Invisible No More: How Redefining Rare Diseases Can Advance Health Equity

Abstract

The prevailing definition of “rare diseases,” typically based on arbitrary prevalence or incidence thresholds, has become a policy tool that increasingly obscures reality and in some cases undermines equity in health systems. While these definitions are well intentioned and originally intended to facilitate regulation and research prioritization, they now function as blunt instruments that fail to reflect advances in diagnostics, clinical burden, societal impact, or scientific opportunity.

To better understand the historical context, some context setting is required. The decision to define rare diseases by prevalence was a pragmatic solution to a crisis in drug development that peaked in the 1970s. Prior to this reference point, “rare” was a clinical description, but it had no legal or economic weight. The transition to a numerical definition was driven by a movement of “medical refugees,” that is, patients whose conditions were known to science but ignored by industry.

This is because commercially inclined pharmaceutical industry focused on “blockbuster” drugs for common ailments like hypertension or infection. In that regard, small patient populations were deemed “unprofitable.” The “Orphan” metaphor gained traction in the 1960s and 1970s, when physicians began calling drugs for rare conditions “orphans” because they lacked a “parent” (a pharmaceutical sponsor) to bring them to market. The movement gained momentum when families of children with conditions like Tourette syndrome and Hemophilia began organizing. They realized the problem was not a lack of scientific interest, but a broken economic model. In the United States, the Waxman–Hatch discussions led to the Orphan Drug Act of 1983. This was the first time “rare disease” was codified into law. Originally, the 1983 Act did not even have a numerical definition. It simply defined a rare disease as one for which there was “no reasonable expectation” that the cost of development would be recovered from sales. This “lack of profit” definition proved too difficult to audit. To provide clarity for the FDA and industry, Congress amended the Act in 1984 to include a hard prevalence cap: fewer than 200,000 people in the United States.

Following the success of the US model, other regions adopted prevalence-based definitions to align with global R&D pipelines, though the specific “cut-off” numbers varied based on population size and healthcare philosophy. During the drafting of these laws, policymakers debated using “severity” or “unmet need” as the metric. However, prevalence was chosen for three historical reasons: (1) prevalence provided a “bright line” for regulators. A disease either met the number or it did not, preventing endless litigation over how “severe” a condition truly was; (2) legislators viewed rare disease policy as a form of social insurance. Since anyone could be born with a rare mutation, the policy was designed to protect the rarity of the event, much like insurance covers low-probability/high-impact accidents; and (3) the primary goal was to fix a market failure. Since market failure is a function of the number of buyers (prevalence), the solution had to be indexed to that same number.

At its core, rarity is a statistical descriptor, not a meaningful proxy for need. Diseases are labeled “rare” solely because they affect fewer than a specified number of people, regardless of severity, complexity, or lifelong impact. This framing can unfortunately equate low prevalence with low priority, even when these conditions are profoundly disabling, fatal, or resource intensive. As a result, patients with rare diseases often face delayed diagnosis, fragmented care, and limited therapeutic options, not because solutions are impossible, but because policy provision has not kept up.

The definition is also inconsistent and jurisdiction dependent. A condition may be considered rare in one country and not in another, based purely on population size rather than biological or clinical characteristics. This inconsistency complicates international research collaboration, regulatory alignment, and equitable access to therapies. It also exposes the artificiality of the category: diseases do not change their nature when they cross borders, but policy labels do.

Moreover, prevalence-based definitions fail to account for cumulative impact. While each rare disease affects a relatively small population, rare diseases collectively affect hundreds of millions of people worldwide. Treating them as isolated exceptions fragments advocacy and policy responses, preventing health systems from addressing the shared challenges they pose, whether diagnostic odysseys, limited clinician expertise, and gaps in evidence generation.

The current definition also distorts research and innovation incentives. By tying regulatory benefits and funding mechanisms to rarity thresholds, policy encourages strategic disease segmentation and reinforces siloed thinking. This can slow the translation of insights from rare disease biology into broader medical advances, despite the fact that many breakthroughs in genetics, immunology, and oncology have originated from studying low-prevalence conditions.

Finally, the language of rarity itself carries unintended social consequences. “Rare” can signal anomaly, marginality, or exception, subtly reinforcing stigma and isolation for patients and families. It frames individuals as outliers rather than as citizens with legitimate and urgent healthcare needs. In policy discourse, language matters: it shapes what is seen, what is funded, and what is solved. Table 1 examines the pros and cons of classifying rare diseases based on prevalence alone.

A more fit-for-purpose framework would move beyond prevalence alone and incorporate severity, unmet need, diagnostic complexity, and potential for scientific insight. Such a shift would better align policy with patient experience, reflect the true burden of these conditions, and support more rational, equitable decision-making. In this context, the EU stepped forward into more of an hybrid approach to its prevalence criteria. The EU (Regulation EC No 141/2000) added a qualitative layer that other regions lacked, by defining rare diseases as a condition affecting no more than 5 in 10,000 people that is life-threatening or chronically debilitating. This was significant in that it was an “alternate” because it reintroduced severity as a requirement alongside prevalence, ensuring incentives were not used for trivial or “cosmetic” rare conditions.

While prevalence has historically served as the principal criterion for defining rare diseases, reliance on prevalence alone may not adequately capture the full spectrum of disease burden experienced by patients. Rare disease policy frameworks were originally designed to stimulate therapeutic development for conditions affecting small populations that would otherwise be commercially unattractive. However, prevalence does not necessarily reflect the degree of suffering, disability, or psychosocial burden associated with a condition. Two diseases with similar prevalence may differ markedly in terms of functional impairment, quality-of-life impact, healthcare utilization, and long-term societal costs.

At the same time, expanding the definition of rare diseases beyond prevalence raises legitimate concerns regarding where boundaries should be drawn. Some conditions that are not life-threatening may nonetheless impose substantial psychological or social burdens, particularly when they affect visible aspects of appearance or daily functioning. For example, dermatologic or autoimmune conditions that alter physical appearance can produce significant psychosocial distress, stigma, and reduced quality of life despite not directly affecting survival. Recognizing such burdens highlights the complexity of evaluating disease impact; however, it also underscores the need to avoid extending policy incentives indiscriminately to conditions that may be perceived as primarily cosmetic or of comparatively limited clinical consequence.

Health systems routinely confront analogous challenges when allocating finite healthcare resources. Many countries employ structured health technology assessment frameworks, including cost-effectiveness analyses and quality-adjusted life-year (QALY) considerations, to evaluate whether new interventions provide sufficient clinical value relative to their cost. These frameworks acknowledge that resource allocation decisions must balance the needs of individual patient populations with the sustainability of the broader healthcare system. Importantly, such processes attempt to make these judgments through transparent and systematic evaluation rather than through ad hoc or purely subjective determinations.

In this context, incorporating disease severity, functional impairment, and unmet medical need into rare disease considerations should not be interpreted as replacing prevalence thresholds, but rather as complementing them. A multidimensional framework could help prioritize conditions that impose the greatest overall burden on patients and families while still maintaining appropriate guardrails for the allocation of incentives and research investment. Criteria such as degree of disability, impact on daily functioning, long-term health consequences, and absence of effective treatments may help contextualize prevalence and guide more balanced prioritization.

Such an approach may also support broader goals of health equity. Health equity does not require that all conditions receive equal levels of attention or investment; rather, it seeks to ensure that patients experiencing the greatest health burdens are not systematically disadvantaged by overly simplistic classification systems. By considering both the size of the affected population and the depth of disease impact, policymakers and stakeholders may be better positioned to identify areas of unmet need and direct resources in ways that more fairly reflect the lived experience of patients.

Redefining rare diseases beyond prevalence, by incorporating measures such as severity, degree of debilitation, disease burden, and unmet medical need, has the potential to advance health equity by better aligning policy incentives, research prioritization, and healthcare resource allocation with the realities faced by patients living with these conditions.

Traditional definitions of rare diseases are based primarily on prevalence thresholds (e.g., fewer than 200,000 individuals affected in the United States). While such definitions are useful for regulatory classification and eligibility for incentives under orphan drug policies, prevalence alone does not capture the profound heterogeneity in clinical burden across rare conditions. Two diseases with similar prevalence may differ dramatically in terms of severity, life expectancy, disability, quality of life, caregiver burden, and healthcare utilization. As a result, relying exclusively on prevalence can inadvertently obscure disparities among rare disease populations and lead to inequitable prioritization in research investment, policy attention, and treatment development.

Incorporating severity or degree of debilitation into the conceptual framework of rare diseases could promote a more equitable approach to healthcare by ensuring that conditions associated with the greatest health losses receive appropriate attention. From a health equity perspective, patients with severely debilitating or life-threatening rare diseases often face compounded disadvantages: limited treatment options, diagnostic delays, substantial out-of-pocket costs, and high caregiver and societal burden. Recognizing disease severity alongside prevalence would help policymakers and stakeholders better identify those patient populations whose unmet needs are greatest and who may benefit most from targeted research incentives and policy interventions.

Such a framework could also influence economic and reimbursement considerations in ways that support equitable access to innovation. In many healthcare systems, willingness to pay for new therapies is influenced not only by prevalence but also by the magnitude of clinical benefit and the severity of the underlying condition. Treatments that substantially reduce mortality, prevent irreversible disability, or significantly improve quality of life may justify higher reimbursement levels because they offset substantial downstream costs, including hospitalizations, complex medical procedures, long-term care, and productivity losses. By explicitly acknowledging severity and disease burden within rare disease classifications or policy discussions, payers and health technology assessment bodies may be better positioned to evaluate the broader societal value of treatments for highly debilitating conditions.

Furthermore, expanding the definition beyond prevalence could improve equity in research prioritization. Many rare diseases remain understudied despite imposing devastating effects on patients and families. Incorporating severity metrics could help funding agencies, public–private partnerships, and philanthropic organizations prioritize research investments toward conditions with the greatest unmet need and highest burden of suffering, rather than solely those that meet arbitrary prevalence thresholds.

Importantly, such a shift does not eliminate the economic challenges inherent in rare disease drug development. However, a framework that recognizes both prevalence and disease burden can help align incentives with societal values, ensuring that the most vulnerable patient populations are not overlooked simply because they fall within small or heterogeneous disease categories. By explicitly accounting for severity, debilitation, and unmet medical need, policymakers and healthcare systems can move toward a more equitable distribution of attention, resources, and innovation across the rare disease landscape.

Ultimately, redefining rare diseases through a multidimensional lens, by combining prevalence with severity and impact, can help ensure that health systems respond not only to how many individuals are affected, but also to how profoundly their lives are altered by disease. Such an approach supports the broader goal of health equity by striving to ensure that patients with the most severe and neglected conditions have fair opportunities to benefit from medical progress.

In an era of precision medicine and global collaboration, defining diseases by how few people have them is an increasingly outdated approach.¹ Health policy should evolve from managing exceptions to addressing complexity, wherever it appears. Given significant advances in precision engineering of drug treatment for complex diseases, is it time to reconsider the prevalence-based criteria of what a rare disease is?

The authors declare no conflict of interest.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.