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In the United States, a rare disease is defined as a condition that affects fewer than 200,000 people nationwide. The World Health Organization defines a rare disease as a disorder that affects fewer than 65 per 100,000 people (1). In the European Union, the definition narrows to five in 10,000 people. Ten percent of the global population is affected by at least one of the >10,000 identified rare diseases — which accounts for about
30 million people in the United States (2). Although the causes of most rare diseases are unknown, many such conditions are traced to mutations in a single gene. In fact, 80% of rare diseases have a genetic origin (1). The average time for diagnosis is four to five years. Many patients remain undiagnosed and receive only symptomatic treatment.

Orphan drugs — medications used to treat rare diseases — offer several potential advantages, including shorter development timelines, reduced research and development costs, and limited generic competition. Yet drug development for such treatments incurs certain challenges due to a number of factors.

Lack of Understanding of the Disease Process: The limited availability of natural-history studies for rare diseases poses a challenge for researchers and physicians. It hinders their understanding of the causes and natural progression of these conditions, increasing the difficulty of assessing new-drug responses effectively.

Lack of Awareness: Most patients and caregivers lack information about the symptoms and signs of rare diseases, which can lead to delays in seeking medical advice and thus narrows the patient base.

Difficulty of Diagnosis: Nonspecific symptoms and a lack of specialized diagnostic tools and tests can delay rare-disease diagnoses. The scarcity of biomarkers to measure disease progression further adds to the uncertainty of evaluating clinical-trial results.

Limited Numbers of Patients: A narrow patient base distributed globally can complicate patient recruitment for rare-disease research. The heterogeneity of these conditions compounds the challenges of developing effective treatments. For example, congenital ichthyosis, a skin disease, exhibits more than 30 known subtypes, displaying overlapping clinical phenotypes, yet each subtype is linked to a distinct gene mutation. Thus, although a number of patients can be diagnosed as having the same disease, one drug can elicit different degrees of efficacy from patient to patient (3).

Funding Difficulties: Because the beneficiary population for rare-disease research is small, securing funding for research and drug development can be less than straightforward. Pharmaceutical companies may not deem investing in rare-disease research and drug development to be commercially viable. As a result, therapeutic development can be delayed (4).

Regulatory Challenges: Navigating through regulatory challenges associated with clinical trials for rare diseases can be difficult. Limited patient numbers can make demonstrating treatment efficacy and safety a cumbersome task.

Affordability: With drugs developed for rare diseases, affordability remains a significant obstacle for patients, arising from limited or no reimbursement from healthcare plans and unaffordable out-of-pocket expenses.

Considering the numerous complexities involved, a patient registry could be a game-changer for rare-disease research and drug development.

The Value of Patient Registries
A patient registry is “an organized system that uses observational study methods to collect uniform data (clinical and other) to evaluate specified outcomes for a population defined by a particular disease, condition, or exposure, and that serves a predetermined scientific, clinical, or policy purpose” (5). Effectively, a patient registry is just that: a collection of patient data. Patient registries can be instrumental for rare-disease research in several ways (6).

Sample Size: With the help of a pool of data from rare-disease patient registries globally, researchers have larger sample sizes in which to conduct studies.

The Natural Progression of a Disease: Drug development relies on understanding disease progression and outcomes. In addition to demographic information, patient registries can include data relating to prevalence, patient distribution, familial characteristics, symptoms, age of onset, and disease progression. Such information can help researchers to identify patterns and prognoses, aiding in clinical-trial design and development of therapeutic interventions.

Shorter Recruitment Times: Subject recruitment for clinical trials can be facilitated through collaborations among patient registries.

Understanding Disease Patterns: Patient registries can help researchers to study correlations between various genetic mutations and symptoms associated with them, enhancing understanding of rare-disease progression.

Safety and Efficacy Studies: Patient registries can track patient-reported outcomes and side effects of treatments. The resulting data inform studies relating to the safety and efficacy of interventions during drug development.

Public Policy: Patient registries can support public policy and resource allocation by providing a bird’s-eye view of the geographic distribution of patients, demography, disease prevalence, and realitive quality of and access to healthcare.

Support System: Patient registries foster care and support by connecting patients and caregivers, forming a platform for the exchange of information regarding disease progression, status of new therapies, availability of specialists, and opportunities to enroll in clinical trials.

Government-Led Actions in Rare-Disease R&D
The US Orphan Drug Act was passed in 1983 to encourage research and development of therapies for rare diseases through tax incentives, market exclusivity, and user-fee exemptions (7). The act resulted in a marked increase in rare-disease research, from fewer than 10 drugs before its passage to more than 300 drugs for rare diseases over the past 25 years.

The Genetic and Rare Diseases (GARD) Information Center (2) is a program of the US National Institutes of Health (NIH) that provides free access to reliable, easy-to-understand information about genetic and rare diseases. Public awareness campaigns such as Rare Disease Day (8) take place worldwide, typically on or near the last day of February each year, to raise awareness among policymakers and the public about rare diseases and their impact on people’s lives.

The National Center for Advancing Translational Sciences (NCATS), another program of the NIH (9), launched its registry-program website to provide rare-disease communities with easily accessible guidance on how to set up and maintain high-quality registries. The goal is to enable patient groups to support and promote patient-focused rare-disease research.

The US Food and Drug Administration’s (FDA’s) Centers for Drug Evaluation and Research (CDER), Biologics Evaluation and Research (CBER), and Device and Radiological Health (CDRH) play essential roles in supporting the development and approval of safe and effective drugs, biologics, and devices for treating rare diseases (10).

To enhance drug development and clinical research for rare diseases, the FDA provides specific incentives and expedited programs, including orphan-drug designation and exclusivity, a pediatric rare-disease priority review voucher, fast-track designation, and priority review. These initiatives aim to expedite the approval process and encourage research in rare-disease therapies, promoting advancements in treatment options (3).

The Value of Government and Nonprofit Collaboration
Patient Recruitment: Outreach programs, nonprofits, and patient advocacy groups can help populate patient registries. They can work with governments to streamline the regulatory process for clinical trials of orphan drugs and research into rare diseases by establishing clear guidelines and expedited reviews.

Standardization: The government can and should fund development of patient registries and establish standardization to encourage data sharing between patient registries and research groups. Such a collaboration can enable access to a widened pool of patient data for rare-disease research and drug development.

Funding: The unification of patient organizations for rare diseases under one umbrella can lead to increased interest from pharmaceutical organizations in funding rare-disease drug development. The larger patient base represented by this collaboration can incentivize pharmaceutical companies to invest in research and development, ultimately benefiting individuals affected by rare diseases.

Patient Engagement: Patients need constant support and engagement. Nonprofit organizations can continue to engage with those people, address their concerns, create and promote information channels, conduct seminars, and keep them abreast of clinical trials. This level of support can help decrease patient dropout rates.

The collective global impact of rare diseases is significant; however, there is a notable gap between basic research and clinical interventions. Fortunately, current opportunities offer ways to expedite drug development for treating rare diseases. Patient registries serve as platforms that unite diverse stakeholders, including patients, clinicians, researchers, and the pharmaceutical industry. Such collaborative environments foster knowledge sharing, helping developers form best practices and valuable connections. Such collaboration ultimately benefits individuals affected by rare diseases and contributes to the advancement of drug development and treatment options.

1 Derayeh S, et al. National Information System for Rare Diseases with an Approach to Data Architecture: A Systematic Review. Intractable Rare Dis. Res. 7(3) 2018: 156–163; https://doi.org/10.5582/irdr.2018.01065.

2 GARD (Genetic and Rare Diseases) Information Center. Public Health Challenges of Rare Diseases. National Center for Advancing Translational Sciences (NCATS): Bethesda, MD, 2023; https://rarediseases.info.nih.gov.

3 Sun W, Zheng W, Simeonov A. Drug Discovery and Development for Rare Genetic Disorders. Am. J. Med. Genet. A. 173(9) 2017: 2307–2322; https://doi.org/10.1002/ajmg.a.38326.

4 Augustine EF, Adams HR, Mink JW. Clinical Trials in Rare Disease: Challenges and Opportunities. J. Child Neurol. 28(9) 2013: 1142–1150; https://doi.org/10.1177/0883073813495959.

5 Workman TA. Defining Patient Registries and Research Networks — Engaging Patients in Information Sharing and Data Collection. Agency for Healthcare Research and Quality (US): Rockville, MD, 2013; https://www.ncbi.nlm.nih.gov/books/NBK164514.

6 Registries for Evaluating Patient Outcomes. Gliklich RE, Dreyer NA, Leavy MB, Eds. Agency for Healthcare Research and Quality (US): Rockville, MD, 2014; https://www.ncbi.nlm.nih.gov/books/NBK208609.

7 Orphan Drug Act of 1983. US Food and Drug Administration: Silver Spring, MD, 1983; https://www.gpo.gov/fdsys/pkg/STATUTE-96/pdf/STATUTE-96-Pg2049.pdf.

8 Rare Disease Day at NIH 2023. National Center for Advancing Translational Sciences (NCATS): Bethesda, MD, 2023; https://ncats.nih.gov/news/events/rdd.

9 National Center for Advancing Translational Sciences (NCATS). US Department of Health and Human Services, National Institutes of Health: Bethesda, MD, 2023; https://ncats.nih.gov.

10 Rare Diseases at FDA. US Food and Drug Administration: Silver Spring, MD, 2023; https://www.fda.gov/patients/rare-diseases-fda.

Further Reading
Who We Are. The International Rare Diseases Research Consortium (IRDiRC); https://irdirc.org/who-we-are-2.

Dr. Padma Rammoorthy is a medical consultant at IndoUSrare. Her work in health education and lifestyle medicine has made significant contributions to the improvement of maternal health in India and worldwide. Corresponding author Dr. Harsha Rajasimha ([email protected]) is the founder and executive chairman of IndoUSrare, a humanitarian nonprofit (501(c)(3) tax-exempt) public charity organization based in the United States; https://indousrare.org.

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