How to ensure participant diversity in clinical trials
While it would be impractical — and unnecessary — to try to conduct trials in every single recognized patient population, researchers should design trials, choose study sites and recruit patients in a way that generates data about the safety and efficacy of drugs for as much of the population as possible. This could mean conducting studies in particular places or merely increasing the numbers of patients recruited to include less-represented populations.
Matching target populations is good clinical practice. If a disease is more prevalent among a certain population by a given percentage, for example, then that population should be represented in a study by the same approximate percentage. Some populations may be more at risk for certain diseases, such as diabetes or heart disease, the FDA wrote in a January 2018 memo, noting that “it is important for patients in those populations who are more likely to be treated for a condition to be included in a trial.”1
In June 2019, the FDA issued a draft guidance clarifying its expectations for population diversity in clinical trials2 to satisfy the FDA Reauthorization Act of 2017 (FDARA), which mandated that the FDA issue guidance on eligibility requirements in general.3 The guidance document recommends that clinical trial sponsors think carefully about whether exclusion criteria are truly appropriate and that they use adaptive trials and address logistical barriers — including financial and transportation issues — to study participation. It also advises researchers to include a broad range of ages when recruiting for trials.
“Over the past few decades, FDA policy initiatives have focused on promoting enrollment practices that lead to clinical trials better reflecting the population most likely to use the drug if the drug is approved, primarily through broadening eligibility criteria,” the agency wrote in the introduction to the draft guidance. “Despite these efforts, challenges to participation in clinical trials remain, and certain groups continue to be unnecessarily underrepresented in many clinical trials.”
The draft guidance was issued in an effort to remedy the gap and suggests several approaches that clinical trial sponsors can take to “broaden eligibility criteria, when scientifically and clinically appropriate and [to] increase enrollment of underrepresented populations in their clinical trials.” These under-represented groups include women, children and the elderly, certain minorities, and those facing geographical challenges to clinical trial participation.
Attaining gender balance in studies
Exclusion of women — or failure to report research data by sex — prevents identification of differences that could influence treatment options, Karen Taylor, research director of the Deloitte UK Centre for Health Solutions, wrote in a September 2019 Deloitte blog post.4 For example, two-thirds of Alzheimer’s patients are women and women are twice as likely as men to develop the disease. Until recently, researchers assumed this was due to the typically longer lifespan seen in women. But recent information gleaned from female-centric studies suggest that hormonal and genetic differences may play a crucial role, Taylor said.
Similarly, women experience major endocrine changes throughout their lives, particularly during puberty, pregnancy and menopause. These are known to increase the risk of depression. But less than 45 percent of animal studies on anxiety and depression use female lab animals, Taylor noted. The result? Treatments could be less effective for women compared to men and/or have more debilitating side-effects for women.
Heart disease is another condition in which women’s experiences often differ widely from men’s. Women have a higher heart attack death rate even though men have more heart attacks than women, the FDA noted in a July 2019 memo on its “Women’s Health Research” web page.5 Women also are more susceptible to drug-induced cardiac arrhythmias. Their inclusion in research for cardiovascular disease treatments is critical to ensuring that safe and effective drug treatments are available for female patients, but studies in this area have traditionally focused on male patients.
And some drugs — such as immune checkpoint inhibitors in cancers — may show greater efficacy in men than women, Nicole Richie, principal clinical science business strategy leader for immunology, infectious diseases and ophthalmology at Roche’s Genentech subsidiary, said during a panel discussion at the Biotechnology Innovation Organization’s 2019 conference, according to MedCity News.6
“FDA’s Office of Women’s Health (OWH) supports research to provide valuable insight into sex differences in the diagnosis and treatment of cardiovascular disease,” the agency wrote in its July 2019 memo. OWH has also worked to support studies on sex differences in other disease states.
Pregnancy, a condition that often excludes women from clinical trial eligibility, is another issue that traditionally has been largely ignored in pharma research. Pregnant women — and the fetuses they carry — are generally considered to be a vulnerable population that should be protected from most of the risks associated with clinical research. Traditionally, clinical trials have excluded pregnant women — and dropped patients who become pregnant during the course of a study — due to concerns about potential harm to the gestating fetus. But the FDA now argues that pregnant women should also be considered when recruiting for studies.8
Many women need to take medications while they are pregnant, the FDA noted in an August 2018 memo on its “Women’s Health Research” web page.7 Some women take medicine for health problems such as diabetes or high blood pressure that can start or get worse during pregnancy. And some women may use certain drug products before they find out they are pregnant.
Not all analysts agree that women are significantly underrepresented in clinical research. Labots, et. al. concluded after a review of publicly available data that there was “no evidence of any systematic under‐representation of women” in clinical trials.
“Our data showed that, overall, women are studied in adequate proportions, and that some type of gender subgroup analysis is performed for most drugs that are approved,” they wrote in a paper published in the April 2018 British Journal of Clinical Pharmacology.
The review analyzed the fraction of women participating in phase 1, 2 and 3 trials, to determine the extent to which women have been included in clinical research. The 38 drug trials reviewed — those that had sufficient publicly available data — enrolled a total of 185,479 patients, 47 percent of whom were female and 44 percent male. Gender was not reported for 9 percent of the participants.
The paper noted that the number of participants varied with the phase of the trial. In phase 1 trials, just 22 percent of patients were female, compared to 48 percent and 49 percent, respectively, in phase II and III studies. When compared with U.S. disease prevalence data, 10 drugs had a greater than 20% difference between the proportion of females affected with the target disease compared to representation in clinical trials.
Bello-Irizarry et al. seemed to agree in a 2017 paper, which reported that 48 percent of patients participating in clinical trials in 2016 were women, up from 40 percent in 2015.9
Richie conceded that the balance between male and female populations in clinical trials is improving, but added that it’s “still not quite to par,” MedCity News reported.
So, for researchers seeking to boost female enrollment, what steps can be taken to improve recruitment and retention of women?
Heidari et. al. said journal editors — the “gatekeepers of science,” as they put it — can play a key role by applying to submissions the Sex and Gender Equity in Research (SAGER) guidelines, a comprehensive procedure for reporting of sex and gender information in study design, data analysis, results and interpretations of findings. The guidelines, created by The European Association of Science Editors (EASE), aim to integrate sex and gender assessment into the editorial process. Knowing that this information must be included in published results can also affect the clinical trial design process, prompting researchers to pay greater attention to gender diversity during study design, data analysis, results and interpretation of findings.
But a random sample of 100 journals and the EASE and International Society of Addiction Journal Editors groups showed that 75 percent were unsure or unwilling to introduce sex and gender considerations as requirements in instructions to authors.
The SAGER guidelines were developed over a three-year period by a multidisciplinary group of academics, scientists and journal editors by means of literature reviews, expert feedback and public consultations at conferences. Key features of papers that apply SAGER guidelines include:
- If only one sex or gender is included in a study, the title and abstract should specify the sex of participants, whether in a human trial or in earlier phases. In technology or engineering work, authors should indicate if the study model was based on a single sex or the application considered for use by a specific sex.
- The introduction should report, if relevant, previous studies that show presence or lack of sex or gender differences or similarities. If such studies are lacking, the authors should explain whether sex and/or gender may be an important variant and if differences may be expected.
- In discussing methods, authors should report how sex and gender were considered for design of the study, ensure sufficient male and female representation and justify reasons for exclusion of any sex or gender.
- When results are presented, data should be reported disaggregated by sex, with an analysis of sex and gender differences where appropriate. Discussion should include anatomical and physiological differences between men and women, along with social and cultural variables, such as socioeconomic status and education. However, authors should not conduct a post-hoc, gender-based analysis if the study design does not enable meaningful conclusions.
- In epidemiological studies, the impact of factors such as socioeconomic variables on health problems should be examined for all genders and analyzed from a gender perspective.
Bello-Irizarry et. al. also pointed out the importance of careful use of terminology both in clinical trial design and in reporting results. Subgroup classifications historically have been inconsistent, which “leads to potentially confusing and inaccurate collection and analysis of data.” For example, the terms sex and gender have been used interchangeably in some FDA and NIH documents, although they have distinct definitions that should be used consistently to describe research results.
Taylor suggested that technology can help solve many problems associated with enrolling specific patient populations. Increased use of mobile technology and social media platforms can help improve communication both between researchers and patients and among research sites, for example. Telemedicine can also be a game-changer when it comes to extending patient reach by giving patients access to mobile and video encounters with health care providers, she said. Virtual clinical trials mean that any qualifying patient who wants to participate in clinical research might not be limited by location.
And the FDA recommended in its July 2019 memo that drug sponsors should consider pregnancy exposure registries, studies that collect health information from women who take prescription medicines or vaccines when they are pregnant. Information is also collected on the newborn baby. This information is compared with women who have not taken medicine during pregnancy.
Including both ends of the age spectrum in studies
Age is another key area in which diversity can be lacking in clinical research. Even where efforts are made to include minorities and women among study patients, the age ranges are often fairly narrow. Pediatric and elderly patients may be left out — in some cases, this is deliberate, while in others it’s an oversight.
The FDA often requires drug sponsors to conduct an additional trial focused on a certain age group if a large percentage of patients likely to use the product fall into that age range. That includes both ends of the age spectrum. If people over age 75 are more likely to use a drug, that population must be represented in study participant makeup. And any drugs intended to be labeled for use in children must be tested in children of the appropriate age range. But these requirements do not address the significant number of drug products that are prescribed to children, adolescents and the elderly even though little-to-no data exists on how those medications perform on safety and efficacy metrics in those populations.
Inclusion of children in clinical research for drugs primarily aimed at adults is important because of the paucity of approved drugs available that are labeled for use in children. That means doctors routinely treat children with a drug that has been tested and approved for adult use but not in children. Other drugs used in children may have been tested in a different group of juvenile patients; for example, a drug may have been tested in adolescents, but not in neonates, according to a March 2017 FDA memo for consumers.
Children’s responses to drugs can’t always be predicted from data collected in studies of adults, or even from studies of children of different ages, the memo noted. As children grow, their metabolisms change, so the way a given drug affects a baby could be very different from its action in a teenager.
Therefore, conducting a pediatric study of a treatment that is aimed primarily at a broader, adult population could be useful, particularly if the targeted disease or condition is one that is known to occur in children or adolescents. Alternately, drug sponsors can conduct a pediatric arm of a larger, adult-targeted study to gain vital data about a drug’s behavior in children of various ages.
There are challenges to enrolling children in clinical trials, particularly for drugs not specifically targeted for pediatric patients. In the case of these patients, parental buy-in is necessary for enrollment, and many parents may be reluctant to enroll a child in a study for an adult-focused drug.
Similarly, researchers are often reluctant to conduct trials in other populations considered vulnerable, including the elderly, pregnant women and cognitively impaired people, noted Taylor in the Deloitte blog post. Concern over doing more harm than good can lead to these populations being excluded from trials.
But this has negative impacts on the data generated in clinical trials. For instance, because elderly people are often omitted, doctors have limited information on how a particular drug might affect older patients, both in terms of safety and effectiveness.
The National Institute on Aging (NIA) at NIH, the Centers for Disease Control and Prevention (CDC), and the Administration for Community Living (ACL) are collaborating on the Recruiting Older Adults into Research (ROAR) project to encourage older adults and their family caregivers, including under-represented populations, to consider participating in research. The coalition started in 2015, with a focus on Alzheimer’s and dementia research. The group offers a toolkit that drug sponsors and clinical researchers can use to collaborate with aging services and other groups about research participation.11 The collection of customizable materials such as PowerPoint presentations and flyers — available in English, Spanish and Chinese — features information on:
- Why research is important to healthy aging;
- What volunteers need to know about research studies; and
- How older adults can make a difference by participating.
These resources can be helpful in addressing a common barrier to enrolling elderly clinical trial patients: lack of information about the availability of clinical trials. But as with other marginalized communities, elderly patients often also face financial and logistical constraints that are less common in younger and middle-aged adults.
Additionally, elderly patients are more likely to have chronic health conditions, or to be managing multiple conditions — factors that often lead to clinical trial exclusion.
Another challenge related to enrollment of older patients is ensuring that study participants accurately reflect the target population they are supposed to represent. In 2012, Beatrice Golomb et. al. investigated whether older age magnifies differences among individuals in a given population by looking at self-rated levels of activity compared to others of the same age.12 They found that successively older participants (aged 40-79) reported successively greater activity relative to others of their age, using a combination of self-rated and objective health predictors, including general self-rated health, depression score, sleep, tiredness, energy, body mass index, waist circumference, serum glucose, high-density lipoprotein-cholesterol, triglycerides and white cell count.
The analysts concluded that some health predictor associations with age were, paradoxically, consistent with greater apparent health in older age for study participants. Therefore, study participants may not necessarily be representative of the population they are intended to reflect, and departures from representativeness may be amplified with increasing age.
In other words, “the older the age, the greater the disparity may be between what is recommended based on ‘evidence,’ and what is best for the patient,” Golomb et. al. wrote.
Overcoming geographic barriers to participation
Gender and age are not the only states at risk for under-representation in clinical trials. Isolation from both study sites and information about pertinent clinical trials — whether due to geographic, financial or community factors — can leave large swaths of potentially treatable patients out of the general pool of clinical trial participants. This puts those populations that are less-represented in clinical trials at greater risk of treatment failures, diversity and inclusion, consultant Joseph Gaspero noted in a June 25, 2018, Kaleidoscope Group blog post.13
For example, genetic differences could render anti-HIV medications ineffective in some patients. Lack of information about how new drugs work in people of different genetic make-up makes it difficult for physicians to determine whether a drug will be effective for all patients.
While primarily discussing genetic variations in racial and ethnic groups, which can cause different reactions to some drugs compared to the larger population, the factors that Gaspero identified as barriers to clinical trial participation — financial considerations, difficulty accessing study sites and mistrust of the clinical trial process itself — are applicable to patients who are separated from clinical trial resources by geography or the culture they inhabit, as well as those facing financial or logistical constraints.
Just as patients of different races and ethnicities have genetic differences that affect disease presentation and responses to treatment, patients from geographic or cultural communities that are traditionally under-represented in clinical research may show treatment responses outside the norm seen in the broader population. For example, both ethnic and geographic differences have been noted in cancer incidence, prognosis and treatment outcomes.
For instance, in the development of a drug used to treat breast, lung and other cancers, research showed marked population differences as early as phase 1, noted Daniel Tan et. al. in a January 2016 paper published in the Journal of Clinical Oncology.14
Therefore, clinical researchers must consider collection and analysis of subpopulation data early in clinical development planning, Bello-Irizarry noted. Key factors include disease prevalence, protocol development, operational considerations and regulatory strategy and approval pathway.
“In terms of subgroup analyses, a clearer understanding of potential differences in subpopulations will occur when more pharmacogenetic data are available and included in clinical studies to correlate disease burden and responses to medical products with genetic makeup,” Bello-Irizarry et al. wrote. “This will help in the overall understanding of variations in drug responses based on genetic, clinical and environmental factors; and to target treatment appropriately.”
Populations that are more likely to have certain health issues, or to have multiple conditions — such as minorities and the elderly — are often precluded from participating in clinical trials, according to an October 2018 article in Biospace.15
And even when such patients are both willing and able to participate, many studies routinely include the existence of potentially complicating additional conditions among their exclusion criteria. This approach, however, ignores the medical reality that many patients diagnosed with one condition may also have other conditions.
Income can be a barrier as significant as geographic distance, the Biospace article notes. Patients who can’t cover treatments that are part of the trial, who can’t afford to take time off from work or commute long distances for the study, or who don’t have easy access to childcare, for example, may not be able to participate in a research study. These factors often affect minorities, but also apply to the elderly and parents of pediatric patients, as well as people in economically disadvantaged and/or geographically remote communities.
The cost of gas to drive to a study site and parking at the facility could be a dealbreaker for some potential patients, noted experts during a panel discussion at the June 2019 Biotechnology Innovation Organization’s annual conference in Philadelphia. The panel discussed ways to address barriers to improved diversity in clinical trials, according to the MedCity News article.
“I can either take my chances in a clinical trial that may or may not work or put food on the table,” said Dana Dornsife, founder of the Lazarex Cancer Foundation, the story noted. “Most parents choose food.”
Some of the barriers to trial enrollment from among these populations may be logistical. If a trial requires frequent visits to specific sites, for example, this could discourage participation by patient groups that require transportation and/or caregiver assistance, such as the elderly, children, disabled patients and cognitively impaired people, as well as patients from rural or remote locations.
For patients who already must visit a clinic frequently — for management of one or more chronic conditions, for example — additional site visits to participate in a clinical trial could be a particular burden and disincentivize them from participating in any studies.
And some communities, due to a history of abuses in the area of medical experimentation, may have a deep-seated and longstanding mistrust of medical research that discourages participation in clinical trials, Dornsife and Stephanie Monroe, executive director of African Americans Against Alzheimer’s, said in the MedCity News article.
The panelists agreed that drug sponsors and clinical researchers need to be able to demonstrate cultural competency to build trust in the clinical trial process and to ensure that members of these communities are adequately represented in pertinent studies. One way to do this is to ensure that clinical trial investigators themselves come from diverse backgrounds; this can help reassure reluctant patients that the trial staff have a true understanding of their community and culture.
Implementing FDA Guidance on Exclusion Criteria, Trial Design
So, what must clinical researchers do to increase diversity among their patient populations? The FDA recommends starting by broadening study eligibility criteria, thus encouraging more diversity among study populations. In particular, the 2019 FDA draft guidance recommends that drug sponsors:
- Examine exclusion criteria during trial protocol development to determine if they are necessary to ensure patient safety or to achieve study objectives. For example, if an investigational product poses unacceptable risks to patients with advanced heart failure, those individuals should be excluded. But exclusion of all heart failure patients may not be warranted; if risk is less to those with milder forms of the disease, the exclusion criteria should narrowly define exactly what level of disease should be excluded.
- Consider whether criteria from phase II studies can be eliminated or modified to avoid unnecessary, diversity-hindering limits on the Phase III study population. Phase II criteria, which frequently are transferred to phase III protocols with little evaluation, can be more restrictive than necessary. Excluding patients for certain reasons — such as drug-drug or drug-disease interactions, or concerns about a given population’s vulnerability to a particular toxin — may be justified. But some exclusion criteria may be removed or modified based on data available from the Phase II trial or other relevant studies. The guidance also noted that, in some cases, the development program may include specific studies in higher-risk populations at sites with expertise in that type of patient.
- Base exclusions on an appropriate measure of organ dysfunction, making sure the criteria do not unnecessarily exclude certain populations due to risks to those with impaired organ function.
- Consider including children (2 to 11 years old) and adolescents (12 to 17 years old) in confirmatory clinical trials when safe and appropriate.
The trial design and methodological approaches chosen for a clinical trial can also have a significant effect on study population diversity. The draft guidance recommends that sponsors consider various trial designs and methodologies to help enroll broader populations. Some specific steps the document suggests include:
- Characterizing drug metabolism and clearance, early in clinical development, across populations that may metabolize the drug differently, such as the elderly or patients with liver or kidney dysfunction. This approach can help avoid later — possibly unnecessary and population-limiting — exclusions.
- Considering an expansion cohort, which may also allow dose modification and be used to assess a reasonably safe dose in specific populations that may have significant differences in systemic exposure to the investigational product, such as pediatric or elderly patients, or those with organ impairment.
- Make use of adaptive clinical trials. The pre-specified trial design changes during these types of studies can include altering the trial population, thus helping to boost diversity. An adaptive design, for instance, might start with a narrow population due to safety concerns and later expand to a broader population based on interim trial data and external data. Adaptive trials may also aid broader enrollment in cases of uncertainty about whether a drug would be effective in certain populations; an interim analysis could enable adjustment of patient profile based on pre-specified response criteria.
- Consider a pediatric development program early in the trial design process. Where there are safety concerns, enrollment could be staggered based on age, with older pediatric patients added first, followed by younger ones. This approach needs to be justified with a clear scientific rationale, such as lack of completed juvenile toxicity studies in younger patients, the guidance says.
- Consider a broader target patient group as part of the secondary efficacy and safety analysis, even if the primary analysis population is narrowed. This could include enrollment of patients across the full spectrum of disease severity, even if the primary endpoint is based on a particular disease stage.
- Consider including pharmacokinetic sampling for women who become pregnant during a trial when appropriate and when sufficient assurances of safety exist. The risks to the pregnant woman and fetus must be reasonable relative to expected benefits. This approach could provide important information about drug metabolism during pregnancy, a time when physiology can change significantly.
Sharing real-world diversity solutions
While the FDA targets diversity from the regulatory angle, many within the clinical research world also recognize that increased diversity in clinical study patients leads to more complete data about a drug’s capabilities and risks.
For instance, Karien Stronks et. al. noted in a 2018 paper published in BMC that, while randomized controlled trials (RCTs) have long been seen as the gold standard in evidence-based medicine, it cannot be assumed that RCTs will produce data applicable to all patients.16 Evidence shows that disease manifestation and progression, along with treatment outcomes, vary among patient groups. For example, there are notable sex differences in heart disease epidemiology. Similarly, black patients respond differently to antihypertensive drugs.
To begin to address the need for diversity in clinical research has led to a new field of study, sometimes called “recruitmentology,” that evaluates the effectiveness of recruitment strategies in enrolling minorities and other less-served populations in clinical trials. As a result of such evaluation, a broad range of recommendations has arisen within the clinical research industry.
Stronks et al. noted that only 25 percent of studies in 2011 reported sex-specific results, according to 86 original articles in medical journals that reported on NIH-funded studies. This showed little improvement compared to similar analyses conducted five years earlier.
Another option could be what Knepper and McLeod dubbed “ethnobridging” studies; a drug assessed in a broad clinical trial could then be tested in a smaller number of people from a less-represented population. This approach could be used to include groups defined by gender, age, geography or culture, as well as racial or ethnic populations. Such smaller studies could provide insights into side effects, appropriate dosing levels and other key factors for the under-represented populations.
They noted that Japanese researchers often use this approach. Medications deemed safe and effective from global trials are subsequently tested on Japanese patients.
But not all clinical trials should automatically include subgroups, Stronks et al. cautioned. Ensuring that subgroups are large enough to allow for meaningful analysis would have a significant impact on study costs, which is another important consideration in designing a clinical trial.
“This implies that confronting diversity in clinical research starts with formulating hypotheses as to why diversity does or does not matter in a specific case,” they wrote.
Several methods are available for drug sponsors and clinical researchers to identify those diversity issues that are critical to health outcomes for each study. These include:
- Re-analysis of past trials, including examination of unexpected phenomena and outliers, along with looking at differences in treatment outcome by subgroup;
- Observational studies, including review of biomedical and pharmacodynamic studies that indicate how age, gender, ethnicity or other factors affect prognosis and treatment effects;
- Databases of routine health care, which can let researchers explore effect modification in treatment outcomes; and
- Qualitative studies to help identify those diversity issues that matter for health outcomes.
Funding organizations, such as the NIH, should also facilitate attention to the diversity issue throughout all processes, including those by which relevant committees review funding proposals, Stronks et al. suggested.
But it’s not enough to just look at diversity generally. The way diversity is conceptualized is crucial, Stronks et al. wrote. The NIH and the EU, for instance, focus on broad subgroups, such as women or older people. But additional dimensions may be needed to develop a broad range of diversity-sensitive clinical evidence.
And Luther Clark et. al. identified five critical barrier categories that clinical trial designers must address to improve diversity in studies in a May 2019 paper.17 Although the paper focused on inclusion of racial and ethnic minorities, the barriers identified also affect other underserved patient populations, including the elderly, members of poorer communities and those geographically isolated from study sites. The barrier categories are:
- Mistrust, stemming from lack of understanding, fear based on lack of knowledge or on past community experience, stigmas associated with study participation and discomfort with the communication style of investigators and staff;
- Lack of comfort with the clinical trial process, including mistrust of the process, fear of being a “guinea pig,” family members’ opinions and lack of information;
- Lack of information about clinical trials, often with accompanying fear and concern about stigma associated with participating;
- Time and resource constraints that make clinical trial participation, including the financial burden, time commitment, transportation and logistics; and
- Lack of clinical trial awareness, or simply not knowing about the existence and importance of clinical trials.
To address the first three barriers, clinical investigators, staff and research sites must gain the trust of under-represented patient groups. Clark et al. suggested that cooperation with trusted individuals and community groups — including patients’ regular healthcare providers, community leaders and, in some cases, faith-based organizations — can help to build trust.
“Trust is the cornerstone of clinical trial recruitment and retention,” Thelma Hurd et al. agreed in a Feb. 7, 2017 paper in Clinical Trials. “There is an urgent need to better understand the complex interactions between trust and clinical trial participation.”18
The paper recommended that drug sponsors and clinical researchers look to business strategies for building trust for inspiration; some of these approaches may be transferable to the clinical trial setting. The challenge is building this trust “under conditions of significant emotional stress and time constraints among people who do not know each other and have never worked together before.”
Swift trust occurs in temporary organizational structures, which can include quick starting groups or teams. This type of trust operates during the recruitment and early active treatment stages of the clinical trial process, Hurd et al. said. Traditional trust, or trust built gradually over time, comes into play during the active treatment and surveillance stages of clinical trials.
Clinical researchers must exploit both types of trust to recruit and then retain patients, especially those in under-represented groups. Clinical trial teams should focus on the process of trust building when dealing with under-represented — and potentially more sensitive and study-shy — populations, rather than charging forward to the outcome, e.g., enrollment of more diverse patients. This involves developing, for each study, consistent ways to understand, measure, and manage trust between study staff and patients.
Logistical and financial considerations are best addressed by practical, tangible patient services, such as providing transportation for those who need it, providing flexible site visit hours for patients and using mobile technology, even providing cell phones for patients who don’t have them, Stronks wrote. Use of mobile technology and social media platforms can also improve communication between study staff and patients, further improving trust in the clinical trial process.
Appropriate compensation for study participation can also encourage more patients with financial concerns to enroll in clinical trials.
Finally, patients cannot enroll in trials unless they know those trials exist, and they won’t enroll unless they appreciate the value of the research. Patients’ regular physicians can be key contacts. Increasing awareness by partnering with patient advocates and social media groups for people with particular illnesses can also be a good approach.
In a July 2019 blog post, Clinical Research Pathways noted that physicians can play a key role in efforts to diversity clinical trial patient populations.19 While the suggestions were mostly focused on minority recruitment, one factor stands out: Patients are more likely to enroll in clinical trials at the recommendation of their healthcare provider. That means that effective recruitment protocols could include partnerships with healthcare providers that not only treat the target disease, but that also have patients in under-represented categories, such as women, children and the elderly.
- “FDA Encourages More Participation, Diversity in Clinical Trials.” FDA memo, Jan. 1, 2018. https://www.fda.gov/consumers/consumer-updates/fda-encourages-more-participation-diversity-clinical-trials.
- “Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs.” FDA draft guidance, June 2019. https://www.fda.gov/media/127712/download.
- FDA Reauthorization Act of 2017. https://www.congress.gov/115/plaws/publ52/PLAW-115publ52.pdf.
- Taylor, Karen. “Why improving inclusion and diversity in clinical trials should be a research priority.” Deloitte blog, Sept. 4, 2019. https://blogs.deloitte.com/centerforhealthsolutions/why-improving-inclusion-and-diversity-in-clinical-trials-should-be-a-research-priority/.
- “Research on Heart Disease in Women.” FDA “Women’s Health Research” web page, June 26, 2019. https://www.fda.gov/science-research/womens-health-research/research-heart-disease-women.
- Dearment, A. “Building trust is key to improving diversity in clinical trials.” MedCity News, June 5. 2019. https://medcitynews.com/2019/06/building-trust-is-key-to-improving-diversity-in-clinical-trials/.
- “Pregnancy Registries.” FDA “Women’s Health Research” web page, Aug. 22, 2018. https://www.fda.gov/science-research/womens-health-research/pregnancy-registries.
- Labots, G., Jones, A., de Visser, S.J., Rissmann, R., and Burggraaf, J. “Gender differences in clinical registration trials: is there a real problem?” British Journal of Clinical Pharmacology, April 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867082/.
- Bello-Irizarry, Sheila N., and Neighbours, Lauren. “FDA Expectations For Diversity Inclusion In Clinical Research.” Clinical Research News, Aug. 15, 2017. http://www.clinicalinformaticsnews.com/2017/08/15/fda-expectations-for-diversity-inclusion-in-clinical-research.aspx.
- “Would Your Child Benefit from a Clinical Trial?” FDA “For Consumers” web page, March 21, 2017. https://www.fda.gov/consumers/consumer-updates/would-your-child-benefit-clinical-trial.
- “Recruiting Older Adults into Clinical Research.” National Institutes of Health, National Institute on Aging, Sept. 18, 2015. https://www.nia.nih.gov/health/recruiting-older-adults-research-roar-toolkit.
- Golomb, Beatrice A., Chan, Virginia T., Evans, Marcella A., Koperski, Sabrina Koperski, White, Halbert L., and Crqui, Michael H. “The older the better: are elderly study participants more non-representative? A cross-sectional analysis of clinical trial and observational study samples.” BMJ, January 2012. https://bmjopen.bmj.com/content/2/6/e000833.
- Gaspero, Joseph. “Diversity in Clinical Trials.” Kaleidoscope Group blog, June 25, 2018. https://kgdiversity.com/diversity-in-clinical-trials/.
- Tan, Daniel S.W., Mok, Tony S.K., and Rebbeck, Timothy R. “Cancer Genomics: Diversity and Disparity Across Ethnicity and Geography.” Journal of Clinical Oncology, Jan. 1, 2016. https://ascopubs.org/doi/abs/10.1200/JCO.2015.62.0096?rfr_dat=cr_pub%3Dpubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&journalCode=jco.
- Burke, Chelsea Weidman. “The Importance of Diversity in Clinical Trials (Because Right Now, It’s Lacking).” Biospace, Oct. 10, 2018. https://www.biospace.com/article/the-importance-of-diversity-in-clinical-trials-because-right-now-it-s-lacking-/.
- Stronks, Karien, Wieringa, Nicolien F., and Hardon, Anita. “Confronting diversity in the production of clinical evidence goes beyond merely including under-represented groups in clinical trials.” BMC, June 2018. https://trialsjournal.biomedcentral.com/articles/10.1186/1745-6215-14-177.
- Clark, Luther T., Watkins, Laurence, Piña, Ileana L., Elmer, Mary, Akinboboye, Ola, Gorham, Millicent, Jamerson, Brenda, McCullough, Cassandra, Pierre, Christine, Polis, Adam B., Puckrein, Gary, and Regnante, Jeanne M. “Increasing Diversity in Clinical Trials: Overcoming Critical Barriers.” Current Problems in Cardiology, May 2019. https://www.sciencedirect.com/science/article/pii/S0146280618301889?via%3Dihub.
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