IPPCR 2019 Considering Inclusion in Research: An Introduction to Scientific and Policy Perspectives

IPPCR 2019 Considering Inclusion in Research: An Introduction to Scientific and Policy Perspectives


>>Janine Clayton: Welcome. I’m Dr. Janine
Clayton, the director of the Office of Research
on Women’s Health here at the National
Institutes of Health, and the NIH associate director
for Research on Women’s Health. I’ll introduce you today
to the concept of inclusion in clinical research, and the importance
of diverse representation in clinical studies. This is a first of a four-part
series on inclusion in clinical research
that provides an overview of the importance
of inclusion in research, data on participants
in clinical trials, policies,
and how to address inclusion in grant applications
and contracts. The goals for this session
are to learn about inclusion, and the importance of inclusion
in clinical research, recognize barriers,
and facilitating factors in recruiting a diverse
population for clinical studies, understand why sex and gender
matter in biomedical research. Inclusion ensures that
the distribution of study participants
by sex, gender, race, ethnicity,
and age reflect the populations needed to accomplish
the scientific goals of a clinical study. Federal law and NIH inclusion
guidelines on a clinical research
were adopted to increase the representation of women,
underrepresented minorities, and children
in clinical research. And in order to address
potential harms, real or perceived, created by their exclusion
or their omission. Federal law in the 1993 NIH
Revitalization Act require that
human subject research must address the inclusion
of women and minorities
in clinical research studies as appropriate for the
scientific goals of the study. In March 1998,
NIH released a policy and guidelines on the inclusion
of children as participants. In response to the 21st
Century Cures Act, that was issued in 2016,
NIH Inclusion Across the Lifespan policy superseded the policy
on inclusion of children. It now requires that individuals
of all ages be included, such as those younger than 18
and those over the age of 65, when conducting
clinical research, unless there is
a strong justification for their exclusion. So why is inclusion important? Certain populations may be
more at risk for certain
diseases, such as diabetes
and heart disease, so it’s important for patients
in those populations who are more likely to be
treated for a condition to be included in a trial
that’s studying that disease. It allows for a full picture
of the risk and benefit of treatments that are being tested
in clinical studies because there are
important differences in how people of diverse
groups respond to a treatment. Information on those differences
can then be included in potentially
a product labeling but importantly to help doctors
and patients make informed, evidence-based treatment
decisions. By using one demographic group
and generalizing findings across all populations, differences between various
groups are not accounted for. When representation
of demographic groups clinical outcomes due to biological, cultural,
social, or economic differences can be reported
and addressed. This ensures equitable
distribution of risks and benefits of participation
in clinical research and researchers
are in a position to study diseases
and test treatments on the groups of individuals who are affected
by those diseases and who will receive
those treatments, helping to ensure safe
and effective treatment for everyone. This is why diversity
in clinical research and clinical trials
is essential. Though this list is
not exhaustive, there are several benefits
from inclusion to the clinical
and scientific community, such as gaining advances
in knowledge from research. For example, uncovering disease
states that differ in prevalence,
diagnosis, severity, and outcomes
between men and women. Incorporating that knowledge
into training and education, implementing new concepts
into practice that can directly
affect patient outcomes. Changing standards of practice
and in public health so that it’ll be
more effective, providing access to sex
and gender, race, ethnicity, and culturally appropriate as well as age
appropriate health care. And then diversifying
the workforce so that in the future
studies can be designed to recruit participants
from diverse backgrounds and implement
those findings for everyone. All of these steps
can increase trust and aid in enrollment and retention of
participants on clinical trials. These benefits serve
as a positive feedback loop to allow for more discoveries
relevant to everyone. Having a well-represented
population in clinical studies allows for researchers
to investigate those treatments and study the outcomes
for everyone. This can also support
addressing health disparities and promote health equity. Recruitment is key to
getting participants involved in clinical studies. Though there may be interest
in participating in clinical research, there may be barriers that limit
enrollment and study compliance. Potential barriers that impact
the involvement of racial and ethnic minorities
in clinical research, as well as women,
have been identified for both researchers
and participants. Some researcher barriers include
lack of knowledge or understanding about
culture differences among racial
and ethnic minorities that can result in ineffective
communication strategies, and that can affect
both recruitment, enrollment, as well as retention. Another barrier
is incorrect assumptions about the effectiveness when transferring information
from one group to another. The inappropriate
use of recruitment strategies among racial
and ethnic minority groups that were developed
for white participants, and the lack of knowledge of how
to adopt recruitment materials culturally and linguistically. Failure to facilitate
culturally sensitive and meaningful discussions and informed consent to ensure
a truly informed choices in the enrollment process
is another example of a barrier. On the participant’s side,
mistrust, fear, or a lack of confidence
in the research enterprise can contribute as a barrier. Logistical concerns
including need for childcare, scheduling conflicts,
lack of transportation, are also barriers. Appropriate support
to research-related factors, such as lengthy
consent documents, and lack of adequate information
about clinical research, can serve as obstacles,
as well. Overt and subtle forms
of racism and discrimination, operating at multiple levels,
can play a role in addition. Historical mistreatment
in medical research, such as the Tuskegee
syphilis study that started in 1952
and lasted — 1932, excuse me,
and lasted for 40 years, is another important
context to consider. The legal status
of an individual and the stigma associated with
the clinical condition that they are experiencing may
provide barriers to enrollment. So how can researchers increase
or enhance the diversity of participants
in clinical trials? They may need to employ efforts
that address culturally and linguistically-correct
recruitment strategies to facilitate the engagement
of different demographic groups. Such efforts can increase
the likelihood of a greater rapport
and trust-building between study staff
and participants and improved adherence to study
protocols by the participants. Translational materials
into appropriate languages is important. Including families and
communities in the dialogue and partnering with community
organizations can go a long way. And including investigators
and staff from the same communities
as participants, and retaining those staff
and interviewers over time to ensure continuity, has been show to be
associated with better outcomes. Strategies for recruitment
should be based on both knowing
what motivates participants and addressing barriers. One case study example is
the Diabetes Prevention Program. The Diabetes Prevention Program
is a multicenter, randomized control trial, designed to test whether diet
and exercise or medications can prevent or delay the onset on type 2 diabetes
in individuals at risk with impaired
glucose tolerance. This study used a variety
of recruitment strategies to reach a diverse, a very diverse,
representative sample. It was conducted
at 27 clinical centers around the United States. The trial enrolled
over 3,000 participants, 55 percent were white, and 45 percent were
from minority groups at high risk for the disease,
including African American, Alaska Native, American Indian,
Asian American, Hispanic or Latino,
or Pacific Islander. The trial also recruited
other groups at high risk for type 2 diabetes, including individuals
over the age of 60, women with a history
of gestational diabetes, and people with a parent,
brother, sister, or child who had type 2 diabetes. This study utilized
a variety of recruitment strategies to reach a diverse
representative sample for prevention trials. The program looked
at recruitment approaches, how they performed, and their cost to find the ones
that were most effective. Some of the lessons learned
were that it’s important to employ methods
for ongoing assessment and revision of recruitment
strategies, as needed. A range of recruitment
strategies may be useful. The most effective methods for
recruiting potential subjects may vary according
to gender, age, and race, ethnicity
of those individuals. Some recruitment strategies
require more or less time on the staff, on the part of staff,
to randomize a participant. And stepped screening
may make it easier to identify
and recruit volunteers who understand the requirements
of the study. Interestingly, the findings of one of the DPP
investigators indicated that attempts to recruit
older individuals might need to concentrate
on direct mail since these individuals
may be less likely to participate in screenings
and community events, or to see posters
or newsletters, or to see emails. Now that we’ve covered
facilitators and barriers to recruitment
for a range of demographics, these next slides
will focus specifically on sex and gender in health and disease
and biomedical research. Inclusion of women
is critical because of sex
and gender differences found in certain diseases. And so there are
crucial variable to consider when conducting research. Though the term sex and gender
are often used interchangeably, they are defined as follows. Sex is the classification of
living things as male or female, according to their reproductive
organs and functions assigned by
chromosomal compliment, according to the Institute
of Medicine Report, published in 2001.
Every cell has a sex. It’s either XX or XY.
Sex begins in utero. Sex effects health and disease
from risk to treatment response. Gender, in contrast, is a
multidimensional psychosocial construct that integrates roles,
behaviors, expressions, and identities of girls, women, boys, men,
and gender diverse people. It influences how people
perceive themselves and interact with others. It begins after birth,
affects behavior and perception, and health.
And in the United States there is no agreed
upon definition of gender. It is important to understand
the underlying variables contributing to differences between health conditions
seen in women and men. Slide 11 highlights sex
as a biological variable and studying sex across the
biomedical research continuum. There’s still a paucity of data
related to female cells and animals
at earlier research stages, basic research,
and preclinical research. And overreliance
on male animal models and cells may obscure findings
of key sex differences in health processes
and outcomes. So as science has progressed, we have learned less
about female biology than we have
about male biology. As a result, NIH issued guidance
on sex as a biological variable and this policy was formulated
as a guiding principle for the biomedical research
continuum. Essentially,
studying both sexes across the biomedical
research continuum is a good practice
for everyone. Consideration of sex
may be critical to the interpretation,
validation, and generalizability
of research findings. And less attention
being paid to females has resulted in a mismatch
in our understanding about male
and female biology. The NIH SABV policy,
in a nutshell, states that NIH expects
that researchers will factor sex as a biological variable
into their research designs, analyses, and reporting
for vertebrate animal and human studies. That policy went to affect
in January of 2016. NIH expects researchers
to study both sexes and to provide
a strong justification for studying just one. For example, if a researcher
is studying a disease or condition that only affects
women, like ovarian cancer, this would be a strong
justification to exclude males. And if an investigator
is studying prostate cancer, which only affects men,
that would be a strong just justification
to exclude females. Research protocols that exclude
either females or males will be evaluated by
other scientific experts through the NIH
peer review process in the context of what is known,
available methodologies, and other
relevant considerations when accounting for sex
as a biological variable. There is no
one-size-fits-all approach to addressing this policy. Adequate considerations of
both sexes in experiments, and desegregation
of data by sex, allow for sex-based comparisons and may inform
clinical interventions. This case study example,
the Women’s Ischemia Syndrome Evaluation Study,
or WISE, is a perspective study involving a cohort of over 900
clinically stable women referred for
coronary angiography to evaluate ischemic
heart disease. Ischemic heart disease is the
leading cause of death of women and presents
a treatment challenge due to a lack
of evidence-based management. The aim of the study
was to improve diagnostic testing for
ischemic heart disease and to explore
female-specific pathophysiology. There are known sex differences
in ischemic heart disease presentation
and pathophysiology. For example,
microvascular involvement, involvement of the small
blood vessels in a heart, is more common in women
than in men, and is not detectable
by conventional angiography. Highlighting the need
for different methods for diagnosing
cardiac ischemia in women. In a ten-year follow-up
of the WISE study, 20 percent of deaths
with an all-cause mortality rate in 115 cardiac deaths
for a 12 percent mortality rate, were reported for the women
who had clinically stable but detectable ischemia. And that’s why this is important
for studies like this to be performed that look
for sex-specific patterns, sex-specific diagnostic
testing, and sex-specific treatment
and interventions, excuse me. The Contemporary Heart Failure
clinical trials is another case study that we’ll
be providing here as an example. This paper was published
in JAMA Cardiology and the objective
of this study was to look at enrollment
patterns by age, sex, and race/ethnicity
and to compare the enrollment in the studies to the
demographic makeup of the U.S. based on epidemiologic studies
of specific heart failure types. In this study, women were
underrepresented in cumulative heart failure clinical trials
at the rate of 27 percent when compared to
their representation in the general population of
individuals with heart failure, which was approximately
50 percent. This study also found
that the enrollment of women was significantly associated
with the mean age of participants
in heart failure trials. Exclusion of older participants
may be due to strict inclusion
and exclusion criteria. Older participants
may have comorbidities that them ineligible
for trials. But it’s important to address
these limitations to enrollment to ensure
appropriate representation of all age groups. For more information
on inclusion, the NIH Office of Research
on Women’s Health has created the
Outreach Inclusion Toolkit to help principle investigators
and their teams fulfill their responsibilities
related to inclusion of women in clinical research
supported by NIH. We provide information
on best practices, federal laws,
regulations, and NIH policies, as well as a variety
of case studies featuring researchers’
actual experiences with including women
in their studies. They share lessons learned. The purpose of clinical research
is to understand how the human body works
and to apply that knowledge to improve health
outcomes for everyone. For clinical research
to be truly useful, it must reflect the populations that are affected
by the diseases and that it intends to help. Given important biological
differences by age and sex, and other differences
by race and ethnicity, it’s important
to integrate inclusion as a guiding principle
for productive science with the aim
of advancing health. Integration of sex and gender,
race/ethnicity, and age in clinical research
is essential to productive, generalizable, and reproducible
scientific inquiry. Studies have shown
that varied approaches are needed to recruit
diverse populations. It is imperative
for clinical trial participants to represent the full
spectrum of individuals affected by diseases
to provide them best, most accurate, and most
complete information possible. Ensuring appropriate enrollment in clinical research
promotes health equity. So here’s some questions
to test your knowledge. Which of these are potential
barriers for recruitment and retention of women and
minorities in clinical trials? Is it: a) fear and distrust
of the research enterprise, lack of transportation, c) interference with work and
family responsibilities, or d) all of the above?
The answer is d. All of these factors
contribute as barriers to recruitment of women and
minorities in clinical trials. Which of these are not
facilitators to recruitment and retention
of women in clinical trials: a) culture
and linguistic adaptation of recruitment strategies, b) translation materials
into appropriate languages, c) lack of culturally and linguistically competent
research staff, d) including families
and communities in a dialogue, and e) partnering with
community organizations? The answer is c. Culturally and
linguistically competent staff can facilitate participation
in clinical trials by serving as a resource and
holding meaningful discussions about informed consent
and other issues to ensure truly
informed choices. We hope that this session
helped you to understand why inclusion is so important. Including women, minorities,
and individuals of all ages is crucial to the integrity
of clinical research. The purpose of research
is to inform and improve
the health of everyone. Turning discover into health
is a crucial mission for all of us in the biomedical
research enterprise, and inclusion is
a critical component of that. Thank you.