Inclusive Research for Multiple Sclerosis

Multiple sclerosis (MS) is a chronic demyelinating disease affecting the central nervous system (CNS) and affecting approximately 1 million people in the US. Historically, MS has been considered a disease that occurs primarily in people with northern European ancestry, but that paradigm is changing. A retrospective study of people newly diagnosed with MS within a 2-year period showed that incidence varied by groups defined by the social constructs of race or ethnicity (Table 1).¹ In this study, compared with white people—traditionally thought of as more likely to have MS—Black people had a 47% increased risk of MS whereas Hispanic/Latinx individuals and people with Asian ancestry had a 50% and 80% lower risk of MS, respectively. Variations among these populations are not limited to incidence but also include the clinical presentation, disease phenotype, course, severity, disability accumulations, mortality rates, and sex ratios.

MS Is Variable by Subpopulations in the US

Several studies provide evidence that both Black and Hispanic/Latinx people in the US with MS have higher risk of early disability and worse prognosis compared with white people.² Although there are differences in clinical, paraclinical, and genetic factors, as discussed briefly below (see also, Multiple Sclerosis in the Black Population in the United States and Multiple Sclerosis in the Hispanic/Latinx Population), data are scant with low power for drawing any definitive conclusions. More research is needed, including large-scale prospective studies.

Clinical Presentation

Meta-analysis of 136 published articles related to MS shows a more severe clinical course and worse outcomes in the Black population compared with the white population.³ Black people with MS tended to have more frequent relapses, incomplete recovery from relapse, and more severe ambulatory impairment, including greater risk of requiring a wheelchair for mobility. Black individuals were more likely than white individuals to present with multifocal signs and symptoms at disease onset and also more likely to be diagnosed at an older age, develop transverse myelitis, and have motor symptoms at onset.⁴ Hispanic/Latinx people, in contrast, presented at a younger age of disease onset and frequently had optic neuritis and transverse myelitis with a more severe disease course compared with white people.^5,6

Paraclinical Measures

Optical coherence tomography (OCT) and contrast visual acuity testing has been used to document faster retinal damage in Black people with MS compared with white people with MS.⁷ Accelerated brain tissue loss, including thalamic atrophy and gray matter contributing to whole brain atrophy has also been seen in Black persons with MS.⁸ Imaging characteristics for Hispanic/Latinx individuals with MS also include a higher frequency of spinal cord lesions and complete transverse myelitis compared with white people with MS.⁹ There are limited data regarding brain volume measurements in the Hispanic/Latinx population in the US.

Genetics

Genetic variations have also been documented in people with African and Latin American ancestry that contribute to the observed differences. Human leukocyte antigen (HLA) has been implicated in disease severity and different alleles associated with different ancestry have been documented in people with MS compared with those without the disease. Notably, these populations are diverse within themselves with differences in ancestral admixture.^10,11

Inclusion in Clinical Research

Although there has been a slight increase in the number of people from historically minoritized groups in the US who participate in clinical trials, rates have been and remain low. A search of the PubMed.gov database showed that of 60,000 articles published up to 2014, fewer than 1% focused on Black or Hispanic/Latinx people with MS. The majority of those few publications are retrospective observational studies or case reports.³ According to US census data, Hispanic/Latinx and Black individuals comprise 18% and 13% of the US population, respectively. Clinical trial participation by people from this population, however, remains at less than 10%.^12,13

How Did We Get Here?

Cultural influences, including religious beliefs and societal distrust, are thought to be potential barriers to participation in clinical trials among members of historically minoritized groups. Mistrust has been cited as a major factor and this is not unfounded. Historically, clinical research has a tainted history with Blacks and Hispanic/Latinx people in the US.

In the infamous Tuskegee Syphilis Experiment, for example, treatment known to be effective for syphilis was intentionally withheld from a group of Black men without their consent so investigators could observe the natural history of the disease. This may be the among the most well-known example of mistreatment of Black people in clinical trials, but it is far from the first or last instance in history. Surgical techniques in obstetrics and gynecology were created by experimenting on enslaved Black women, without anesthesia in Alabama in the 1800s.

Fast forward to the twenty-first century; in 2018, Centers for Disease Control (CDC) data showed Black women had the highest maternal mortality rate, 2.5 times higher than white women,¹⁴ suspected to be a result of institutionalized racism and lack of access to quality prenatal care. In 2016, a study showed that half of white medical students and residents endorsed false beliefs about biologic differences between Black and white people, rated Black patients’ pain level as lower, and made less accurate treatment recommendations.¹⁵

Hispanic/Latinx individuals are less likely to use preventive care or engage with the health care system for any type of care in the US—a major barrier to participation in trials.³ Studies show that Hispanic/Latinx individuals delay seeking care because of concerns they will receive a lower quality care.¹⁶ Lately, there have been efforts to train physicians in cultural competency during medical school, but up to 25% of physicians do not feel competent to provide culturally sensitive care,¹⁷ and, as noted, significant numbers of physicians continue learning falsehoods about biologic differences of cultural groups. This raises the question of whether such education should begin earlier in training, such as in the premedical school years, to increase physician competence. A physician who understands and respects cultural issues is more likely to be a trusted messenger in discussing clinical trials.

Other barriers to enrollment and participation include lack of information regarding clinical trials, financial burden, resources, and time constraints. Table 2 outlines some of the reasons for decreased participation of underrepresented groups in clinical research.¹⁸

The Importance of Diversity and Inclusion

Medical management of MS today for all but white individuals is based on data that is not representative of the population. In the small amount of data that does exist, there are significant limitations including retrospective designs, post hoc analyses, and low cohort sizes that make it impossible to generalize. Regardless, these analyses and observations provide valuable insight to make the case for a more diverse and inclusive clinical trial cohort.

The primary objective of human research is to produce results regarding safety and efficacy that are generalizable to the intended population. A homogenous cohort of study participants results in skewed data that cannot be generalized. It is well recognized that there are barriers to diversity in clinical trials. The National Institutes of Health (NIH) Revitalization Act signed into law in 1993, directed the NIH to establish guidelines for the inclusion of women and minorities in clinical research.¹⁹ The demographics of MS have changed over time and incidence in Blacks and Hispanic/Latinx populations, in particular, has significantly increased, but the demographics of clinical trials for MS have not seen a similar trend. This raises the question of how generalizable are data for this changing population. Table 3 outlines some key benefits of inclusive research trials.

A diverse patient cohort helps expand the knowledge base of a specific disease process and provides a complete data set. This knowledge can lead to improved treatment options. It can help identify specific efficacy and safety signals early in the drug development phase. The alternative of not including a diverse population may result in treatment response that may not be acceptable for all populations. This was seen for MS when post hoc analysis of interferon β-1a showed Black people with MS were less responsive to this treatment with more relapses while using the treatment compared with white people with MS using interferon β.²⁰ Although the sample size was small, this study was important as the first to provide information on differences in patients’ response to disease modifying therapies (DMTs) in MS. Subsequently, similar post hoc analysis has been performed on newer agents, including dimethyl fumarate in Hispanic/Latinx people and both alemtuzumab and dimethyl fumarate in Black individuals,^21-23 showing similar effects across these groups. Efforts to assess efficacy across cohorts have since increased, but these are still post hoc analyses of a small subset of participants (because of a lack of diverse enrollment) and thereby lack generalizability.

Inclusive trials are also important for patient education and vice versa. There is increased participation in trials if there is awareness and understanding of the trial. Aspects of awareness include education regarding the nature of the disease, disease effects, and biology and treatment response. An important aspect of awareness is educating subjects on how clinical trials are conducted, the process of collecting scientific data and how the findings affect the entire community. Inclusive information allows for empowerment of underrepresented groups to actively participate in decision-making processes affecting their and their community’s lives. Armed with quality information, efforts can be made to achieve health equity and provide benefits to the intended population.

Looking Forward

In 2019, the Food and Drug Administration (FDA) issued nonbinding recommendations to industry for enhancing the diversity of clinical trial populations.²⁴ Among these are broadening eligibility criteria to decrease adversity of enrollment; using inclusive trial practices, design, and methodologies; and using enrichment strategies. An example is modifying phase 2 criteria in phase 3 to include more participants. Other approaches include making trial participation less burdensome for participants and adopting enrollment and retention practices that enhance inclusiveness and expand access. Engaging stakeholders including advocacy groups, persons living with the disease, and experts early in the drug development process also serves to encourage recruitment.

As previously stated, lack of access to care has been cited as a barrier to inclusion in clinical trial participation. MS centers with specialized health care professionals providing comprehensive care may have more resources available to address the needs of minority patients. These centers may also have more clinical trials available for patients to be considered for enrollment. Partnering with advocacy groups to address the needs of minority patients and educate them regarding clinical research is important to help address this issue.

In 2020, the Multi-Regional Clinical Trials Center also issued guidelines but expanded them to include diversity, inclusion, and equity in clinical trials.²⁵ Inclusive strategies include public outreach and education and collaborating to educate participants about clinical trial participation. Educating health care providers about cultural differences, recognizing barriers to care and participation, and providing them with kits to help foster inclusion is also important in building trust and assuring patients that their needs are being addressed. A wider variety of research sites that include different populations can be recruited. Trials can be made less burdensome for participants by reducing logistic burdens with flexible timing and staffing, provisions for transportation, and adequate compensation, as well as making participants aware of these options.

Research outside the traditional clinical trial paradigm, including the incorporation of real world data, will afford new opportunities to plan and execute studies examining variability across subgroups. Trials with diverse populations of the intended treatment group are better positioned to develop effective treatments (Table 4).

To improve trust, it is essential to educate participants about the process, engaging early and soliciting input from patients and the community. Providing feedback and study results can promote effective communication and a sense of collaboration. Ensuring site investigators, staff, and trial leadership are representative of the population should be a goal.

The National African American with MS Registry (NAAMSR) goals are to accurately estimate the number and geographic distribution of African Americans diagnosed with MS in the US, document the existing barriers to accessing care, and create strategies to undo inequities of access. The Alliance for Research in Hispanic MS (AHRMS) consortium goal is to improve understanding of the Hispanic population with MS, the genetic contribution to disease, and social and cultural factors in MS disease progression.

Summary

Research trials of potential disease treatments should yield results that are generalizable to the population intended to be treated. As the incidence and prevalence of MS changes, including more Black and Hispanic/Latinx people, it is essential that research trials include and have a diverse cohort of patients that represents the current face of MS.

A diverse patient cohort improves our knowledge base, can lead to development of effective treatment for the intended population, and identifies variability in treatment response and early identification of important safety signals. An inclusive trial also enhances patient education, which in turn can lead to increased participation. Inclusive trials that provide quality data have the potential to influence change on multiple levels including policymaking and patient involvement. Such trials can also increase public confidence and trust.

Inclusive studies tend to improve the quality of scientific data, facilitate discovery of important safety and efficacy information, and assist in identifying population-specific differences. A diverse and inclusive clinical trial cohort requires effort and collaboration of all stakeholders, including sponsors, principal investigators, patients, regulatory groups, and oversight bodies.