtaining the data. The authors did not have any
special permission/access to these data.
Funding: This study was funded by the the
National Institutes of Health, National Institute of
Allergy and Infectious Disease (K23 AI108293), the
Harvard University Center for AIDS Research (P30
Over a 7-year period, 89,647 clinical trials operated 784,585 trial sites in 175 countries,
contributing 2,443,850 trial site-years. Among those, 652,200 trial sites (83%) were in 25
highincome OECD countries, while 37,195 sites (5%) were in 91 lower-middle or low-income
countries. Trial density (trial site-years/106 population) was 540 in the United States, 202
among other high-income OECD countries (excluding the United States), 81 among
highincome non-OECD countries, 41 among upper-middle income countries, 5 among
lowermiddle income countries, and 2 among low-income countries. Annual compound growth
AI060354), the University of Washington Center for
AIDS Research (P30 AI027757), and the Program
in AIDS Clinical Research Training Grant (T32
AI007433). The funders had no role in study
design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Competing interests: The authors have declared
that no competing interests exist.
rate was positive (ranging from 0.8% among low-income countries to 14.7% among
lowermiddle income countries) among all economic groups, except the United States (-0.5%).
Overall, 29,191 trials (33%) were funded by industry, 4,059 (5%) were funded by the United
States government, and 56,397 (63%) were funded by organizations. Countries with
emerging economies (low- and middle-income) operated 19% of phase 3 trial sites, as compared
to only 6% of phase 1 trial sites.
Human clinical research remains concentrated in high-income countries, but operational
clinical trial sites, particularly for phase 3 trials, may be migrating to low- and middle-income
countries with emerging economies.
Research involving human subjects has evolved over millennia±from an observational study in
the Old Testament [
] to the first randomized clinical trial in 1944 [
]. Historically, clinical
research has been financed by pharmaceutical companies and conducted in affluent regions,
but rising drug development expenditures have increased demand for faster and cheaper trial
]. Currently, over 3,000 clinical research organizations (CROs) operate worldwide
with total combined market revenues exceeding $21 billion [4±6]. Since researchers, including
CROs, use global networks to accelerate patient recruitment and reduce costs, we sought to
quantify the global distribution and migration of clinical research [
Since the ethical conduct of international clinical research remain a prominent concern, we
sought to perform a comprehensive assessment of the global migration of clinical research.
During the 1990s, underreported and unethical human studies led to calls for research
transparency through clinical trial registration [
]. The United States Food and Drug
Administration (FDA) mandated the creation of an open-access clinical trial registry, ClinicalTrials.gov
, and the World Health Organization (WHO) established the International Clinical Trials
Registry Platform . In 2005, the International Committee of Medical Journal Editors
(ICMJE) required registration in order to publish results, and compliance to trial registration
accelerated quickly [11±14].
We expand upon our prior analyses of the WHO International Clinical Trials Registry
], which is a more comprehensive database, by using more detailed operational data
in ClinicalTrials.gov and new methodological contributions to estimate the global conduct of
clinical research. By using the ClinicalTrials.gov data, we have been able to integrate analyses
on study site locations, duration of trial site operation, study phase, and funding source. We
developed a metricÐclinical trial site-yearsÐto more accurately compare research activity
across countries. By presenting a detailed account of the conduct of clinical research, we may
better understand the global implications of advancing medicine while maintaining protection
for human research subjects.
Primary data source
Our primary data source was ClinicalTrials.gov [
], created in 1999 by the National Institutes
of Health's Library of Medicine as the first open-access clinical trial registry [
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its inception, ClinicalTrials.gov has remained the primary registry of human clinical research
]. When the ICMJE required trial registration in 2005, ClinicalTrials.gov was the
only acceptable registry [
]. By 2008, the vast majority of published clinical trials were
registered in ClinicalTrials.gov [
]. While other open-access registries have been created [
ClinicalTrials.gov has remained the largest and most comprehensive clinical trial registry
We obtained the Aggregate Analysis of Clinical Trials (AACT) dataset, a reformatted
version of publicly available data, from the Clinical Trials Transformation Initiative on 5 May
]. The dataset contained available data through 27 September 2013. We limited our
analysis to operational clinical trials through the end of 2012 to have a sufficient reporting
grace period. Since one clinical trial may have multiple trial sites, we obtained data on
individual trial site locations to better represent the volume of clinical research activity in different
countries. Trial site opening and closing dates were not available, so we assumed each site
operated for the entirety of the associated trial for assessing time trends in research activity.
This new metric, trial site-years, better reflects a comparison of research activity across
The dataset included primary funding source and study phase for each clinical trial.
Funding source was categorized as United States government-sponsored (ªNational Institutes of
Healthº or ªOther United States Federal Agencyº), industry-sponsored (ªpharmaceutical
companiesº), or organization-sponsored (ªIndividual/University/Organizations, including
community-based organizationsº). Clinical study phase was based on the United States FDA's
classification system (Phase 1 defined as ªconducted with healthy volunteers and emphasize
safetyº; Phase 2 defined as ªpreliminary data on effectivenessº; Phase 3 defined as ªinformation
about safety and effectiveness by studying different populations and different dosagesº). We
combined Phase 0 studies (defined as ªexploratory studies involving very limited human
exposure to the drugº) with Phase 1 studies as both reflect early clinical trials. We excluded phase 4
studies [defined as ªstudies occurring after FDA has approved a drug for marketingº; 10,778
(11%) of 100,425 studies], since post-marketing studies are confounded by geographic disease
burden and drug affordability. In addition, including post-marketing surveillance studies, may
have detracted from our goal of understand the global migration of clinical and translational
research. We retained studies with phase coded as N/A [42,319 (42%) of 100,425 studies] for
the analysis of study sites. Studies with multiple phases (1/2 or 2/3) were reported separately.
We excluded trial site records without a country code (N = 6) and records from countries
or regions without an economic classification by the World Bank [regions of France
(Martinique, Guadeloupe, and Reunion; N = 19), Former Yugoslavia (N = 5), Former Serbia and
Montenegro (N = 87), Kosovo (N = 1), Palestinian Territories (N = 4), and Holy See (N = 1)].
Puerto Rico and Taiwan were represented as independent entities. We excluded 465,871 trial
sites occurring only before the year 2006, only after the year 2012, or only in phase 4 studies.
Other data sources
We classified each country's economic development status according to World Bank
categories [ªHigh Income and a Member of the Organization for Economic Co-operation and
Development (OECD)º, ªHigh Income and Non-Member of the OECDº, ªUpper-Middle Incomeº,
ªLower-Middle Incomeº, or ªLow Incomeº] in the World Development Report for 2006,
which was the first year of our study period (S1 Table) . We obtained each country's
estimated total population for the year 2006 from United Nations Populations Division [
obtained populations for Taiwan from International Monetary Fund [
] and Netherlands
Antilles from United Nations statistics [
3 / 13
Although we did not include active patient engagement in setting the research agenda for this
article, all participants of human clinical research trials worldwide may be impacted by the
implications of these findings.
We separated the United States from other high-income OECD countries in all analyses, due
to its high proportion of clinical trials. We used the term ªemerging economiesº to refer to
upper-middle income, lower-middle income, and low-income countries. We used the term
ªtrial site-yearsº to represent an operational clinical trial site during one calendar year, and
used this measure to calculate average annual density and compounded annual growth rate.
Trial density was calculated as the annual number of operating trial site-years per million
people. Since the total number of registered clinical trial sites remained low during the first 7
calendar years (1999±2005) and increased by 22% from 2005 to 2006, we restricted all analyses to
the 2006±2012 calendar years. In addition, excluding the underreporting period before and
through 2005 prevented spuriously high estimates for annual growth rates. We independently
ranked the top 20 countries by number of trial sites, average annual trial-site density, and
annual compound growth rate. The growth rate rank list was limited to countries with 5 sites
for each year and 100 total trial sites between 2006 and 2012 to prevent spuriously high rates
due to small relative changes. We excluded countries with few clinical trials, since very small
changes in number of clinical trials or trial sites spuriously reflected very large growth in
clinical research, but only a small change in absolute numbers of clinical trials. To calculate
compound annual growth, we used linear regression on the log of trial sites per year and 95%
confidence intervals were calculated based on the standard error of the regression coefficient,
converted back to percent growth. We calculated the annual proportion of all trials by funding
source and by study phase. All calculations were performed using SAS version 9.4 (Cary, NC,
Over the 7-year period, 89,647 clinical trials operated 784,585 trial sites in 175 countries,
contributing 2,443,850 trial site-years of observation (Table 1). Among those, 652,200 trial sites
(83%) and 2,052,126 trial site-years (84%) were operating in the 25 high-income OECD
countries. Conversely, the 125 countries with emerging economies accounted for 115,684 trial sites
(15%) and 342,053 trial site-years (14%). As expected, the distribution of clinical trial sites was
very heterogeneous between economic development categories (Fig 1).
Since 2006, the average annual number of trial sites was 112,084, ranging from 93,975
(2006) to 127,024 (2010). Over the seven-year period, the global proportion of clinical trial
sites in the United States decreased from 52% to 43%, while the proportion among other
highincome OECD countries increased from 33% to 40%. The proportion of trial sites also
increased among lower-middle income countries (2% to 4%) from 2006 to 2012.
Fourteen (70%) of the top 20 countries by total number of trial site-years were high-income
(13 OECD countries and one non-OECD), and the top 10 countries accounted for 77% of trial
site-years (1,883,571 trial site-years) during the 7-year period (S2 Table). The United States
operated the most trial site-years during the study period and the most trial sites in the year
2012. In addition, Germany, France, Japan, and Canada also operated >20,000 trial sites
between 2006±2012. The countries in the top 20 that were not high-income OECD countries
were the Russian Federation, Poland, China, India, Brazil, and Hungary.
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Average Annual Trial-Site- Trial-Site-Year Density
Year Density (/106 people) in 2012 (/106 people)
Rate (95% CI)
-0.5 (-3.3, 2.4)
3.9 (-2.1, 10.2)
6.1 (1.4, 11.0)
4.6 (0.2, 9.1)
14.7 (9.0, 20.7)
0.8 (-5.7, 7.7)
2.2 (-1.6, 6.2)
Clinical trial density
The global average annual clinical trial density, which accounts for population size, was 54
trial site-years/106 people (Table 1). The United States had the highest trial density (540 trial
site-years/106 people), followed by other high-income OECD countries (202/106) and
highincome non-OECD countries (81/106). Countries with upper-middle income (41 trial
siteFig 1. Total annual number of registered clinical trial sites beginning a study by World Bank economic development category. Data for the United States and other
high-income OECD countries are displayed separately. Organization-sponsored funding sources included individuals, universities, foundations, and community-based
PLOS ONE | https://doi.org/10.1371/journal.pone.0192413
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OECD (Organization for Economic Co-operation and Development). OECD±High-income: OECD; N-OECD±High-income: non-OECD; UMC±Upper-Middle
Trial site year density was the number of registered clinical trial site-years divided by country population in millions.
years/106 people), lower-middle income (5/106), and low-income (2/106) had lower densities
of clinical trial site-years. This pattern was consistent for the year 2012, and trial site densities
varied considerably by economic development status.
Seventeen (85%) of the top 20 countries with the highest density of clinical trial site-years
were high-income countries (Table 2). The United States (540 trial site-years/106 population),
Belgium (503/106), Israel (392/106), Denmark (361/106), and Canada (356/106) had the highest
average annual density. The members in this list that were not high-income countries were
Hungary, Slovakia, and Latvia. Notably, some countries, such as Japan, the United Kingdom,
and Italy had a large total number of trial sites, but were not among the top 20 countries for
trial site density due to a large relative population size.
Average annual clinical trial growth rate
Since 2006, the overall annual clinical trial compound growth rate was 2.2% (Table 1). Annual
growth rates were highest among lower-middle income countries (14.7%), high-income
nonOECD countries (6.1%), and upper-middle income countries (4.6%). Annual growth rates
were positive across all economic development strata, except the United States (-0.5%).
In sharp contrast to trial site density, 17 (85%) of the top 20 countries ranked by highest
annual growth rate were countries with emerging economies (Table 3). Countries with the
highest average annual growth rates were Lebanon (41.9%), Egypt (28.3%), Saudi Arabia
(27.4%), Guatemala (27.0%), and China (24.8%). High-income countries on this list included
Saudi Arabia, Republic of Korea, and Japan.
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CI±Confidence Interval, OECD (Organization for Economic Co-operation and Development). OECD±High-income: OECD; N-OECD±High-income: non-OECD;
UMC±Upper-Middle Income; LMC±Lower-Middle Income; LIC±Low Income.
Due to underreporting before 2005, we ranked countries with 5 sites for each year and 100 total trial sites between 2006 and 2012 by compounded average annual
clinical trial growth rate from 2006±2012.
Clinical trials by funding source
During the 7-year period, 29,191 (33%) trials were funded by the pharmaceutical industry,
4,059 (5%) were funded by the United States government, and 56,397 (63%) were funded by
other organizations (Fig 2). Between 2006±2012, trials sponsored by the United States
government decreased from 8% in 2006 to 3% in 2012. Clinical trials sponsored by other
organizations increased from 5,558 trials (58%) in 2006 to 9,451 trials (66%) in 2012. During the same
period, industry sources funded between 35% (year 2007) and 31% (year 2012) of all clinical
Clinical trial site by study phase
The overall proportion of trial sites remained relatively steady by clinical study phase during
the study period. Among studies with an identified phase, 27% were phase 1 trials (12,599
trials), 8% were classified as both phase 1 and phase 2 studies (3,939 trials), 35% were phase 2
studies (16,565 trials), 4% were classified as both phase 2 and 3 studies (2,055 trials), and 26%
were phase 3 studies (12,170 trials). When each clinical study phase was stratified by economic
development status differences were apparent. High-income OECD countries, including the
United States, decreased their proportion of phase 1 clinical trial sites from 93% (year 2006) to
91% (year 2012) (Fig 3). Phase 1 trial sites in countries with emerging economies had risen
from 5% (112 trial sites) in 2006 to 7% (267 trial sites) in 2012. The United States and other
high-income OECD countries decreased phase 2 trial sites from 90% (year 2006) to 84% (year
7 / 13
Fig 2. Total annual number of registered clinical trial sites beginning a study by proportion of clinical trials
starting by funding source. Data for the United States and other high-income OECD countries are displayed
separately. Organization-sponsored funding sources included individuals, universities, foundations, and
2012) (Fig 4). Countries with emerging economies increased their proportion of phase 2
clinical trial sites from 9% (year 2006) to 14% (year 2012). High-income OECD countries,
including the United States, decreased their proportion of phase 3 trial sites from 82% (year 2006) to
79% (year 2012) (lowest point was 76% in 2011) (Fig 5). Phase 3 trial sites in countries with
emerging economies increased from 16% (8,829 trial sites) in 2006 to 22% (11,555 trial sites)
in 2011Ðdeclining to 19% (9,468 trial sites) in 2012. Countries with emerging economies
Fig 3. Proportion distribution of registered clinical trials among phase 1 studies by World Bank economic development
category. Data for the United States and other high-income OECD countries are displayed separately.
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Fig 4. Proportion distribution of registered clinical trials among phase 2 studies by World Bank economic development
category. Data for the United States and other high-income OECD countries are displayed separately.
(low- and middle-income) operated 19% of phase 3 trial sites, as compared to only 6% of
phase 1 trial sites. Countries with emerging economies operated a considerably lower
proportion of exploratory phase 1 clinical trials sites, as compared to the United States and other
high-income OECD countries. Relative proportional increases for all clinical study phases
were highest among upper-middle income and lower-middle income countries.
Using a large global repository of open-access clinical trial data, we demonstrated that the vast
majority of clinical trials remain concentrated in high-income countries. Although annual
growth rates were highest among low and middle-income countries with emerging economies
for both aggregate measures and when stratified by clinical study phase, there remained a
relative underrepresentation of phase 1 trials as compared to phase 3 trials in countries with
emerging economies. The majority of clinical research was funded by organizations and the
pharmaceutical industry; organization-sponsored trials have been increasing. This overall
global migration of operational clinical trial sitesÐparticularly for phase 3 trialsÐto low- and
middle-income countries with emerging economies has numerous implications.
These findings are consistent with, but expand upon, several small, geographically limited
], including our own prior analysis [
]. Thiers et al. used ClinicalTrials.gov
data between 2004±2007 to show that most trials were conducted in North America, Western
Europe, and Oceania, while growth was occurring in other regions [
]. We expanded on our
previous analyses of WHO data [
] by using more comprehensive data based on registration
in ClinicalTrials.gov with a longer follow-up period after mandatory registration; by
accounting for the number of operational sites within each country and estimated duration of trial site
operation; and by evaluating the impact of funding source and clinical study phase [
Our findings suggest that a global migration of clinical research is occurring from
highincome countries to low and middle-income countries with emerging economies, such as
Egypt, Guatemala, China, and Belarus. The relevance for the migration of clinical research is
9 / 13
Fig 5. Proportion distribution of registered clinical trials among phase 3 studies by World Bank economic development
category. Data for the United States and other high-income OECD countries are displayed separately.
important not only for the protection of human subjects in countries with less regulatory
oversight, but also for the translation of clinical research findings to populations with different
ethnic and genetic backgrounds. Application of research findings from different populations may
have less relevance for clinical effectiveness, and research findings that require additional
confirmation would not constitute a cost-effective approach to biomedical research.
Since clinical trials represent approximately 40% of drug development costs [
], it has
been suggested that clinical trials may be migrating to resource-limited settings to reduce
]. Moving clinical trials to countries with emerging economies can accelerate
patient recruitment amidst less regulatory oversight [
]. As some estimate that roughly
70% of global biomedical research funding is provided by either the United States-based
foundations or corporations [
], our data suggest an increase in the outsourcing of clinical
research, primarily phase 3 clinical trials, to countries with emerging economies [
expansion is supported by the growth of FDA-regulated clinical investigators based outside the
United States [
] and the recent expansion of pharmaceutical companies into Asian markets.
This practice raises numerous questions about the translation of clinical trial results to other
population, as well as regulatory controls and inspections among governing bodies, including
the WHO and FDA.
The small trial density among low-income countries may relate to several factors, including
a limited supply of trained clinical researchers. In 2005, when the British Medical Journal
launched a themed issue on `addressing inequalities in research capacity in Africa', they
received few submissions from African countries [
]. A review of randomized clinical trials
conducted on HIV/AIDS in Africa found only 25% included an African principal investigator
and most (56%) were funded by agencies outside Africa [
]. Following this, experts agreed
that increasing representation of scientists from developing countries was essential for HIV
]. Since only 1% of recently discovered drugs target neglected tropical diseases
, addressing global health inequalities may require more clinical scientists to conduct
phase 1 trials for the most prevalent conditions in low- and middle-income countries [
Furthermore, there are multiple ethical implications about ensuring adequate health care
10 / 13
provisions, including providers and hospital beds, to study subjects among all phases of clinical
trials, while not occupying already limited health care resources in low- and middle-income
countries. At a minimum, all countries should have functioning research ethical review boards
in place with community participation and oversight.
Our approach had strengths and limitations. ClinicalTrials.gov is reliant on voluntary
registration and subject to underreporting [
]. While >95% of registered clinical trials had
complete data in Clinicaltrials.gov after 2005 [
], a period during which there were still changing
registration requirements, some trials may have remained unregistered or appeared in other
international trial registries, which might bias the observed results [
]. Requirements and
definitions of trial registration changed during the study period. Registration of phase 1 trials
was not required by the ICMJE until 2007 . Further, ICMJE adopted the WHO definition
of clinical trials (ªany research study that prospectively assigns human participants or groups
of humans to one or more health-related interventions to evaluate the effects on health
outcomesº) for trials that commenced after June 2008 [
]. Strengths of our analysis included
using clinical trial site-years, which attempted to account for the length of time each trial site
was operational, and obtaining data at least nine months after the end of 2012 to allow for lags
in trial registration. Other strengths were using the most comprehensive global clinical trial
registry, assessing trends over a 7-year period, and accounting for the conduct of individual
clinical research trials in multiple study locations. In future analyses, smaller, local registries
may be queried in order to understand regional patterns of clinical trials. Some more detailed
analyses could be performed if clinical trial registries provided data on the individual number
of participants enrolled at each clinical trial site.
In conclusion, while clinical trials continue to be concentrated in wealthy countries, the
largest percentage growth in registered human clinical research appears to be occurring in
countries with emerging economies. This migration of clinical research to emerging
economies may be related to expanded training opportunities and/or the high cost of operating
clinical trials in high-income countries. Good clinical practices and ethical assurances must be
adequate as human clinical research continues to expand, and reporting of clinical trial results
should be improved [
]. The geographic expansion of clinical trials requires attention to
ensure quality and participant protection, since human participation in clinical research will
remain an essential component of advancing medicine.
S1 Table. Country classification by World Bank economic development status.
S2 Table. Number of clinical trial site-years by country, ranked by trial site-years 2006±
The content is solely the responsibility of the authors and does not represent the official views
of the National Institutes of Health or other funding agencies.
Conceptualization: Paul K. Drain, King K. Holmes.
Data curation: Paul K. Drain, Robert A. Parker, Marion Robine.
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Formal analysis: Robert A. Parker. Funding acquisition: Paul K. Drain.
Methodology: Paul K. Drain. Project administration: Marion Robine. Writing ± original draft: Paul K. Drain.
Investigation: Paul K. Drain, Robert A. Parker, Marion Robine, King K. Holmes.
Writing ± review & editing: Robert A. Parker, Marion Robine, King K. Holmes.
12 / 13
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