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Article
CLINICAL
TRIALS
Clinical Trials
1–11
ÓThe Author(s) 2022
Article reuse guidelines:
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DOI: 10.1177/17407745211069153
journals.sagepub.com/home/ctj
The representation of Indigenous
peoples in chronic disease clinical trials
in Australia, Canada, New Zealand,
and the United States
Valerie Umaefulam , Tessa Kleissen and Cheryl Barnabe
Abstract
Background: Indigenous peoples are overrepresented with chronic health conditions and experience suboptimal out-
comes compared with non-Indigenous peoples. Genetic variations influence therapeutic responses, thus there are poten-
tial risks and harm when extrapolating evidence from the general population to Indigenous peoples. Indigenous
population–specific clinical studies, and inclusion of Indigenous peoples in general population clinical trials, are perceived
to be rare. Our study (1) identified and characterized Indigenous population–specific chronic disease trials and (2) identi-
fied the representation of Indigenous peoples in general population chronic disease trials conducted in Australia,
Canada, New Zealand, and the United States.
Methods: For Objective 1, publicly available clinical trial registries were searched from May 2010 to May 2020 using
Indigenous population–specific terms and included for data extraction if in pre-specified chronic disease. For identified
trials, we extracted Indigenous population group identity and characteristics, type of intervention, and funding type. For
Objective 2, a random selection of 10% of registered clinical trials was performed and the proportion of Indigenous pop-
ulation participants enrolled extracted.
Results: In total, 170 Indigenous population–specific chronic disease trials were identified. The clinical trials were predo-
minantly behavioral interventions (n = 95). Among general population studies, 830 studies were randomly selected.
When race was reported in studies (n = 526), Indigenous individuals were enrolled in 172 studies and constituted 5.6%
of the total population enrolled in those studies.
Conclusion: Clinical trials addressing chronic disease conditions in Indigenous populations are limited. It is crucial to
ensure adequate representation of Indigenous peoples in clinical trials to ensure trial data are applicable to their clinical
care.
Keywords
Clinical trials, Indigenous people, Indigenous health, chronic disease, health disparities
Introduction
Inequities in health outcomes and experiences in the
health system exist for certain population groups due to
unfair and avoidable differences in determinants of
health. The term ‘‘Indigenous’’ in this article refers to
the original peoples of Australia, Canada, New
Zealand, and the United States and their descendants
who share a similar history of colonization and its detri-
mental impact on health.
1
Indigenous peoples are dis-
proportionately affected by chronic conditions, and
these inequities may increase risk for chronic disease,
and influence presentation, characteristics, and out-
comes. For instance, type 2 diabetes mellitus is more
prevalent in Native American populations than the
general population and is more likely to result in
impaired kidney function.
2
Indigenous populations in
Australia, Canada, and the United States are overrepre-
sented with inflammatory arthritis and experience
higher disability and mortality rates compared with
non-Indigenous populations.
3
Colonization events
Departments of Medicine and Community Health Sciences, Cumming
School of Medicine, University of Calgary, Calgary, AB, Canada
Corresponding author:
Cheryl Barnabe, Departments of Medicine and Community Health
Sciences, Cumming School of Medicine, University of Calgary, 3330
Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
Email: ccbarnab@ucalgary.ca
instigate and maintain inequities in social determinants
of health; however, there are genetic variations contri-
buting to disease risk and treatment efficacy differ-
ences.
4
Furthermore, racial identities are known to
influence clinical presentations and therapeutic
responses.
5
For example, a Canadian Early Arthritis
Cohort observational study demonstrated that despite
similar disease activity at treatment initiation and with
applying the same therapy for early rheumatoid arthri-
tis as White patients, Aboriginal patients were 60% less
likely to achieve remission. This may be related to poor
prognostic factors influenced by inequities of determi-
nants of health, but the alternative explanation is that
the rheumatoid arthritis medications were not as
efficacious.
6
Randomized controlled trials (RCTs) are regarded
as providing the highest level of evidence for evaluating
intervention efficacy and allows for the effectiveness of
an intervention to be determined while controlling for
confounders of the effect.
1,7
Data from clinical trials
are essential for testing the safety and efficacy of poten-
tial new therapies and interventions, and results are
translated into practice for patient benefit.
8
Although
Indigenous peoples have a high burden of chronic con-
ditions, they are perceived to be underrepresented in
clinical trial research.
2
Results obtained in other popu-
lation groups are being extrapolated to Indigenous
patients, which may not be appropriate.
9
Treatment
effectiveness may differ between Indigenous and non-
Indigenous peoples; thus their inclusion in clinical trials
can identify both benefits and harms and improve
informed and shared decision-making for treatment
decisions. Therefore, underrepresentation of
Indigenous peoples in clinical trials has serious implica-
tions for medical science by limiting validity and gener-
alizability of research findings, contributing to inequity
in treatment outcomes,
8
and influencing the allocation
of resources for services and research.
10
Reporting and enrollments of ethnic minority
groups in clinical trials have been reported in the past.
11
A previous systematic review from 1999 found there
were limited well-designed clinical trials addressing
medical interventions and health needs of Indigenous
Australians.
12
Another systematic review examined
clinical trials on health-related issues in Indigenous
communities of Canada, the United States, Australia,
and New Zealand published from 1999 to 2010.
13
The
trials identified addressed mental health issues, dia-
betes, obesity, and parenting, but the study was limited
by the inability to identify unpublished studies.
13
Hunter et al.
14
explored clinical trial registrations for
the Australian Indigenous population from 2008 to
2018 via the Australian New Zealand Clinical Trials
Registry (ANZCTR) and the US National Library of
Medicine (NLM) clinicaltrials.gov. Trials were predo-
minantly on topics in public health, mental health, or
cardiovascular-disease related, and represented just
1.5% of all trials registered during that time period.
14
None of the previous studies mentioned focused on
identifying published and unpublished chronic disease-
related clinical trials. This article builds on these studies
by expanding the search and extraction methods to
gain insights into the representation of Indigenous peo-
ples in chronic disease trials in Australia, Canada, New
Zealand, and the United States. Our study has two
objectives: to identify and characterize Indigenous
population–specific chronic disease trials, and to sum-
marize the representation of Indigenous peoples in gen-
eral population chronic disease clinical trials conducted
in Australia, Canada, New Zealand, and the United
States.
Methods
Methodologic approach
Environmental scan methodology was utilized in this
study because it is a valuable tool to systematize and
synthesize knowledge and can provide evidence for stra-
tegic action, decision-making, health policy, and pro-
gram planning.
15
We conducted our scan in June 2020
of registered Indigenous population–specific chronic
disease trials in two registries; the US National Library
of Medicine (NLM) clinical trial registry (https://clini-
caltrials.gov) and the Australian New Zealand Clinical
Trials Registry (ANZCTR) (https://www.anzctr.or-
g.au). The NLM clinical trial registry consists of pri-
vately and publicly funded studies that explore studies
in 50 US states and in 216 countries (including Canada,
which does not have its own registry), and the
ANZCTR is a primary registry of clinical trials carried
out in Australia, New Zealand, and in other locations.
Institutional review board approval and informed con-
sent were not obtained, given that the study was an
environmental scan of publicly available information.
The research team comprises members of an epidemiol-
ogy and health services research lab working to resolve
care disparities experienced by Indigenous patients and
consists of a member (C.B.) of the Me
´tis Nation of
Alberta. Two researchers (V.U. and C.B.) indepen-
dently conducted the searches and identified the studies,
and all three investigators extracted the data.
Identification of studies
Indigenous population–specific trials. Clinical trials regis-
tries from May 2010 to May 2020 were searched for
Indigenous population–specific terms (Table 1) in the
title, abstract, or in the protocol. Key terms used to
describe Indigenous peoples in Australia, Canada, New
Zealand, and the United States were included.
16
Some
search terms included are now recognized as racist, but
were used historically in the literature and thus were
retained. Eligible studies were then included if
2Clinical Trials 00(0)
conducted specifically in a pre-specified chronic condi-
tion of interest related to known overrepresentation of
disease incidence or prevalence, or more severe out-
comes, in the Indigenous population of the four coun-
tries of interest.
17,18
These included arthritis, diabetes,
hypertension, cardiovascular disease, mental illness,
respiratory disease, kidney disease, and dental/period-
ontal disease. Cancer was not included given variabil-
ities within cancer types and prognoses.
19,20
The terms
listed in Table 2 were used to identify the chronic con-
ditions of interest. For each country, we conducted sep-
arate searches with individual chronic disease terms,
general Indigenous population terms, and country-
specific Indigenous population terms. Table 3 provides
more information on how the terms were entered in the
advanced search function of the databases to conduct
the search.
Indigenous enrolment in general population clinical trials. We
searched any clinical trials registered between May
2010 to May 2020 in the four countries using the pre-
specified chronic diseases terms (Table 2) mentioned in
the title, abstract, or protocol. The studies selected were
listed in both registries as having completed recruitment
and for the clinicaltrial.gov registry, with submitted
results, in the aforementioned time period. Indigenous
population–specific studies previously identified were
excluded. All identified studies from the registries were
collated and sorted based on the type of intervention,
specified in the following section, to ensure sufficient
sample of each study type. Ten percent of the studies
from each intervention type were randomly selected for
data extraction using an online random integer set gen-
erator, to identify the proportion of enrolment that was
Indigenous. We included studies that were conducted in
at least one of the chronic conditions, and conducted
the searches in each registry, eliminating the duplicate
of a study that was already randomly included in the
first databases.
Data collection
Indigenous population–specific trials: for each regis-
tered trial meeting inclusion criteria, we extracted
details on Indigenous population group identity and
geographic location(s) of research, chronic condition,
participant age category (i.e. child, adult, or both), gen-
der, type of intervention, study design, number of
Indigenous participants enrolled, community involve-
ment if described (which is an essential aspect of
Table 1. Indigenous population search terms.
Search terms
General Indigenous population terms Aboriginal, Indigenous, Tribe, Tribes, Tribal, Native People
Country-specific population terms Australia Aborigine, Torres Strait islander
Canada First Nation, First Nations, Indian, Indians, Me
´tis, Half-Breed, Inuit, Eskimo
New Zealand Maori, Pacific Islander or Pacific People, Pasifika
US American Indian, Amerindian, Native American,
Alaska Native, Native Hawaiian
Table 2. Pre-specified chronic disease conditions of interest.
Chronic disease Search terms
Arthritis Arthritis, osteoarthritis, inflammatory arthritis, rheumatoid arthritis, psoriatic arthritis,
ankylosing spondylitis, rheumatic diseases, connective tissue disease, systemic lupus
erythematosus, lupus, scleroderma, vasculitis
Diabetes Diabetes, diabetes mellitus, diabetes complications
Hypertension Hypertension, high blood pressure
Cardiovascular Disease Heart disease, myocardial ischemia, myocardial infarction, congestive heart failure, vascular
diseases, stroke, cerebrovascular accident, atherosclerosis, hypercholesterolemia
Mental illness Mental disorders, anxiety disorders, mood disorders, depression, substance-related
disorders, trauma and stressor-related disorders, suicide ideation, schizophrenia, loneliness,
and gambling
Respiratory disease Respiratory tract disease, lung disease, asthma, COPD, chronic obstructive pulmonary
disease, chronic obstructive lung disease, emphysema, chronic bronchitis, bronchiectasis
Kidney disease Chronic kidney disease, renal disease, nephritis, post-transplant
Dental/periodontal disease Dental disease, tooth disease, mouth disease, periodontal disease
COPD: chronic obstructive pulmonary disease.
Umaefulam et al. 3
Indigenous research ethics), and funding type. We con-
tacted investigators associated with the studies selected
and searched Medline and Embase to identify publica-
tions for these studies in peer-reviewed journals so as to
acquire any further details on demographic
information.
Indigenous enrolment in general population clinical
trials: for each selected study, we obtained details of the
geographic location(s) of research, chronic condition
studied, type of intervention, total number of partici-
pants enrolled, total number of Indigenous participants,
study design, and funding type. For studies with no
information in the registry, we contacted the authors/
investigators associated with studies selected and
searched for peer-reviewed publications via Medline
and Embase, and extracted Indigenous population
information from the study’s demographic tables. We
searched Medline and Embase using the registration
number and principal investigator name(s) as key-
words. The linked publications feature in the registries
was also used to retrieve publications related to the
study.
For both objectives, in the clinicaltrial.gov registry,
data were extracted using the comma-separated values
(CSV) format and in ANZCTR, using the Excel for-
mat, and we viewed the full record of selected studies
to extract further information. The study design was
categorized as listed in the registry based on the alloca-
tion and intervention mode/assignment. The location
data extracted was centered on the recruitment site.
The intervention-type data collected was grounded on
how it was classified in the registry (behavioral (includ-
ing education, training),
21
drug, device, procedure,
other). For clinicaltrial.gov, we extracted the interven-
tion/treatment type listed in the registry, while for
ANZCTR, we obtained the information listed in the
study’s intervention code. Information on community
collaboration was extracted from the entries in the
registries and from the publications obtained. We col-
lected both the anticipated and actual enrollment data
as indicated in the registry and/or study publication,
but the final accrual data were used in the analysis.
From the publications of studies identified, we
extracted demographic information on the participants
included in the study’s primary analysis report. Where
discrepancies existed between the information obtained
from the registry and the published data, we reported
the data from the published paper.
Results
Characteristics of Indigenous-specific trials
The Indigenous population–specific search retrieved a
total of 2757 records from the two registries (2025 from
NLM clinical trials.gov and 732 from ANZCTR).
Following removal of duplicates, 1823 studies were
screened. After excluding studies that did not meet the
inclusion criteria, 170 studies were retained for analysis
(Figure 1). Medical education and health service
research studies were excluded because they focused on
the training of health professionals working with
Indigenous peoples and quality improvement studies
for health programs and systems. A complete list of
studies is summarized in Supplemental Table S1. The
number of studies conducted in each country was 46 in
Australia, 11 in Canada, 46 in New Zealand, and 67 in
the United States; 1 New Zealand study was multi-
national (Australia, Canada, and New Zealand); 110
studies enrolled only adults, and 60 studies included
children \18 years. The chronic condition most
addressed was mental illness (36%). The interventions
were classified based on the categorization provided in
the registry. The type of intervention across the four
countries was predominantly focused on behavior
change interventions (56%, n = 95) followed by a
combination of behavioral, lifestyle, education, and
rehabilitation interventions (15%, n = 25) and drug
interventions (10%, n = 17) (Table 4). In all, 153 stud-
ies included participants of all genders, while 13 studies
Table 3. Search strategy in registries.
Registries Sections in advanced search
a
Example of search combination
b
Clinicaltrials.gov Condition or disease Diabetes
Other terms Aboriginal
Study type Interventional studies (Clinical Trials
Country Canada
Study start 1 May 2010 to 31 May 2020
ANZCTR Registry ANZCTR
Description of intervention(s)/exposure Maori
Study type Interventional
Health condition(s) or problem(s) studied Systemic lupus erythematosus
Registration date 1 May 2010 to 31 May 2020
Countries of recruitment (AND) New Zealand
a
No selections were made in the other search rows.
b
We conducted separate searches with a combination of chronic disease terms, general Indigenous population terms and country-specific Indigenous
population terms.
4Clinical Trials 00(0)
enrolled only females and 4 studies recruited only
males. About 51% (n = 86) of the studies reported
some level of community collaboration, while the other
studies neither reported community involvement nor
was it clearly stated. The primary government research
agencies of the four countries, that is, the National
Health & Medical Research Council (NHMRC),
Canadian Institutes for Health Research (CIHR),
Health Research Council (HRC), and National
Institutes of Health (NIH) funded 87 studies. The other
studies were funded by individuals, hospitals, universi-
ties, research institutes, industry, or other government
agencies.
Published Indigenous-specific trials
Of the 170 trials we identified from the clinical trial
registries, 48 were ongoing and did not provide final
accrual data. Of the completed trials, 74 studies pro-
vided details of Indigenous enrolment within the regis-
try enrolment data; for 47 of these 74 studies we
obtained final accrual data from peer-reviewed publica-
tions, whereas 3 studies had no data on Indigenous
enrollment listed and 45 studies did not provide final
accrual data. Among the studies with either data in the
registry or published results, a total of 16,635
Indigenous participants were enrolled (Australia =
2827; Canada = 1495; New Zealand = 3507; United
States = 8806), ranging from 1 participant up to 1451
participants (in a trial, n = 1 Indigenous participant
published). The Indigenous peoples enrolled in the clin-
ical trials were mainly American Indian and Alaska
Native peoples (n = 7939), followed by Maori and
Pacific Island peoples (n = 3178). Studies related to
oral health enrolled the highest number of Indigenous
participants (n = 4499). Also, Indigenous peoples were
Figure 1. PRISMA flow diagram of studies included in environmental scan.
Umaefulam et al. 5
mostly enrolled into behavioral studies (n = 8951)
compared with other intervention types. A total of
3905, 927, 1793, 888, 153, and 18 participants were
enrolled in combined, drug, other, procedure, screen-
ing, and device intervention studies, respectively.
Studies where community collaboration was mentioned
were predominately in mental health (n = 38). The
clinical trials were a combination of parallel, sequential,
factorial, crossover, or single group allocations. In
Australia, Canada, and New Zealand, the trials were a
combination of randomized and nonrandomized
designs, whereas in the US studies the design was pre-
dominantly randomized.
Indigenous population enrolment in general
population trials
The search of general population studies with results
posted within the 10 years in Australia, Canada, New
Zealand, and the United States in the chronic condi-
tions of interest, identified 15,313 completed studies.
After removing duplicates, 8302 studies were sorted
based on the type of intervention (Supplemental Figure
S1), 830 (10%) of the studies were randomly selected
(Supplemental Table S2), and the proportion of
Indigenous people enrolled in the studies extracted.
Demographic characteristics of participants were not
Table 4. Number of clinical trials in chronic diseases of interest by intervention types in Indigenous populations of Australia,
Canada, New Zealand, and the United States.
Chronic condition Intervention Australia Canada New Zealand United States
Arthritis Combination
a
1
Drug/biological 2
Total = 3 3
Cardiovascular disease Behavioral 2 7 2
Combination
a
442
Device 1
Drug/biological 2 1 1
Other
b
21
Procedure/screening 2 1
Total = 32 12 13 7
Dental/periodontal disease Behavioral 2 2 1
Combination
a
11
Other
b
21
Total = 10 512 2
Diabetes Behavioral 1 2 5 8
Combination
a
12
Device 2
Drug/biological 2 1 2
Other
b
11
Procedure/screening 1 1 1
Total = 31 659 11
Hypertension Behavioral 1 7
Device 1
Other
b
1
Total = 10 11 8
Kidney disease Behavioral 1 2
Other
b
2
Procedure/screening 1
Total = 6 11 4
Mental illness Behavioral 9 3 8 29
Combination
a
12
Device 1 1
Drug/biological 2
Other
b
31
Procedure/screening 1 1
Total = 62 17 3 11 31
Respiratory disease Behavioral 1 2
Combination
a
132
Drug/biological 2 2
Other
b
1
Procedure/screening 1 1
Total = 16 574
Bold italic values indicates the total number of clinical trial studies per chronic disease per country.
a
Combination: a mix of Behavioral, Lifestyle, Education, and Rehabilitation interventions.
b
Other: gardening, digital stories, lifestyle coaching, case management, Ma ka hana ka a
¨Ike, Hanap
u Provider Toolbox.
6Clinical Trials 00(0)
available for 26 studies. Although we attempted to con-
tact the investigators connected with these studies to
obtain demographic data, responses were not obtained.
Indigenous peoples identified as Aboriginal, American
Indian, or Alaska Native, Native Hawaiian or Pacific
Islander, Aboriginal, Torres Strait Islander, Maori, or
Indigenous. Of the remaining 804 studies, 278 (35%)
studies did not provide race/ethnicity information to
allow analysis. There were 526 studies (n = 208,941
participants) with race or ethnicity of participants
reported, and Indigenous participants (n = 11,714)
represented 5.6% of the total enrolled population.
However, 354 (67%) did not include Indigenous parti-
cipants at all. In studies with Indigenous participant
enrolment, there was a median of 3 Indigenous partici-
pants per study (interquartile range (IQR: 1–6)),
whereas the total enrolment for these same studies was
a median of 225 (IQR: 98–612), of which 383 (48%) of
the studies were funded by industry. Table 5 sum-
marizes Indigenous population enrolment in chronic
disease RCTs relative to general population enrolment.
Discussion
Given the known diversity in treatment effects—both
benefits and harms—it is important to include
Indigenous populations in clinical trials. We have
approached describing the current reality of Indigenous
persons’ enrolment in clinical trials in two ways—the
first to identify the frequency of Indigenous
population–specific trials and their characteristics, and
the second to identify how frequently Indigenous peo-
ple are enrolled in general population clinical trials. As
observed in this study, Indigenous population–specific
clinical trials were frequently focused on behavior
change.
22
The behavioral interventions integrated and
utilized several strategies, including education or group
sessions offered in person or via mobile platforms. This
type of intervention is critiqued for limitations in dura-
tion and sustainability of effect.
23
Scale-up of interven-
tions that are proven useful is a major problem in
Indigenous research,
24
and communities are burdened
from contributing to research that is not scaled and
sustained. Few Indigenous peoples were enrolled into
drug-related clinical trials with limited enrolment in
arthritis, hypertension, and kidney disease studies. This
reduces the information about drug reactions regarding
these conditions in this population, despite being
among the most frequent conditions affecting
Indigenous populations.
17,18
Knowing that there are
often differences in drug metabolism or response by
Table 5. Summary of Indigenous population enrolment in general population chronic disease randomized controlled trials.
Location and total
study enrolment
Population identity
and enrolment
Chronic condition studied in the trial
Arthritis CVD Dental Diabetes HTN Kidney Mental
illness
Respiratory
Australia
(n = 49,692)
Indigenous, Aboriginal,
and
Torres Strait Islander
(n = 7032, 14.2%)
– 14% – – – 0.002% 0.1% –
General population
(n = 42,660, 85.8%)
1.5% 65.9% 8.0% 0.2% 0.4% 9.6% 0.3%
Canada
(n = 804)
First Nations, Inuit and
Me
´tis
(n = 0, 0%)
––––––––
General population
(n = 804, 100%)
7.5% 34.5% 23.9% 18.4% 2.0% 9.7% 4.0%
New Zealand
(n = 654)
Maori and Pacific
Islander
(n = 96, 14.7%)
0.8% 1.7% – – – – – 12.2%
General population
(n = 558, 85.3%)
15% 16.8% 33.3% 6.1% 14.1%
US (n = 187,391) American Indian or
Alaska Native,
Native Hawaiian or
Other Pacific Islander
(n = 4180, 2.2%)
0.1% 1.4% 0.1% 0.4% 0.01% 0.01% 0.1% 0.2
General population
(n = 183,211, 97.8%)
4.3% 29.3% 2.6% 25.0% 6.8% 1.9% 13.4% 14.6%
Multiple countries
(n = 120,385)
Indigenous
(n = 406, 0.3%)
0.1% 0.02% – 0.1% – 0.01% 0.02% 0.1%
General population
(n = 119,979, 99.7%)
6.6% 40.3% 0.04% 32.6% 1.0% 2.0% 4.3% 12.8%
CVD: cardiovascular disease; HTN: hypertension.
Proportions rounded to 1 decimal place unless \0.05%.
Umaefulam et al. 7
race or ethnicity, it cannot be assumed that reactions to
drugs are similar between different races.
25
With the
ongoing impact of colonialization on the health
of Indigenous peoples, the increasing prevalence of
chronic diseases in the population, and the upsurge of
patient-focused medicine, representation of Indigenous
peoples in clinical trials during the approval for new
therapeutic drugs is vital in improving our understand-
ing of how to prescribe the treatments and how the
therapies function in the population.
26
In addition, it is
worth noting that certain chronic conditions are mostly
studied in some Indigenous populations, which may be
due to community, researchers, or government interest.
For instance, although cardiovascular disease dispro-
portionately affects Indigenous peoples in Canada
compared with the general population,
27
we were
unable to identify Indigenous-specific clinical trials
focused on this condition, rather there are more studies
focused on other cardiometabolic conditions such as
diabetes.
Indigenous peoples are a growing population in
Australia, Canada, New Zealand, and the United
States, with an estimated population of 7 million.
28
Indigenous people account for about 3.3%, 4.9%,
15%, and 1.7% of the total Australian, Canadian, New
Zealand, and the US population, respectively.
16,29
The
number of Indigenous people enrolled in clinical stud-
ies is below their overrepresentation in chronic disease
prevalence.
30
For example, it is estimated that 12.1%
of American Indians and Alaska Native peoples above
18 years of age have coronary heart disease,
31
but
fewer than 1% are represented in clinical studies.
32
Our result shows that among Indigenous
population–specific chronic disease trials, a total of
16,635 participants were enrolled in the four countries,
which is below population proportion. Although not
every clinical trial needs to include all racial/ethnic
groups, group(s) involved in studies must be represen-
tative of their larger population.
5
This will provide
meaningful opportunities to examine the multifaceted
relationship between ancestral influences, environmen-
tal exposures, and social factors.
5
Research ethics, particularly in regard to Indigenous
research, focus on reducing health inequities, and
research approaches framed around the cultural values
of communal relationships and respect of world
views.
33,34
When working with Indigenous commu-
nities, clinical trials may not be plausible mainly due to
ethical concerns arising from historical mistrust of
researchers and the purposeful exclusion of some indi-
viduals from a beneficial intervention. Nevertheless,
cultural appropriateness of the research should be
encouraged and addressed.
1
Clinical trial acceptance
can be increased by design, particularly if traditional
RCTs are not ethically applicable. Thus, methods that
support access to the intervention to all participants,
such as delayed interventions,
35
should be considered.
Our environmental scan provides examples of delayed
intervention, and these approaches often coincide with
cultural values of inclusion, which is essential for
Indigenous community engagement.
36
Although com-
munity engagement is often more reported in the North
American literature due to differences in research fund-
ing policies and legislative framework differences
regarding government–Indigenous community rela-
tions,
37
this study showed that some level of community
involvement that involved engaging Indigenous com-
munities in the research processes was reported across
all four countries. Prioritizing community engagement
and education,
38
and utilizing engaging strategies to
recruit Indigenous peoples in clinical trials can assist in
reducing barriers to enrollment.
39
The principal government-funded health research
bodies in Australia (NHMRC), Canada (CIHR), New
Zealand (HRC), and the United States (NIH) have dif-
ferent policies regarding the inclusion of Indigenous
peoples in research and the criteria to obtain research
funding. In Australia, qualifying funding applications
must address the NHMRC
40
Indigenous Research
Excellence criteria. Funded health research in New
Zealand must address the attributes of the
Prioritization Framework.
41
In Canada, one of CIHR’s
Institute of Indigenous Peoples’ Health strategic direc-
tion is to drive research, via increasing funding in
Indigenous health research and providing funding
directly to Indigenous communities.
42
In the United
States, to encourage including racial minorities in clini-
cal trials, the NIH Revitalization Act passed the man-
date that clinical researchers applying for NIH-funded
research include women and people of diverse racial
backgrounds in their studies based on analysis of the
variables studied in the trial affect minority groups.
11
The NIH also stipulated that clinical trials must include
subgroup analyses to assess ethnic differences in treat-
ment efficacy.
43
In our study, most of the randomly
selected general population trials either did not enroll
Indigenous peoples or did not provide race and ethni-
city information. About 56% of Indigenous
population–specific chronic disease clinical trials were
funded by the primary government funding agencies in
the different counties. Nonetheless, sponsorship from
government funding agencies could be improved to fur-
ther meet their mandates and responsibilities of pro-
moting Indigenous health and diversity in clinical
research.
44,45
It is essential that policies that support
Indigenous people involvement and representation in
clinical trials be created and put into practice. If the
inclusion of Indigenous peoples is crucial, then better
efforts need to be made, so they are adequately repre-
sented in clinical trials
39
and ensure sufficiently pow-
ered subgroup analyses.
38
In addition, integrating the
Consolidated Standards of Reporting Trials
(CONSORT)-Equity extension
46
in clinical trials design
may assist with creating awareness to consider equity
8Clinical Trials 00(0)
when designing trials, guide in the revaluation of how
to ensure engagement of subgroups, and advance anal-
ysis across population groups.
In Canada, the Truth and Reconciliation
Commission of Canada
47
calls on researchers to under-
stand gaps in Indigenous health outcomes as a result of
colonization. Research is essential to reconciliation and
a vital aspect of closing the gaps in research, which
often focuses on health conditions and outcomes. Yet,
the type of research conducted equally matters. It is
essential to increase the proportion of well-designed,
high-quality Indigenous health clinical studies that
address population health issues, supports reconcilia-
tion, and respects the right of Indigenous peoples to
the highest attainable standard of health.
47
Limitations
We included only trials that were registered in the US
NLM and the ANZCTR database. Accordingly, our
results could have missed clinical trials registered in
other databases, especially studies conducted across
multiple locations. While this could be mitigated by
conducting a systematic review of published studies as
done by Saini and Quinn,
13
we did not take this step.
Replication of that study should be considered to pro-
vide updated results. Also, in the general population
trial search, since we included studies designated in the
registry as clinical trials/interventional studies, trials
inappropriately registered as observational studies
could have been missed.
48
Since selection required
being ‘‘completed recruitment’’ or ‘‘submitted results’’
and the other database was not verified, it is a limita-
tion of our approach.
49
We did not contact the authors
of the published general population trials that did not
report ethnicity to obtain this data, and our interpreta-
tions and conclusions resulting from the other studies
that did are limited to the ability of participants to self-
report their ethnicity.
Conclusion
There is limited representation of Indigenous peoples in
chronic disease clinical trials. This critique is not
intended to impose on community which research
topics or methods they choose to participate in, but
rather highlights that large gaps exist when attempting
to apply the evidence base to Indigenous peoples.
Failure to create more racially diverse clinical research
cohorts could increase existing health disparities if those
most affected by disease continue to be excluded.
50
Underrepresentation of Indigenous peoples in clinical
trials decreases the opportunity to fully understand the
factors that lead to poor health and outcomes of thera-
peutic interventions in the population.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) disclosed receipt of the following financial sup-
port for the research, authorship, and/or publication of this
article: V.U. was awarded the Eyes High Postdoctoral
Scholarship from the University of Calgary and C.B. was the
Canada Research Chair, Rheumatoid Arthritis and
Autoimmune Diseases, CIHR.
ORCID iD
Valerie Umaefulam https://orcid.org/0000-0003-4239-7715
Supplemental material
Supplemental material for this article is available online.
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