Rare Disease Day 2024: IndoUSrare's Frontline Efforts in Tackling Global Inequities

Indo US Organization for Rare Diseases (IndoUSrare) has always been a steadfast ally to rare disease patients, and Rare Disease Day 2024 will be no exception. Beyond honoring these individuals on February 29 through online and in-person events, IndoUSrare will be addressing the enduring challenges faced by the rare disease community: the high costs of treatment, gaps in research and development, diagnosis complexities, limited patient pools for clinical trials, equity and access issues. IndoUSrare contends that a framework encompassing cross-border international collaboration, data sharing and patient registries, and decentralized clinical trials is imperative for overcoming these obstacles.

HERNDON, Va., Feb. 29, 2024 /PRNewswire-PRWeb/ -- Established on February 29, 2008, Rare Disease Day aims to raise awareness about the approximately 7,000 (now 11,000) rare diseases affecting 300 million people worldwide.¹ The day also marks a moment to reflect on the progress made in the field. Once untreatable conditions such as spinal muscular atrophy and juvenile idiopathic arthritis now have effective treatments, and the adoption of genome sequencing technology has greatly improved the speed and accuracy of rare disease diagnoses.

However, the rare disease landscape is not improving as rapidly as it should, not least due to several intertwined challenges ranging from unequal treatment access to the high cost of drugs. Addressing these issues requires creativity and collaboration on the part of the experts, patient advocacy organizations, and stakeholders. As it stands, a combination of patient-centric accessible clinical trials, extensive patient data sharing, and robust international cooperation appears to be most promising for making headway in the battle against rare diseases.

"While we celebrate our significant progress, we must continue to look toward the still foggy road ahead," says Dr. Harsha Rajasimha, a champion of the rare disease community through his work with IndoUSrare.

The state of the field: challenges and solutions
Heading into Rare Disease Day 2024, the main challenges that hinder progress in the community are as follows:

• Challenge 1: 95% of rare diseases do not have any approved treatment options

"Because the number of patients affected by a rare disease is relatively smaller compared to common indications, and because these affected patients are geographically distributed globally, development of treatment options for rare diseases have to overcome numerous challenges and higher costs. Despite over 1100 orphan drugs approved by the U.S. FDA, most rare diseases (~95%) still remain without any treatment options." Says Frank Sasinowski, JD, MPH, Founding Board Director of IndoUSrare and Director at Hyman, Phelps & McNamara P.C.

It should be no surprise that the cost per patient of the 5% of rare diseases with approved treatments is notably higher compared to conventional treatments. In the US, the median price for orphan drugs is roughly 20 times higher than that of non-orphan drugs.² The higher costs associated with orphan drugs are partially ballooned by the need to recapture the cost of R&D from small patient populations. The cost of prolonged patient enrollment and inefficient clinical trials have to be recovered from a small number of patients. Patients are either too difficult to find or prone to dropping out. Optimizing the orphan drug development process is critical to reducing the costs of orphan drugs.

One way to enhance clinical trial design entails expanding the patient pool via cross-border collaboration, especially with densely populated yet underrepresented regions of the world. IndoUSrare has been active in this regard, serving as a bridge between the US and India in order to boost the representation of ethnic patients in US rare disease clinical trials.

Modern clinical trial management platforms developed by empathetic and purpose-driven social entrepreneurs, such as Jeeva Clinical Trials, have the potential to significantly lower the drug development costs. Such platform technologies can help reduce costs by making patient registries and clinical trials global in scope yet highly efficient with the use of technology and AI. By engaging patient advocacy groups and providing a patient-centric experience, these tools improve patient access and retention in clinical trials, making them cost-effective.

"One question to the sponsors of orphan drugs is, could we bring down the costs of orphan drugs by expanding the market access globally to larger patient populations rather than the current model where most of the R&D costs have to be recovered from the small patient population in the US alone? What does it take to move beyond the usual sequence of orphan drug launches in the US, EU, and Japan?" asks Rajasimha.

• Challenge 2: Limited research and development

The small market size for each rare disease has discouraged some pharmaceutical and biotechnology companies from investing in the research and development of treatments. Medical advancements are often driven by small companies that face fewer demands from shareholders.³ Niche interest in this area has resulted in only 500 of the 11,000 identified rare diseases having approved treatments.⁴ Recently, we see a change in trend for better. One in 3 drugs approved by the FDA in recent years is a precision medicine or targeted therapy.

R&D is unlikely to accelerate in the upcoming years, especially with the Inflation Reduction Act subjecting small molecule medicines to price negotiation. The imperative to derive greater value from existing investments is more urgent than ever.

Data sharing can play a pivotal role in offsetting limited investments. Access to more patient data helps experts gain a better understanding of disease pathogenesis and response to treatment, resulting in more efficient medical breakthroughs despite resource constraints.

Recognizing the research benefits of data sharing, RARE-X has created a data platform that tap into the commonalities and differences among rare diseases and among the patients affected by a rare disease. The Indian government has been trying to establish a national patient registry at the Indian Council for Medical Research (ICMR). A working model is necessary for other low- and middle-income countries to adopt.

AI is revolutionizing all fields of life sciences including rare disease research. Scientists from IndoUSrare recently contributed an article to the Clinical Leader Magazine on the topic.

• Challenge 3: Inaccurate and delayed diagnosis

Getting a rare disease diagnosed can be so convoluted that the process is often referred to as an "odyssey."

One difficulty lies in accurately diagnosing the condition. While whole genome sequence is widely considered as the most effective method for identifying rare diseases, its diagnostic utility currently stands at around 62.5%.⁵ False-negatives (test results indicating the absence of a condition when it is, in fact, present) are commonplace.

"There is a huge scope for misinterpretation of the genetic results as neither the commercial organizations nor consumers understand the complexity of genomic assays in the absence of medical genetics professionals," says Dr. Nisha Venugopal, Associate Director at IndoUSrare.

Even if a patient receives a correct diagnosis for their disorder, they have probably endured a lengthy wait; the average time to diagnosis for a rare disease in the US is eight years.⁶ Diagnostic delays (and incorrect diagnoses) frequently contribute to mental distress for patients.

Here as well, data sharing is likely to be beneficial. Larger datasets make the analysis of patterns and trends more credible, potentially leading to more confident diagnoses.

• Challenge 4: Limited patient populations for clinical trials

Whether in North America or in the European Union, rare disease clinical trials are hampered by low participation rates. The median number of patients involved in these trials is only 29, as opposed to 69 for non-rare disease trials.⁷ As a result of low patient participation, 50% of rare disease clinical trials face discontinuation or remain unpublished after four years.⁸

Recruiting patients for rare disease clinical trials is often a struggle because the patient population is small to begin with. "We must ensure voices of marginalized populations within the rare disease community are heard and represented." says Charlene Son Rigby, Chief Executive Officer at Global Genes. "Running clinical trials for rare diseases is more challenging due to their nature - there are fewer patients that can participate. Industry, advocacy organizations, and patient advocates must come together and rethink the way we recruit for and run clinical trials so we can better serve people across the globe who have rare diseases."

As previously mentioned, IndoUSrare has been remedying this issue by expanding the patient pools of rare diseases via the creation of global patient registries. This enables clinicians to search for suitable candidates for their trials beyond their country borders and address potential patient shortages at the local level.

• Challenge 5: Equity and access issues

Considering that rare disease clinical trials are relatively uncommon to begin with, the locations where they take place can pose accessibility challenges to patients. This problem is particularly pronounced for ethnic or female patients, who may lack the means to travel.

"To have equity and health means everyone has the opportunity to be as healthy as possible regardless of social, geographic, economic, or other obstacles that may be working against them," says Reena Kartha, Board Director for Research Programs at IndoUSrare and Associate Professor at the University of Minnesota.

To cater to a more diverse patient demographic, the design of clinical trials, especially when opting for an international or more inclusive patient pool, should contemplate adopting a decentralized model. Electronical clinical platforms incorporate AI-powered tools to recruit, screen, and communicate with patients remotely. A clinical trial that requires minimal travel (and associated costs) is accessible to more patients.

Pre-requisite to the decentralization of global clinical trials is the establishment of national or global patient registries, especially in LMICs?a core part of IndoUSrare's current mission. These secure registries, provided they are actively maintaining data security and patient privacy, allow researchers conducting clinical trials to connect with eligible patients everywhere.

Decoding the rare disease conundrum: the IndoUSrare way
The current rare disease challenges are linked in a complex web and cannot be tackled in isolation. The fundamental issue lies in the fact that 90% of the rare disease research is conducted in 10% of the world's population living in the US/EU. In order to engage the general population, we need epidemiology data about individual rare diseases from all countries including LMICs. Towards this goal, IndoUSrare collaborated with researchers across borders at the All India Institute for Medical Sciences (AIIMS), Generating Research Insights for Development (GRID) Council, MS Ramaiah University of Applied Sciences, University of Minnesota, Hyman Phelps & McNamara P.C., and George Mason University to publish an article on "A review of methods for estimating the prevalence of rare diseases" in the rare disease and orphan drugs journal.

Though the total number of rare disease patients worldwide is substantial, the number of individuals affected by a specific condition can be comparatively small. Experts opting to investigate a specific disease are likely to conduct clinical trials for which the natural history of the disease is well understood and where the necessary number of patients are readily available to participate in research. The lack of access to clinical trial sites and attrition further drives down the number of participants, often leading to the suspension of these studies or treatment options that do not meet regulations.

To answer the amalgam of challenges noted here, IndoUSrare proposes a multi-pronged solution encompassing inclusive and modern, decentralized clinical trials, data sharing and global patient registries, and cross-border collaboration is necessary. For example, stakeholders from different middle- and low-income countries can compile a common patient database that can be subsequently shared to researchers looking to recruit participants from a larger patient pool for their clinical trials. Such a registry is likely to be ethnical diverse, thereby enhancing the clinical trial's representativeness and generalizability.

Cross-border collaboration is the key ingredient in making a global patient registry possible. The patient data drawn from participating countries must be standardized to be useful, but each country has its own healthcare system and regulations. Only concerted efforts from patient advocacy groups, research organizations, and regulatory bodies across participating countries can facilitate the harmonization of this data.    

If implemented effectively, a shared patient registry can accurately digitize the natural history of a rare disease and the centralized repository of patient population can be utilized for research and clinical trials. This is foundational for the globalization of modern clinical trials that are so heavily data/AI driven and patient-centric. Decentralizing these clinical studies and evidence generation process through patient-centric clinical management platforms, that are also affordable, can significantly enhance patient accessibility and retention. Clinical trials in which participants are digitally well characterized, inclusive, and engaged, are critical to accelerate research and development in a domain where funding is inherently scarce.

Be "rare" on Rare Disease Day 2024
Dr. Rajasimha, founder and chairperson of IndoUSrare, will be presenting a poster and exhibiting at the Rare Disease Day at NIH 2024, Bethesda, MD. Other IndoUsrare events of interest:

• IndoUSrare RARE Event ? February 28, Online
• FDA Rare Disease Day Event ? March 1, Online
• Indo US Bridging RARE Summit ? November 16-18, New Delhi

About IndoUSrare:
IndoUSrare is a humanitarian nonprofit 501(c)(3) tax-exempt public charity organization based in the United States. Founder and Executive Chairman Dr. Harsha Rajasimha, who lost a child to a rare disease in 2012, has been a rare disease advocate for more than 10 years. To address the unmet needs of diverse patients with rare diseases globally, the leadership team comprised of experienced professionals from research, advocacy, regulatory, and drug development seeks to build cross-border collaborations connecting stakeholders of rare diseases in low- and middle-income regions such as India, with their counterparts and clinical researchers in the United States to improve the diversity of clinical trial participants, accelerate research and development, and improve equitable access to life-saving therapies to diverse populations of rare disease patients. Visit https://indousrare.org.

References:
1. Nguengang Wakap, Stéphanie et al. "Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database." European Journal of Human Genetics, nature.com/articles/s41431-019-0508-0. Accessed 14 Feb. 2024.
2. Atlhobaiti, Hana et al. "Disentangling the Cost of Orphan Drugs Marketed in the United States." Healthcare (Basel), ncbi.nlm.nih.gov/pmc/articles/PMC9957503/. Accessed Feb 14. 2024.
3. Yates, Nathan, Jennifer Hinkel. "The economics of moonshots: Value in rare disease drug development." Clin Transl Sci, ncbi.nlm.nih.gov/pmc/articles/PMC9010265/. Accessed 14 Feb. 2024.
4. National Institutes of Health. "Rare Diseases." National Institutes of Health, nih.gov/about-nih/what-we-do/nih-turning-discovery-into-health/promise-precision-medicine/rare-diseases. Accessed 14 Feb. 2024.
5. Liu, Hong-Yan et al. "Diagnostic and clinical utility of whole genome sequencing in a cohort of undiagnosed Chinese families with rare diseases." Scientific Reports, nature.com/articles/s41598-019-55832-1. Accessed 14 Feb. 2024.
6. Prater, Erin. "It takes an everage of 8 years for a rare disease patient to get diagnosed. Why is it so hard to get life-altering genetic testing in the U.S.?" Fortune, fortune.com/well/2023/02/28/rare-disease-patients-diagnostic-odyssey-whole-genome-sequencing-wgs-genetic-testing/. Accessed 14 Feb. 2024.
7. Bell, Stuart A., Catrin Tudur Smith. "A comparison of interventional clinical trials in rare diseases versus non-rare diseases: an analysis of ClinicalTrials.gov." Orphanet Journal of Rare Diseases, ojrd.biomedcentral.com/articles/10.1186/s13023-014-0170-0. Accessed 14 Feb. 2024.
8. Rees, Chris A. et al. "Noncompletion and nonpublication of trials studying rare diseases: A cross-sectional analysis." PLoS Med., pubmed.ncbi.nlm.nih.gov/31751330/. Accessed 14 Feb. 2024.

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