Bridging the Diversity Gap in Clinical Trials
Melva Covington on strategies to encourage the production of clinical-trial data that more accurately reflects real-world diversity.
According to the FDA, African-Americans represent 12 per cent of the total U.S. population but comprise less than 5 per cent of clinical trial participants. Similarly, Hispanics account for 16 per cent of the total population but just 1 per cent in trials. Compared to Caucasians, African Americans are on average twice as likely and Hispanic Americans are 1.7 times more likely to develop type II diabetes. Yet, they are often underrepresented in studies of promising new treatments. African American men are twice as likely to die from prostate cancer as their Caucasian counterparts, but represent only 4 per cent of prostate cancer clinical trial participants. Cancer is the leading cause of death for the Asian-American population, yet Asian Americans represent less than 3 per cent of clinical trial participants.
This may look like a statistics overdose but is actually the vital signs of an industry that continues to design clinical trials wholly unrepresentative of the wider population impacted by debilitating conditions.
People from under-represented racial and cultural backgrounds are largely not effectively targeted by trial recruiters for studies. Recruiting for clinical trials is, in itself, a challenging task, particularly in an era of more targeted therapeutics with more precise inclusion and exclusion criteria. However, the results in many cases are generalized and applied to the larger population without the examination of data based on the prevalence of occurrence in the real world.
A recent report published by the FDA (FDASIA Section 907) in 2013 presented data on the collection, analysis, and availability of demographic subgroups in clinical trials submitted for review to the Agency. It found that overall, Caucasians continue to represent a high percentage of clinical trial study participants for biologic, drug, and medical device applications. The FDA later produced a 3-point action plan to address how patient disparities might be addressed and prioritized to increase inclusion of under-represented groups in trials.
“In many cases, other racial subgroups were underrepresented,” stated the FDA report. “It remains important that clinical trials include diverse populations, whenever possible and appropriate.”
According to John Lechleiter, CEO of Eli Lilly, writing for Forbes, this diversity gap can lead to sub-optimal development of new medicines and can further exacerbate health disparities in outcomes among racial and cultural groups.
Furthermore, the importance of patient representation from diverse groups in clinical trials is the focus of negotiations on the sixth authorization of PDUFA and addressed under the 21st Century Cures initiative. There is a private public partnership focused on the development of science-based approaches for collecting patient input that is inclusive of patients who have been under-represented in clinical trials.
Why has diversity among clinical trial participants been such a recruitment nightmare for those conducting clinical research within Pharma? It seems almost instinctive that there may be variations in safety and efficacy outcomes of a drug in different groups based not only on genetic variations, but also due to other influences like environmental exposures, multiple comorbidities and patient adherence to medications. These variations in treatment options, healthcare access, utilization and outcomes can be impactful across racial and ethnic groups.
“The pharmaceutical industry is slowly beginning to examine these issues and seek solutions to strategically address them,” explains Melva Covington, Senior Scientist in Global R&D at Sanofi.“However, we have a long way to go.”
“It’s about taking this perspective in more developed countries, such as the United States, and also globally as our exposure to diverse patient populations substantially increases, particularly in emerging markets. It is important that we build effective relationships and partnerships with stakeholders to better understand the dynamics that are associated with treatment, perceptions and health outcomes in these communities,” she tells eyeforpharma.
Covington says it is crucial to ensure that patient diversity in clinical trial populations becomes embedded in the mindset of organizations and reflected in the recruitment process, trial operations and analysis of results. This will help to enhance the value of the trial outcomes for patients, payers and healthcare providers. She believes it ultimately supports the value proposition of products and services.
“The importance of diversity in clinical trials is to ensure that we are doing our due diligence and being as strategic as possible in our efforts. We want to better understand the unmet medical needs of patients who will benefit from a therapy or drug. If we know, for example, that we will have a health condition that impacts a diverse patient population in terms of “race” and ethnicity, then we should be strategically thinking of ways to make sure that those patients are proportionately included early in the recruitment and retention planning process.”
When I say diversity, I mean not only having people who are diverse in terms of their cultural and ethnic background but I am also talking diversity in terms of gender and geographic distribution of rural versus urban areas as examples. You need to really get insight into the problem you are trying to address from multiple dimensions.
According to Covington, this kind of strategy around diversity can be useful in efforts to have more targeted collection of information pertaining to treatment and its associated health outcomes.
What we have developed for our clinical trials is to have randomized trials that are predominantly Caucasian and predominantly male for mainly liability reasons. However, over the last decade or so, there have been initiatives put in place to try to get more females in clinical trials; and we have seen these numbers increase. Although focus over the past 20 years has been directed to this type of recruiting, women remain underrepresented.
It’s also really important to get more diverse patients in trials because if your drug or therapy is to reach a wide range of people in the real world, you want to be more confident that appropriate representation matches the epidemiology of the patient population that’s going to be served.
Diversity can also mean different things, depending on the context in which it is looked. “When I say diversity, I mean not only having people who are diverse in terms of their cultural and ethnic background but I am also talking diversity in terms of gender and geographic distribution of rural versus urban areas as examples. You need to really get insight into the problem you are trying to address from multiple dimensions,” explains Covington.
Covington was ahead of the game, in that her desire to make clinical research more inclusive and diverse began when she was in college. “I was very interested in this area in graduate school; it was definitely a focal point. From a personal perspective, I wanted to look at not only the clinical, social and economic “risk” factors that impacted health outcomes but also examine the protective factors that existed in culturally diverse communities. Specifically, what were the positive things that people were doing to improve their health and promote good outcomes such as proper nutrition and building strong social support networks. Once I finished graduate school, I worked as a member of a public health consortium with the CDC, Emory University and the Morehouse School of Medicine that examined health services research in this manner. So, it really has been a part of my foundation and lifelong work. I think it’s very important as we think about and create a healthcare system that values people and the perspectives that they bring to the table.”
Engaging with underrepresented communities and addressing problematic issues to increase empowerment and dialogue is essential for improved health care services. So, how is this done on the ground?
Covington emphasizes that the process of engaging with patients and building external stakeholders can require a number of different approaches. The end goal is to be truly inclusive and sustaining trust in partnerships. She asserts that patient engagement, particularly with individuals from diverse groups, starts long before a particular clinical trial commences.
“The process of engaging patients is a commitment in which we are not only partnering with different groups, advocacy organizations, and patients, but developing a process in which patients feel like they are a part of our research process, from beginning to end. My work involves looking at real world and secondary data (also known as Big Data) to understand disease and treatment patterns, follow the patient healthcare journey and develop ways to demonstrate its value in improving health outcomes. I am fascinated with how to address this from a strategic and operational perspective within my company, and tapping into the expertise and experiences from my colleagues across functions. This dynamic kind of internal engagement within a matrix organization lends itself to discussing problems and solutions from multiple angles. The goal is to have diverse voices at the table to develop robust and relevant solutions.
“We value the collaboration of patients, advocates and experts. We seek to build relationships and engage in dialogue from multiple perspectives. So that when it comes to conducting research at different points of the drug development process, then we already have those relationships more established and can leverage that to enhance our understanding and impact."
What clinical design parameters and recruitment and retention strategies can be used to increase the engagement of patients from diverse and under-represented sub-populations in research and health interventions?
CISCRP (Center for Information and Study on Clinical Research Participation), a non-profit organization dedicated to educating the public about the clinical research process, conducted interviews with 81 clinical research professionals in 2011. They discussed the top 7 barriers to effective recruitment, which were poor protocols, conflicting studies, poor planning and execution, poor retention support, low public awareness and trust, volunteer concerns (e.g., convenience, timing) and lack of patient incentives to seek alternative treatments. These were issues in recruitment that cut across the board and not just related to recruitment and retention of patients from diverse cultural backgrounds, notes Covington.
“Relative to clinical endpoints, we want to make sure that we hear from patients early in the development process concerning endpoints that are relevant to them and are used appropriately in treatment. Also, we should seek ways to make it more convenient for patients to participate in studies and provide information digitally given the advancements in and proliferation of technology,” she says.
“This supports the concept of engaging with patients where they are, so as to better understand issues and address their needs. This helps us to partner effectively to be co-designers of solutions. Different groups or organizations may be using information and technology in different ways. There is no easy answer and engagement cannot be addressed in a vacuum or with a one-size-fits-all strategy. We want to be as culturally competent and authentic in our collaboration as possible. This, to me, is patient or consumer engagement.”
Covington explains that there are a myriad of strategies that can be employed in order to enhance diversity in clinical trials, such as accessing expertise via engagement with advocacy groups, payers, government agencies, scientists, trade groups and the like. She says these broad partnerships are needed in order to better understand issues and barriers in various communities across patient populations. That is the foundation for designing the trial or intervention in a way that incorporates diversity and helps to sustain volunteers who have been recruited to provide us with their valuable information.
“We have a lot more to do to make sure we, number one, at the beginning of our research process are strategically thinking about who is the patient population that might benefit from a treatment. Secondly, due diligence is needed to make sure that we are effectively connecting with patients (or their representatives), healthcare providers or organizations in the community to identify research sites for partnership. This may involve training new research centers or strengthening the infrastructure of existing ones to better reach out to and serve patients who may be interested in volunteering for a study.”
Another important strategy is to contact and provide information to potential study volunteers using more community-based avenues that are consistent with how people may be accustomed to getting information, such as barber shops, beauty parlors or community centers, for example. Covington states that these non-traditional outreach strategies may go a long way in building valuable relationships and demonstrating commitment.
Ensuring that educational material is clear and culturally relevant based on the character of the community in which you are engaging is critical, she notes. You need to take the time to better understand what this is on the micro-level or consult people and organizations that do.
Is it more difficult to engage culturally diverse populations and does it require a different approach? According to Covington, the answer to this is no, it is not more difficult if you approach it respectfully and include representatives who are a part of the community of interest. She is keen to stress that it is not simply a question of organizations deciding to engage – we must engage and build relationships that are reciprocal. People from diverse backgrounds should also be willing to participate and gain value out of the experience. “It is not a one way street. Many individuals are willing to help, if you ask them and provide the appropriate information to help, if you explain your objectives,” she says. “For example, are we creating a welcoming environment in which people can see what you are trying to do and understand how their partnership can help? Are we engaging with site investigators to communicate our goals and objectives of recruiting diverse patients? Will there still be some resistance or will some still refuse to participate? Probably so to the latter, but you are trying to build long-term relationships with stakeholders in communities impacted by conditions. Pharma can help and bring solutions to improve outcomes. This creates a win-win for all involved.”
There are now many efforts underway to formalize the enhancement of cultural and racial diversity within clinical trials. The Pharmaceutical Research and Manufacturers of America (PhRMA) last year teamed up the National Minority Quality Forum to launch “I’m In,” a national education program designed to engage underrepresented participant populations and communicate the value of clinical trials. “I’m In” identifies and connects with prominent local figures and care providers to encourage patients to enroll. Covington adds that PhRMA has also been very engaged in partnering with the FDA, NIH and PCORI to address these issues from a policy perspective.
Lilly has also launched a first-of-its-kind program which will train, mentor and equip investigators to conduct clinical trials that are well-designed and relevant to diverse patient populations. This is in response to the finding that people are much more likely to volunteer for a trial if their contact person or healthcare provider is familiar with their cultural background.
Sanofi’s CHOICE Initiative is rooted in efforts to be a “Partner of CHOICE” in clinical research and improve patient recruitment and retention in clinical trials. This is done by identifying issues or barriers to recruitment early, targeting resources to improve investigator site engagement and providing a guidebook on an electronic portal (internal) to help navigate users to find answers relative to recruitment and retention, explains Covington.
“We want to know what is it that we can do so that we are the partner of choice when it comes to conducting clinical research and engaging with research sites, advocates and other partners. When we get to the part of the research where we are measuring outcomes, we should have built a platform internally and externally that values these partnerships,” she explains, admitting it is “a lot of work”.
The science bit
How can the clinical trial ecosystem be modernized to better serve underrepresented populations so that they are more easily included in clinical research?
We, as an industry are still working on this. However, there are some basic things to consider. “Specifically, we have worked to increase the proportionalities in clinical trials to more closely match the proportion of the actual sub-groups being impacted by the particular disease or condition. Is the calculation appropriate to ensure that there are enough eligible patients for screening and enrollment for the needed sub-group analysis?” explains Anthony Homer, MS, statistical leader at Sanofi Pasteur. Covington adds, “When you think about it from a technical perspective, you should also consider how the statistical strategy or techniques impact recruitment for certain groups. For example, does the inclusion and exclusion criteria in the protocol eliminate certain patients from eligibility to participate? How might these criteria impact on the ability to recruit or get an adequate sampling of volunteers who represent specific patient groups. What is needed to ensure that these patients are retained to meet study completion goals? Are we targeting and building relationships with the right recruitment sites or healthcare facilities?” ”While ensuring gender diversity within trials is improving, there are experts looking to ensure that the information examined by race and/or ethnicity is more “harmonized,” that is collecting data consistently across various information sources. This helps to maintain consistency in the methodology, data analysis and subsequent interpretation of results", suggests Covington.
There are initiatives under way across industry by organizations (e.g., TransCelerate, the FDA) to look at the tools and techniques to make sure that it is harmonized. When we are looking at different groups, we need to make sure that it is on the same scale or go by the same standards.
Clinical trial diversity is undergoing further evolution in the era of personalized medicine or targeted therapeutics. Breakthrough research techniques have made it possible to tailor pharmaceutical treatments to an individual’s genetic profile. If the focus is on genetic variations using genomic data, then why might you need to collect data by race or ethnicity? Do you then need to examine or customize treatments for conditions that disproportionately affect people of a particular race or ethnic background?
The advent of personalized medicine means that a bit more thought is required when it comes to addressing the inclusion of people from diverse racial or ethnic backgrounds,” Covington admits. “Looking at personalized medicine, biomarkers and genetic sequencing may take us down one road versus looking at the social and cultural factors of diversity which will take us down a different school of thought. One's perspective on this will really drive the conversations now as well as in the future. Looking at disparities of racial or cultural outcomes in this context is quite interesting. For example, you may have individuals who identify with distinctly different ethnic groups, but are matched genetically together relative to a specific expression of disease. On the other hand, there are observed health outcomes for individuals by race and ethnicity regardless of the clustering of genetic variation; therefore, the patient recruitment approach might follow the path of the environmental, socio-demographic or economic clustering of factors. We have to be clear about our approach and framework for research and discuss the assumptions in the research strategy. In any case, we need data from multiple perspectives as well as opportunities to examine decision-making from a broad array of viewpoints. ”
The new normal
Covington is adamant that bridging the diversity gap in patient recruitment and retention should not simply be seen as a “rescue attempt or niche area” within clinical trial operations, in which last ditch efforts are made to increase the numbers of patients from diverse racial and ethnic backgrounds. That rarely works, she says. “I think that this should not be a niche area, although I know it currently is approached that way at times. I understand the realities of the environment in which we are working; we need to speed up our research process as we bring solutions to the marketplace; delays are expensive. There are great demands on the systems to get research completed as quickly and efficiency as possible because of the competitive nature of the environment. We know that billions of dollars a year are spent on doing clinical research - it’s big business. However, what I am proposing takes time, effort, resources and leadership.” My proposal is really to reach out and show that not only our internal systems are built to be able to think about this strategically and operationally. Covington believes that the desire to enhance cultural diversity within clinical trials and engage with communities who have been vastly under-represented is a very important mission for anyone who is doing research to help people.
“My proposal is really to reach out and show that not only our internal systems are built to be able to think about this strategically and operationally.
Every engagement we do with our patients and communities enable us to look at rich information and understand the diversity in the populations we are querying. We want to diversify the clinical research portfolio in terms of the patient population recruited so that it can be of as much value as possible in addressing the needs across patient groups in different environments.”
Covington’s personal mission is to help close the gap in disparities in health outcomes across race, gender and cultures. A critical component will involve a greater voice being given to patients and partners in the industry. This empowerment will lead to greater dialogue and opportunity to develop strategies that reach across groups and communities involved in clinical research. This will ultimately lead to more effective medicines.
Let’s commit to getting a research strategy in place early, that reflects the diversity of the patient population impacted by the condition and implement from that perspective. The second is to build strong links with the patients and communities making decisions about their health using multiple means, including culturally competent outreach, social media or wearable technologies.
References: FDA Report Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Products August 2013 Closing the Diversity Gap in Clinical Trials
Melva T. Covington, M.P.H., M.B.A., Ph.D. is currently a Senior Leader within the Global Research and Development organization at Sanofi, where she has worked since 2010. Her leadership skills, expertise and impact in public health, clinical research and behavior analysis have spanned over 15 years and covered the full range of lifecycle development. She has a background in health services research, pharmacoeconomics, critical thinking and business management. Her goal is to apply these diverse skills strategically to address innovation and complex issues within healthcare systems, organizations and communities. Much of her work focuses on population-based disparities in health outcomes, research operations and cultural competency.
Melva Covington will be presenting on "Diversity & Inclusion in Clinical Trials - Where Community Outreach Still Matters" at Patient-Centered Clinical Trials in Philadelphia in October. For more information click here.
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