18-19 - IDENTIFYING RARE DISEASES - The challenges of identifying rare diseases

Several factors contribute to the difficulty of accurately identifying and counting rare diseases. On one hand, the definition of what constitutes a rare disease differs between different countries around the world, ranging from five to 76 affected individuals per 100,000 people in the general population.

In Europe, a disease is considered rare when less than 50/100,000 individuals are affected, while in the US a rare disease is one affecting less than 200,000 people in the country. On the other hand, their rarity itself can make some conditions go unnoticed by the international scientific community unless the patients’ symptoms or phenotypes are properly classified and described in the medical literature and, ideally, the disease aetiology studied and defined.

The fewer the number of patients affected, the less probable that the disease will be described, classified and studied. Since most healthcare professionals (HCPs) are not experienced in recognising and managing the vast majority of rare diseases, in many cases a rare disease might not be diagnosed for years, or might be misdiagnosed as another more prevalent disease that it might resemble. Finally, computational differences motivated by the use of different nomenclatures or inclusion criteria also have an impact on the estimation of the number of rare diseases.

When interrogating the scientific literature, as well as public web pages from official governmental institutions or charities, figures between 5,000 and 8,000 rare diseases are frequently cited, with 7,000 rare diseases being one of the most repeated.

These numbers have remained unchanged over the last ten to 15 years, in spite of hundreds of new disorders being added to databases such as Online Mendelian Inheritance in Man (OMIM) each year. In addition, there have been advances in the identification of new, rare medical conditions and their associated causative genes over the last decade thanks to the reduced price and increased availability of techniques such as next-generation sequencing.

Two recent studies, however, have identified more than 10,000 rare diseases by computing and harmonising rare disease information from multiple data sources such as Orphanet, OMIM, GARD, DOID and NCI Thesaurus.

The first study was published in 2020 by a group of scientists who were part of the Monarch Disease Ontology (Mondo) initiative. This study identified 10,393 rare diseases. The second study was published in June 2022 as a report from the non-profit organisation RARE-X and it identified 10,867 rare conditions. Thus, it is safe to conclude that there are more than 10,000 rare diseases and this number is likely to increase in the coming years as a consequence of increased awareness and improved diagnosis.

Several analyses have tried to estimate the number of patients worldwide who have a rare disease. Epidemiological studies are limited, for reasons similar to those mentioned above, for the estimation of the number of existing rare diseases. It is often quoted that rare diseases affect 6-8% of the population. These figures were first referred to in 1992 by three studies that became the basis of the EU legislation on Orphan Products in 1999. Some additional estimations were published later, based on limited diseases and population coverage, or not considering only unique clinical disorders, which can lead to double counts by inclusion of groups and subtypes.

These disparities penetrate throughout the entire population and clinical trials often fail to encompass the diversity in the population. Further analysis has found that Asian, Hispanic and Latino, Native American and Alaska Native, Native Hawaiian and other Pacific Islander patient sub-populations were all significantly and consistently under-represented in clinical trials during the past decade. This means almost a third of the US population is not being represented adequately in clinical trials.

Trial diversity doesn’t only vary based on location, but also by disease indication. In 2016, clinical trials for cardiovascular therapies had less than 3% inclusion for black patients, despite this group being more likely to experience severe cardiovascular disease. Yet, trials focusing on psychiatric diseases have an over-representation of black and African-American patients – with 24.2% of patients participating in trials for psychiatric diseases being black or African American.

Given the inconsistencies in patient recruitment based on race, it is key that trials are better designed. Selection of adequate investigator sites and countries is needed at the planning stage to ensure adequate representation of racial groups in patients recruited into the trials. Population and disease occurrence data are vital tools for trial sponsors, allowing them to avoid oversights such as these and ensure that trial participant groups are an accurate representation of the patient population.

The most recent and methodologically solid estimate of the global burden of rare diseases was published in 2020 by a group of Orphanet researchers.
After excluding rare cancers, infectious diseases and poisonings, this study estimated that 262.9 to 446.2 million people worldwide are affected by a rare disease.
Of these, 17.8 to 30.3 million live in the European Union.
Considering methodological limitations and the fact that this estimation was based on the world population in 2017, a figure of 400 million affected patients worldwide is recommended.

According to a National Organization for Rare Disorders (NORD) report from 2020, as of 1 January 2020, 564 orphan products had been approved by the US Food and Drug Administration (FDA) to treat 838 rare diseases. By applying a simple proportion, 7.7-8% of rare diseases have an approved drug treatment (based on the RARE-X and Mondo figures cited above, of 10,867 and 10,393 rare diseases, respectively).

Even if we are conservative about the number of diseases and restricted to mainly clinical entities, such as Orphanet describes (around 9,300 rare clinical entities), the figure is still similar, at 9%.

It should be taken into consideration that this estimation does not take into account that some rare conditions can be treated with interventions other than drugs, such as surgery or diet, and that the estimated figure is likely to slowly change year-by-year as new treatments are approved. Thus, the real number of rare diseases with a treatment is likely to be slightly higher, but it is safe to say that at least 90% of rare diseases do not have a treatment.

The challenges of identifying rare diseases

With increased awareness and improved diagnosis, more rare diseases are being recognised and this number is likely to increase in the coming years

How many patients are there with a rare disease?

How many rare diseases have available treatments?