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Current Opportunities and Outcomes in Rare Disease Clinical Trials

A rare disease affects, by definition, fewer than 200,000 individuals in the United States, and an ultra-rare disease affects many fewer1. Altogether, there are more than 10,000 identified rare diseases affecting more than 30 million Americans and their families, with similar numbers in other parts of the world2. Individuals with rare diseases and their families face significant challenges due to such factors as uncertainty in and availability of a diagnosis and potential treatment options that ultimately affect their medical, psychological, economic, and social health. Considering rare disease prevalence, a lack of diversity, equity, and inclusion (DEI) considerations in research of these conditions, and practices around treating them leads to diminished opportunity for care and poorer outcomes. These include limited access to diagnosis and care, ongoing clinical trials for a person living with a rare disease, their child or their partner, and the availability of support for their concerns and ongoing needs.  

Patients and families from minority groups, and those who come from less economically stable environments often face significant barriers to safe and accessible health care. These can include a lack of supportive resources, such as parental education and awareness of diagnosis and treatment options, or available access to ongoing clinical trials for their conditions. Further impacting access is the historical mistrust toward clinical research studies many minority communities hold, a lack of community representation, and limited engagement with patient advocacy groups that provide supportive guidance and direction. These limitations can readily lead to a delay in diagnosis and access to available treatment options, impacting potential outcomes. A further challenge for many families, both in urban and rural areas, can be more limited access to resources and facilities where diagnosis and intervention take place. Together, these contribute to diminished opportunities for care and poorer outcomes for diverse communities affected by rare diseases.  

When we think about social determinants of health-related access barriers, we must consider factors related to healthcare professional education and knowledge regarding rare diseases. It is the case that many families first rely on available sources of primary care, including family and general practice physicians or nurse practitioners, who may not be as informed about current information regarding rare and ultra-rare diseases. Similarly, primary care practices may not have enough resources or advanced technologies available for faster diagnosis and treatment options. These challenges can be further complicated for minority and under-resourced communities when awareness of specialty care and the availability of practitioners versed in understanding the diverse needs of affected individuals is more limited. 

Importantly, it has been recognized that there is a significant need to provide healthcare professionals and clinical trial investigators with relevant continuing education and training about the importance of diversity, equity, and inclusion strategies regarding the diagnosis and treatment of individuals with rare diseases. Starting early with medical and health care training, the integration of curricula regarding the social and behavioral determinants of health has begun to contribute to better coordination of elements of care, leading to faster diagnosis and, when available, access to developing and approved treatments. Furthermore, improving resources and availability of specialist care and adding greater diverse community representation, such as connecting with patient advocacy groups, have improved outcomes for minority persons with rare disease and their caregivers.  

More specifically, sponsors running clinical trials, including pharmaceutical companies and the individual investigators conducting their studies, have been directed to think more clearly and to state explicitly within their study objectives and design how they will directly address diversity and equity considerations. Unique in 2024 is the extent to which emerging practices regarding equitable clinical trials have begun to standardize as drug developers and other stakeholders become familiar with the methods of diversification required of them, which will ultimately lead to a required increase in the numbers of diverse participants who are represented in and serve as beneficiaries of treatment research. 

During protocol development, sponsors and investigators are also encouraged to carefully assess research methodologies and approaches, research outreach and recruitment methods, and improve the availability of adequate resources to accommodate minority populations for ease of recruitment. Community-based participatory research methods can support this effort, ensuring that individuals from minority communities with rare diseases are included in the design and implementation of the research from the start, and by identifying and resolving potential clinical biases. Community-based participatory research uses collaborations between research organizations, investigators, and community members throughout all aspects of a research project. This approach is important given its commitment to engaging and representing intersectionally diverse populations affected by rare and more common diseases and fostering greater engagement across minority communities. 

Trial diversity and rare disease drug development together will benefit from the growing collaboration by the FDA regarding the necessity for diverse and equitable representation in clinical trials and biotech companies’ increasing familiarity with the resulting best practices in development. Tools to reduce the diagnostic odyssey will continue to reduce the cost and burden of rare diseases, while advocates’ work with policymakers will better open access to these tools and investigation strategies.  

The new DEPICT Act passed recently by the U.S. Congress requires the FDA to require sponsors to submit Diversity Action Plans with their Phase III or other pivotal trials. The FDA has urged both large pharmaceutical companies and the growing number of smaller biotech drug developers involved in rare disease research to reach out and work with them early in the investigatory process to develop protocols and find solutions to the challenges this new requirement presents. The DEPICT requirement comes at a time when the industry is a few years further down the road from the events of 2020, including the COVID-19 pandemic, which awakened a new, sincere investment in being more inclusive in health care across all stages of development and ultimate treatment, including clinical research. 2024 is a specific year to watch this investment translate directly into best practices.  

Additionally, better tools in genomic screening are available now, which help reduce the diagnostic odyssey and connect rare disease patients with new treatments and early interventions that can save their lives and prevent unnecessary damage from the disease. Policies to open access to these fresh solutions more broadly across diverse affected communities will remain an active focus for rare disease advocates and collaborating policymakers in 2024.  

A growing body of evidence shared recently has shown how policies that help families of rare diseases also benefit society. Two studies commissioned by the EveryLife Foundation for Rare Diseases3,4 will be used in dialogue with policymakers: one quantifies the cost burdens on families and society of rare diseases, and the other quantifies the avoidable costs of the diagnostic odyssey. Legislation is in the works to provide access to treatments and diagnostic tools to people regardless of zip code and income level. Watch for legislative efforts to open access to newborn screening, including rapid genome sequencing, genetic counseling, and early intervention services. Small patient populations have always hampered rare disease research. As we expand our definition of who participates in the research and its benefits, the population sizes grow.  

Lastly, and important to how the process regarding greater diversity and equity in clinical research will unfold, the FDA has already issued draft guidance on enhancing the diversity of clinical trial populations, providing recommendations to sponsors to enroll representative numbers of participants from underrepresented racial, ethnic, gender diverse, and economically diverse populations in the United States. This is being further supported by Institutional Review Boards (IRBs) reviewing current research proposals with an eye toward DEI and representative justice. IRBs play a key role in determining the availability of clinical trials for minority populations in rare diseases. One of the criteria for approval is consideration of the equitable selection of research subjects. As per the Belmont Report, no individual group should be absolutely included or excluded from clinical study without justifiable scientific or ethical reasoning. IRBs can review the submitted justification and study design for scientific and ethical validity, and ensure adequate safeguards and protections are in place for the study population more broadly. This will lead to both greater recruitment of diverse participants and clearer knowledge regarding potential outcomes. 


  1. Bainbridge, M.N. (2020). Determining the incidence of rare disease. Human Genetics, 139, 569-574. DOI: 10.1007/s00439-020-02135-5 
  2. Smith, C.I.E., Bergman, P., & Hagey, D.W. (2022). Estimating the number of diseases – the concept of rare, ultra-rare, and hyper-rare. iScience, 25, 104698. DOI: 10.1016/i.isci.2022.104698 
  3. The national economic burden of rare disease in the United States in 2019 
  4. The Cost of Delayed Diagnosis in Rare Disease – a Health Economic Study 

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