1 Introduction
Rare diseases affect between 25 and 30 million people in the United States, or 10% of the population, and an estimated 350 million people worldwide [
1‐
3]. Although there is some variability in how a rare disease is defined between regions, a disease or disorder is considered rare in the United States when there are fewer than 200,000 cases at any given time, and in Europe, when the condition affects fewer than one in 2000 individuals [
3,
4]. Globally, 75% of rare diseases are pediatric and 30% of the affected children do not live past the age of 5 years [
1]. Despite the staggering number of individuals whose lives are altered due to a rare disease diagnosis, 90% of the approximately 7000 known rare disorders have no US Food and Drug Administration (FDA)-approved treatment [
1,
5]. Barriers to research for effective treatments include restricted funding support, limited foundational disease-specific knowledge, gaps in understanding of the heterogeneity of the condition, caution around risk–benefit thresholds and clinically meaningful impact for the patient population, small and dispersed patient communities that challenge traditional methodologies, and fragmentation of efforts that impede timely scientific discovery [
1,
6]. To reduce and mitigate some of these barriers, patient registries are increasingly utilized by experts within the rare disease research field to facilitate learning networks and research collaborations between industry, scientific researchers, regulators, clinicians, community organizations, and patients and families [
7‐
9].
By definition, 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 one or more predetermined scientific, clinical, or policy purposes” [
10,
11]. The Agency for Healthcare Research and Quality’s registries guide identifies four primary use cases for patient registries: (1) describing a disease’s natural history; (2) determining clinical effectiveness of treatments; (3) assessing the safety of treatments; and (4) evaluating or improving quality of care [
9,
12]. Often, registries collect additional individual-level details not typically captured within traditional clinical settings that can inform the design of clinical trials to better reflect the needs of the patient population [
13].
Patient registry frameworks vary significantly, reflecting design differences that accommodate intended use cases and a predetermined purpose. Recognizable examples include (1) public health and epidemiological disease (tracking) registries that monitor the prevalence, incidence, and trends of specific diseases; (2) clinical registries which gather physician-entered information regarding a patient’s disease progression, treatment, and symptom management, often with the collection of biological samples; (3) product registries which capture data on the efficacy and safety of new or repurposed drugs, medical devices, and other therapeutic and pharmaceutical products; and (4) natural history registries, particularly relevant for rare disease research, that generate patient-reported data to document the foundational characteristics of a condition [
6,
7,
13].
The challenges to rare disease research are many, including the heterogeneity of disease presentation and limitations in knowledge about true natural history within and between the ranges of rare diseases. We are at a critical moment: rare diseases are gaining recognition as a public health priority, and as such, the marketplace is rapidly expanding, resulting in community fragmentation from redundant initiatives in already small patient populations. In addition, emerging trends in precision medicine have focused on exploring more common, complex conditions, such as diabetes and heart disease, with the goal of identifying individual-level variations and smaller subgroups based on genetic subtypes, variations in drug response, and/or social and environmental disparities [
14,
15]. The identification of subgroups effectively creates rare disease subtypes of common conditions that likely will also be subject to similar limitations persistent and prevalent for rare diseases related to research methods, data collection, standards of care, clinical specialization, and policy challenges.
As the FDA turns its focus to natural history studies, real-world data, and accelerated approvals for rare diseases, there is a parallel emergent trend and broad acknowledgement of the importance of building collaborative relationships in rare disease research that empower patients and community organizations, while supporting formal partnerships with academic, industry, and government agencies to advance high-value, high-utility research for rare conditions. The recent FDA Draft Guidance “Rare Diseases: Natural History Studies for Drug Development” clearly states the importance of natural history registry studies in the drug development process and also acknowledges additional benefits through establishing communication pathways for the community, identifying centers of excellence for rare conditions, and evaluating differences and reducing variations in treatment practice, while establishing improved standards of care and tracking the disease to provide demographic and prevalence data [
16]. In relation to the utility of real-world data, which is the basis for real-world evidence, the “Framework for FDA’s Real-World Evidence Program” recognizes the importance of patient registries as a source, and highlights that processes to minimize missing or incomplete data and the collection of rigorous, high-quality data are critical to ensuring that the data generated are fit for use as real-world evidence [
11]. In concordance with certain provisions of the
21st Century Cures Act, foundational, structural, semantic, and organizational interoperability processes must be implemented and widely adopted, thereby optimizing the utility of data, in order to accelerate research and development [
17,
18]. This is particularly salient for rare diseases, where harmonizing data from different sources through the use of common data elements, core outcome sets, and standardized data structures can support the exchange and comparability of data across datasets and the utility and scalability of patient registries [
19‐
22]. Finally, the FDA has prioritized, through the
21st Century Cures Act and the institution of the Accelerated Approval Program, the expedited approval of drugs that fill a critical unmet medical need for treating serious conditions based on a surrogate endpoint thought to predict clinical benefit, rather than on an initial measure of clinical benefit itself [
18,
23]. The subsequent increase in new molecular entity (NME) submissions and approvals for rare diseases over the last 5 years represents a much-needed expansion of research and product development. Patient registries and natural history studies are a critical piece of the puzzle, promoting the acceleration of scientific advancement and product development informed by the lived experiences of the community. This manuscript outlines use cases and specific considerations for the implementation and application of patient registries and natural history studies.
3 Conclusion
Patient-centered registries collect cohort data to inform researchers of the natural progression of a disease; assist in the recruitment of participants for clinical trials; enable the monitoring of clinical treatments and outcomes in patients; and provide support for the establishment of disease-specific standards and care [
7,
26]. The wide use of these registries increases research accessibility for individuals affected by rare diseases and provides researchers efficient access to valuable patient data, a cornerstone of improving disease-specific knowledge, management, and treatments. Throughout the development of a patient registry, it is essential for all stakeholders to clearly define the study objectives and ensure that the registry is designed with maximum sustainability and is ethically governed, the data purpose and analysis plans are well-established, and there are sustainability and transition protections set forth [
7]. Although patient registries provide substantial value to specific rare disease communities, it is important to note that they may have greater impact when combined with multiple data sources [
9].
The current global movement towards innovative and patient-centered healthcare is enabling patient registries to increasingly emerge as valuable tools within the rare disease research field [
7,
9]. The United Nations, on September 23, 2019, adopted a declaration on Universal Health Coverage, as part of the 2030 Sustainable Development Agenda, that included, for the first time, recognition of rare diseases, marking a major milestone and priority indication for the population [
39]. The declaration provides leverage for policy makers and practitioners to advocate for national action toward providing health services for all people affected by rare diseases, ensuring that no population is left behind. This declaration represents a critical shift in the dynamics of rare disease policy and research, with the potential to transform how national and international goals are set, prioritized, and pursued in order to best address the needs of and accelerate progress for the rare disease community. In the United States, the US FDA recently announced a landmark initiative, the Rare Disease Cures Accelerator–Data and Analytics Platform (RDCA–DAP), a centralized, standardized infrastructure platform to support and accelerate rare disease characterization, scientific discovery, and drug development [
40]. The program establishes processes for the characterization of rare diseases and addresses some of the most complex and persistent research challenges to support innovation and expedite clinical trial design and regulatory review. The investments and advancements that are made today will be felt for generations to come. The power of patients is undeniable, and for rare diseases, it has never been more clear: the time to act is now.