Strategies for Building Greater DE&I in Rare Disease Trials

Applied Clinical TrialsApplied Clinical Trials-03-01-2023
Volume 32
Issue 3

Outlining new approaches and resources to help ignite progress in this area.

Diversity, equity, and inclusion (DE&I) in clinical trials is an increasing point of focus for regulatory bodies and the industry at large. In late December 2022, the US Congress enacted a law that requires diversity action plans for clinical trials that FDA reviews to determine market approval. The agency’s draft guidance for sponsors on preparing Race and Ethnicity Diversity Plans has been available since early 2022. What does this mean for rare disease clinical research, where challenges are multifold compared to clinical research in common conditions?

The importance of DE&I is arguably even greater within rare disease, as clinical trials have immense prominence in the patient journey compared to common conditions where multiple treatment options often exist. With only 5% of the 7,000-plus known rare diseases having an approved treatment, clinical trials are often the only option for patients for a potentially meaningful treatment, but diverse communities are still underrepresented in rare disease clinical trials.

The goal in rare disease clinical research is to include as many people with the particular disease from diverse backgrounds as possible in order to understand and treat it—this is what will drive increased understanding and progress. While some gene variants are known to be more prevalent within certain communities, ultimately any genetic variant can occur in any individual regardless of ethnicity or sex. Not all individuals affected by a rare disease are the same, and not all these conditions have a genetic origin.

Barriers to clinical research that affect diverse populations with rare diseases arise from multiple layers of complications with accessing healthcare and support within health systems, rare disease advocacy, conservative regulatory perspectives, and traditional clinical research models.

We recently discussed this topic with key players in the industry that are dedicated to broadening access to clinical research for underserved populations affected by rare diseases. During our conversation with representatives from the Sumaira Foundation, BridgeBio, Duke University’s ALS Clinic, and RARE-X, we explored ways for drug development stakeholders to employ strategies to improve DE&I in rare disease clinical trials.

This article outlines some of the systemic factors that produce barriers at different stages of the rare disease drug development process and delve into some of the strategies we identified through our discussion with industry leaders that have been working to improve diversity in these trials. The goal of these conversations is to identify and share opportunities where clinical research stakeholders may be able to drive progress forward.

Systemic barriers to achieving representative rare disease clinical trials

Typically, factors that form barriers to achieving representative rare disease clinical trials impact drug development on four levels: strategic (disease and clinical strategy setting); protocol (development of a clinical trial protocol); site (traditional locus of clinical trial research); and patient (potential trial participant). See Figure 1 below.

The impacts of these factors are interactive and cumulative as the drug development process unfolds. For example, at the disease strategy level, limitations in data availability and the pharmaceutical industry’s competitive incentive framework create foundational barriers to achieving representative trial populations.

At a protocol level, a lack of bespoke outcome measures for rare diseases and the conservative practices of regulators creates barriers to more inclusive rare disease trials. For example, homogenous patient populations and restrictive inclusion and exclusion criteria compensate for the use of outcome measures designed for common conditions that aren’t sensitive enough to track changes in rare disease.

The limited pool of expertise and sites with research experience in a specific rare disease creates geographic and socioeconomic barriers to trial participation in studies targeting these diseases. In addition, we find that the investment of time and resources required discourages sponsors from utilizing research-naïve sites that may be closer to potential participants’ residences.

At a patient level, lack of support or outreach between patient advocacy organizations (PAOs), sponsors, and diverse patient communities present barriers to equitable access. Lack of education or awareness about rare diseases and the drug development process, which often comes from PAOs, further impacts underserved individuals in rare disease.

Strategies for sponsors, sites, and PAOs to affect change

Systematic changes can evolve from the groundswell of support for increased DE&I in rare disease clinical trials. Stakeholders of the drug development process, including sponsors, sites, and PAOs, can affect change in a variety of ways across the four levels of the development process. We will explore some of the potential strategies for each stakeholder group ahead.


As the largest stakeholders in the clinical research and development process, sponsors have a variety of opportunities for additional DE&I strategies available to them, from protocol and trial design to site selection and cross-industry collaboration.

As early as possible, sponsors should assess feasibility in terms of cost, timeline, potential, and advantages and explore more inclusive design strategies. For example, selecting novel outcome measures to allow for more heterogenous patient groups, non-placebo controls to improve patient interest and engagement and protocol designs (including potential decentralized trial elements) that limit in-person visits to reduce patient burden.

Other opportunities to reduce patient burden could include implementing concierge services or financial or travel support for patients. To identify potential strategies or barriers, we suggest obtaining input on study designs from as many diverse patient communities within a rare disease as possible. ICON’s free “Rapid Burden Assessment Survey Template” is a resource that sponsors can leverage to ask patients and caregivers for relevant study
design input.

To affect more systemic change, sponsors can deliberately cultivate openness and innovation within the industry. Decentralized clinical trials or novel outcome measures could significantly impact DE&I efforts by removing barriers for diverse patient participation, but they are not often approved by regulators in rare disease trials. Sponsors can partner with relevant PAOs to engage with regulators about the increased trial population diversity that these methods could afford compared to traditional designs.

More immediately, sponsors can foster openness toward new investigators and sites that are nearer to patient populations to mitigate geographic and socioeconomic barriers to rare disease trial participation.

Typically, sponsors prefer not to engage study-naïve sites, but the increased feasibility of participation may offset the additional time and capacity required to support them—potentially saving timeline delays, protocol amendments, and delays/failure to recruit and reaching the market faster.

In direct contrast to the competition within the industry, we see opportunities where sponsors can leverage collaboration by proactively forming or joining collaborative initiatives that support diversity and inclusion. Regeneron has an initiative to improve diversity in genomics databases, which is an important problem to solve as 80% of rare diseases have a genetic cause, yet 80% of genomic databases represent genomes of white European ancestry.


Sites can improve DE&I by removing barriers to access and reducing patient burden. Sites can identify potential barriers and either address them independently or collaborate with sponsors who can potentially support sites with additional participant materials in target languages and various trainings.

Sites can also harness the voices of diverse communities by empowering potential participants to communicate the obstacles they may experience and advocate for the support they would need to participate in a clinical trial. One way we have facilitated this for potential participants is through theWhat to ask when you’re interested in a clinical trial: A guide for rare disease patients and families” that we developed with our Rare Disease Advisory Council. They can also share through the Study Participant Feedback Questionnaire™ (SPFQ) and custom surveys supplied by the site.


The advent of the internet and modern communication technologies enabled disparate patient communities to connect and form PAOs, driving basic research and providing researchers and industry with opportunities for discovery. Rare disease PAOs play a vital role in providing practical and emotional support and education to their members. PAOs are also the proper channel through which pharma companies engage patient communities. Without a representative population in PAOs, there is a lack of diversity in the patient voice that helps to shape disease clinical strategy.

PAOs are often underfunded and under-resourced, making it difficult to enact comprehensive DE&I efforts despite their willingness. However, there are resources available. RARE-X has developed a DE&I metrics toolkit specifically for rare disease PAOs. While the toolkit implementation requires capacity and expertise, organizations may be able to work with other stakeholders, appeal to sponsors for support, or combine resources to implement it.

Understanding the drug development and clinical research process may be fundamental to overcoming distrust among diverse patient communities. Often, rare disease PAOs are patients’ and caregivers’ only source of education about the drug development and clinical research processes. For those patient communities that PAOs don’t engage, these resources may be completely out of reach.

PAOs can collaborate with academia to look to existing patient education programs, such as the ALS Clinical Research Learning Institute, the Parkinson’s Foundation’s Parkinson’s Learning, or the Bladder Cancer Advocacy Network’s Patient Empowerment through Engagement Research (PEER) training program. Approaching the founders of these programs to inquire about sharing their methodology and documentation to be adapted for a rare disease setting may save time and budget while forwarding educational goals underpinning DE&I efforts.

Rare disease PAOs can also strive for large-scale systemic change by joining forces with health disparities advocates in lobbying policymakers for policies that incentivize drug development stakeholders to implement DE&I strategies. A recent example of success in this strategy is the Accelerating Access to Critical Therapies for ALS Act (ACT for ALS),
authorized on Dec. 23, 2021.

Focus and dedication required

The rarity of individual rare diseases introduces many unique challenges and complexities in clinical research, including barriers to achieving representative trial populations and equitable access to trials. Underrepresentation of diverse populations in rare disease clinical trials is the result of systemic barriers that impede inclusion across race, ethnicity, socioeconomic resources, geography, gender, sexual orientation, age, and disability. Progress toward representative trial populations is moving slowly, even though study participation is often the only means of accessing a potentially meaningful treatment for rare disease patients.

Focused effort and dedicated action across all levels of the development ecosystem are essential to creating an equitable clinical research environment and driving progress across the industry. We have outlined several strategies that stakeholders across the drug development process could implement to improve DE&I in rare disease clinical trials and have highlighted some of the resources available to assist in these efforts.

Laura Iliescu, director, patient advocacy strategy, ICON

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