Advancing Rare Disease Research With Patient Registries

A conversation with Harsha K. Rajasimha, Ph.D., founder and executive chairman, Indo US Organization for Rare Diseases (IndoUSrare)

“Rare dad” Harsha Rajasimha, Ph.D., knows how dire rare disease research can be. Rajasimha has been a rare disease advocate for more than a decade, after losing a child to a rare disease in 2012, and has endeavored to address the unmet needs of diverse patients with rare diseases globally. Now the founder and executive chairman of IndoUSrare, Rajasimha has sought to build cross-border collaborations with stakeholders in rare diseases from low- and middle-income regions such as India with their counterparts and clinical researchers in the U.S. to improve clinical trial diversity, accelerate research and development, and improve equitable access.

In this Q&A, Rajasimha discusses the current state of rare disease research and explains how patient registries can help propel drug development for rare disease therapies.

What are the current obstacles faced in rare disease research and treatment?

Rajasimha: Obstacles in conducting rare disease research are many and include:

• a lack of scientific literature and patient symptoms data from sufficient patients to understand the disease etiology,
• sparse distribution of patients within a country or across the world,
• a lack of training or education among medical experts in rare diseases, as they tend to affect multiple organ systems with significant symptom heterogeneity,
• a lack of cross-border data sharing guidelines, which are also complicated by local regulatory frameworks,
• typically, smaller budgets despite the same regulatory expectations of safety and efficacy,
• protocol complexity in terms of trial design, operational and logistical complexity in terms of supplies, travel, and remote or decentralized patient engagement or assessments, and
• unexpected changes such as a pandemic, war, or natural disaster that cause significant obstacles in this space, where the return on investment (ROI) may be limited for sponsors with a single asset for orphan indications.

All these barriers in addition to general obstacles that apply to common indications place unprecedent demand on operational efficiency in terms of timelines, costs, quality, and compliance.

Why are patient registries vital to advancing the research and treatment of rare diseases?

Because the scientific literature is limited for most rare diseases, the success of any R&D program depends on the availability, reliability, integrity, and sharing of real-world data (RWD) including those reported by the patients and caregivers in addition to clinically captured data sets. Since 2010, the NIH and the FDA have been recommending and supporting the creation of patient registries and natural history studies for each disease. There is also a need to tap into the commonalities among rare diseases to gain research efficiencies.

How can clinical trial sponsor companies, government organizations, and nonprofits collaborate in the creation and maintenance of a patient registry?

Government acts, policies, and guidelines have played a vital role in the progress of rare disease research. As an example, the Orphan Drug Act of 1983 spurred innovation leading to the approval of about 1,100 orphan drugs by 2023. Since the epidemiology or the prevalence and incidence of most rare diseases remain unknown, particularly in different populations, any policy updates are handicapped due to a lack of epidemiology data. The number of new rare diseases discovered in recent years due to the healthcare community’s ability to diagnose new rare and genetic diseases has taken the count close to 11,000 known rare diseases in 2023 (according to a recent report by RARE-X).

Sponsors rely on the Office of Patient Affairs and the Office of Orphan Products Development at the FDA for guidelines and advice to collaborate with patient advocacy organizations and to develop or access patient registries in a fair and compliant manner to recruit patients into clinical research programs. There are several challenges here. There are multiple siloed registries for the same rare disease created by different groups or sponsors, causing a lack of centralized access to the already limited number of patients’ data. Also, registries developed within specific countries or regional boundaries are limited in their usefulness. Lastly, there is a lack of patient and caretaker awareness about the usefulness or the role of these registries in the drug development process, so they don’t yet understand the value of investing their time and effort in contributing to registry programs.

What features constitute a usable and useful patient registry?

The creation and maintenance of a patient registry is a highly interdisciplinary project requiring multistakeholder collaboration. I believe the ideal scenario is for nonprofit patient groups to receive the funding to lead the creation of a global patient registry for a given rare disease(s), supervised by academic principal investigators (e.g., medical geneticist research doctor). Following proper good clinical practice (GCP) guidelines with institutional review board (IRB) approved protocols in the U.S., or ethics committee approved protocols in the rest of the world, would make the registry most useful in the long term for clinical research, guiding public health policy development, and controlling data of patients enrolling in clinical trials.

What’s more, the patients enrolling in patient registry studies have to be properly informed and consented on what data is collected and how that data will be used for research and development in the future. Defining those intended uses of the data is a critical hallmark of usable and useful patient registries. Plus, any data capture systems used for remote assessments or electronic data capture have to adhere to regulatory standards and guidelines such as FDA 21 CFR Part 11, GCP, HIPAA, GDPR, and SOC2 for data security and privacy. These guidelines may vary based on geographic location, funding agency, and intended uses.

PHUSE, an independent, not-for-profit organization  for data managers, biostatisticians, statistical programmers, data scientists, and eClinical IT professionals, has become the industry voice to regulatory agencies and standards organizations such as the FDA, EMA & CDISC. PHUSE recently developed and published Best data practices for rare disease patient foundations and researchers as guidelines for the creation of usable and useful patient registries.

As the parent of a child with a rare disease and former NIH data scientist, I took to social entrepreneurship in leading the development of a cloud-based scalable technology platform for sponsors, patient groups, government agencies, and others to launch global patient registries faster, cheaper, and better.

If a sponsor company is looking to recruit patients for an upcoming trial, what is the best way to identify and leverage a patient registry?

Usually, a sponsor company first recruits principal investigators (PIs) and sub-investigators (subPIs) for their clinical trial, who are likely to include the PI of a patient registry. This is part of the KOL selection process, which is a critical early step in planning a clinical trial. Having the right investigators who already have a trusted set of patients makes it easy for the sponsor to reach patients via the PIs. If the registry is stewarded by a patient advocacy group, the sponsor may contract with the advocacy group so the PI can utilize the registry to screen patients for inclusion/exclusion criteria and enroll eligible patients into the clinical trial per the protocol. This ensures that patients are treated as research partners, not a means to an end. Sometimes, the sponsor has invested in the creation of such a registry and the informed consent obtained during the registry creation and during clinical trial enrollment governs the patient recruitment process.

Patient registries exist but don’t cover all indications. Of all the indications, and especially rare diseases, where is the greatest need for a registry?

The key to understanding here is that the patient’s electronic medical records (EMRs) are the ultimate source of the truth of a patient’s health and disease in one location. Unfortunately, there are 200+ EMR systems in the U.S. alone, making it difficult to access this information. Even within a given EMR system, the challenge is that they were originally developed to support the insurance claims process and not healthcare delivery. If we go beyond the U.S. and maybe the EU, most countries have yet to adopt EMR systems, making it a very heterogenous environment for global research and development programs. Sponsors will need a global strategy —usually one for the U.S. and another for the “rest of the world.”

Patient enrollment in clinical trials is a well-known challenge for many reasons (awareness, trust, convenience, etc.). What is the patient response to joining a registry?

Patients and families need proper awareness and education about the critical role of patient registries in clinical trials and beyond. Patients with rare diseases are often altruistic in helping others and in trusting the healthcare ecosystem to do the right thing to accelerate progress toward finding a treatment for their rare disease. There are, of course, exceptions to this general rule, especially when we go out of the U.S./EU region to emerging markets. In these places, patients tend to be skeptical about the need for an organization to collect data without any assurance of free or affordable treatments.

Patient groups in the U.S./EU have worked hard to advance patient registries and orphan products development programs. Emerging markets, such as India, are now rising to the occasion with national policies for rare diseases and budget allocation toward rare disease research, digital health, and orphan drugs. At the Indo U.S. Organization for rare diseases, we have taken a rare patient concierge approach to developing a common data registry and remote patient assistance for most rare diseases that we can leverage to provide opportunities for consented patients, particularly of the Indian diaspora, to be matched and potentially enrolled in clinical trials.

Because patient registries contain protected health information (PHI) and therefore must adhere to the Health Insurance Portability and Accountability Act (HIPAA) privacy rule, what are some of the challenges to setting up and maintaining a secure registry?

The HIPAA privacy rule applies in the U.S., and Global Data Protection Regulations (GDPR) apply in the EU and certain countries, but many countries have yet to develop their own national regulatory frameworks for data protection or privacy. This is usually perceived as a huge barrier for data collection and sharing programs. The best resource to refer to is the NIH global rare disease registry (GRDR), now known as the Rare Diseases Registry (RaDaR) Program.

About The Expert:

​Harsha Rajasimha, MS, Ph.D., is the founder and executive chairman of Indo US Organization for Rare Diseases. He is also founder and CEO of Jeeva Informatics Solutions Inc., is affiliate faculty of systems biology at George Mason University, and sits on the board of directors at Greater Gift.

Harsha is a serial entrepreneur with a background in clinical genomics data science and 17+ years of experience in precision medicine data research in academia, the NIH, healthcare and life science consulting, and multiple startups. Harsha made a bold career move after losing a newborn child to a rare congenital disease in 2012 and his younger brother to juvenile diabetes in 2017. He decided to apply his years of postdoctoral training at NIH and FDA to take on social entrepreneurship.

At IndoUSrare, Harsha is fostering cross-border collaborations between stakeholders of rare diseases in the U.S., India, and globally. Harsha earned his MS in computer science (2004) and Ph.D. in genetics, bioinformatics, and computational biology (2007) from Virginia Tech.