Current Status of Statistics and Future Improvement Plans on Rare Diseases in Korea- Focusing on 2021 Annual Report on the Rare Disease Patients in Korea -

Abstract

This study presents statistical methods and findings from the 2021 Annual Report on the Rare Disease Patients in Korea and discusses future improvements. Using data from five institutions, the report tracks rare disease codes and provides statistics on incident cases, deaths, and healthcare utilization. In 2021, 55,874 new rare diseases were reported. Although the scope of rare disease statistics is expanding, further improvements are required. These improvements include creating new statistical indicators, implementing rare disease registration and statistics programs, and proposing an integrated information management system.

Key messages

① What is known previously?

Since 2020, the “Annual Report on the Rare Disease Patients in Korea” has provided information on incident cases, deaths, and healthcare utilization for rare diseases annually.

② What new information is presented?

In 2021, there were 55,874 new cases, with 1,845 deaths. The average medical expense per person in the first year after registration was 6.17 million KRW. The 2021 report extended healthcare utilization data from 3 to 12 months and expanded regional coverage from 7 to 17 areas.

③ What are implications?

Despite these advancements, new statistical indicators are needed, and the promotion of registration and statistical programs should be increased to improve the usability of reports.

Introduction

More than 7,000 different rare diseases have been identified worldwide, affecting an estimated 300 million people [1]. A rare disease is generally defined as any condition with a low prevalence, but each country has its own criteria for defining a rare disease. In the European Union (EU), a rare disease is defined as “a disease with a prevalence of 50 or fewer patients per 100,000 people in the EU.” In the United States (US), it is defined as “a disease with a prevalence of 200,000 or fewer cases in the US.” In Japan, it is defined as “a disease with no clear mechanism of pathogenesis and no established treatment.” In Australia, it is defined as “a disease with fewer than 2,000 patients, whether incurable or not” [2]. In the Republic of Korea (ROK), it is defined as a disease that affects fewer than 20,000 people or that has an unknown number of carriers due to diagnostic difficulties; this definition is determined according to the procedures and standards outlined in the Ordinance of the Ministry of Health and Welfare (Article 2 of the Rare Disease Management Act), as notified by the Commissioner of the Korea Disease Control and Prevention Agency (KDCA).

Since 2020, the KDCA has been publishing the Statistical Yearbook of Rare Disease Patients based on the aforementioned definition, establishing it as the only nationally recognized source for rare disease statistics in ROK. Prior to 2020, limited survey data were available, making it challenging to use as a foundation for improving policies and systems related to rare diseases. In response to the need for active government engagement in the efficient management of patients with rare diseases, as well as research and projects related to rare diseases, the Rare Disease Management Act was enacted in December 2015. This legislation led to the development of the First Comprehensive Plan for the Management of Rare Diseases (2017–2021) and the initiation of the National Statistics Project of Rare Diseases by the KDCA [3]. Consequently, rare disease statistics were first published in the “2019 Annual Report on the Rare Disease Patients in Korea” in December 2020, followed by four subsequent editions including the “2020 Annual Report on the Rare Disease Patients in Korea” in 2021, the “2020 Annual Report on the Rare Disease Patients in Korea (2)” in 2022 (which included revisions in statistical calculation criteria such as mortality rates and details of healthcare utilization from the 2021 edition), and the “2021 Annual Report on the Rare Disease Patients in Korea” in 2023.

Thus, this study introduces the method used to compile statistics on rare diseases in ROK, focusing on the “Annual Report on the Rare Disease Patients in Korea,” and proposes measures to improve rare disease statistics in the future, which are essential for the development of various systems and policies related to rare diseases.

Methods

1. Data Collection System and Contents

The Annual Report on the Rare Disease Patients in Korea are based on data collected from five relevant organizations: the National Health Insurance Service (NHIS), the Social Security Intelligence Service (SSIS), the Health Insurance Review and Assessment Service (HIRA), Statistics Korea, and the Ministry of the Interior and Safety. The data are categorized into three types: incidence statistics, mortality statistics, and healthcare utilization statistics. The collected data include information on individuals eligible for co-pay relief related to rare diseases from NHIS and SSIS, healthcare utilization data from the HIRA, cause of mortality information from Statistics Korea, and civil registration database information from the Ministry of the Interior and Safety. The data collected from each source are processed according to statistical standards and ultimately managed through the integrated information management system for rare diseases at the KDCA.

The specific collection items and details depending on each source are shown in Supplementary Table 1.

2. Selection of Subjects for Rare Disease Statistics

In the Annual Report on the Rare Disease Patients, patients with rare disease are defined as those who developed a new rare disease during the relevant year. The time of first occurrence was determined based on the date of initial application (new registration) for the special co-payment calculation system applicable to rare diseases. If the same person developed different rare diseases in the same year, the classification and criteria of rare diseases (excluding ultra-rare and other chromosomal abnormalities) were applied based on the diagnostic criteria of the co-pay relief system for rare diseases. Among multiple rare diseases (excluding ultra-rare and other chromosomal abnormalities), the first occurring rare disease was selected as the newly developed rare disease for that individual. If multiple rare diseases were classified as ultra-rare diseases or other chromosomal abnormalities, they were considered separate rare diseases. The rare diseases included in the statistical analysis for each year are those designated and notified by the KDCA at a certain time each year in accordance with the Rare Disease Management Act, including 926 rare diseases in 2019, 1,014 rare diseases in 2020, and 1,086 rare diseases in 2021.

3. Procedures and Methods of Data Processing

1) Data processing procedures for statistical analysis

For the purpose of the Annual Report on the Rare Disease Patients, data collected from NHIS and SSIS are used to identify subjects for analysis. In other words, the data for rare disease statistics are derived from administrative procedures and specialized roles of each organization, rather than from primary data collected directly. To finalize the selection of subjects and the corresponding rare disease information, the data must be processed to meet the criteria for rare disease statistics as described above.

2) Establishment of the database for managing the codes and history of rare diseases

The disease code information for patients with rare diseases, which is included in the co-pay relief data collected from the NHIS and SSIS, comprises a rare disease code (Korean Standard Classification of Diseases, KCD), a co-pay relief specific code, and a disease classification serial number. For statistical analysis of rare diseases according to the KDCA notification criteria, the rare disease codes assigned by the co-pay relief criteria from the NHIS and SSIS are matched with the disease codes in the annual report. For rare diseases without an assigned disease code in the KDCA notification, a new disease code is assigned based on consultations with Statistics Korea and disease code experts. As noted, the disease codes collected from the original sources and those listed in the KDCA notification, which serve as the basis for the annual report, differ from each other. Furthermore, new rare diseases are added, and existing ones are deleted or modified, causing changes in the historical data each year. To manage and utilize these codes effectively, a database was established to track the codes and history of rare diseases. This database includes information such as “change code” , “change contents”, “rare disease start year”, “rare disease end year”, “year of the annual report”, “serial number based on KDCA’s rare disease list”, “KCD based on KDCA’s rare disease list”, “KCD based on annual report”, “disease serial number based on NHIS”, “Korean disease name base on annual report”, “English disease name base on annual report”, “classification of rare diseases (rare diseases, ultra-rare diseases, and other chromosomal abnormalities)”.

4. Contents of Statistics for Rare Disease Patients

A total of four Annual Report on theRare Disease Patients have been published, beginning with the 2019 edition and concluding with the 2021 edition. The 2019 Annual Report on the Rare Disease Patients included only incidence statistics. In subsequent years, mortality and healthcare utilization statistics were added, and some criteria for generating statistics were updated. Table 1 provides a summary of the statistics and criteria reported for each year.

Table 1. Key findings and features of annual rare disease patient statistics (2020–2023).

Category	2020	2021	2022	2023
Annual report name	2019 Annual Report on the Rare Disease Patients in Korea	2020 Annual Report on the Rare Disease Patients in Korea	2020 Annual Report on the Rare Disease Patients in Korea (2)	2021 Annual Report on the Rare Disease Patients in Korea
Reference perioda)	2019.1.1.–2019.12.31.	2020.1.1.–2020.12.31.	2020.1.1.–2020.12.31.	2021.1.1.–2021.12.31.
Rare disease	926	1,014	1,014	1,086
Data collection date	2019.1.1.–2020.2.29.	2020.1.1.–2021.2.28.	2020.1.1.–2021.2.28.	2021.1.1.–2022.12.31.
Main contents	Incident cases (2019)	Incident cases (2020)	Incident cases (2020)	Incident cases (2021)
		Deaths (2019)	Deaths (2020)	Deaths (2021)
		NHIS benefit (2019) (during 3 months)	NHIS benefit (2020) (during 3 months)	NHIS benefit (2021) (during 12 months)
Changes contents		Include deaths & NHIS benefit (during 3 months)	Incidence, deaths, NHIS benefit (unified reference year)	NHIS benefit (during 12 months), detailed regional statistics

NHIS=National Health Insurance Service. ^a)Registration period for newly diagnosed rare disease patients in NHI benefit coverage system.

5. Improvements to the Statistics for Rare Disease Patients

First, new indicators and management measures related to rare disease statistics were developed through a review of literature from ROK and other countries. The final improvement plan was then formulated based on surveys and consultations with experts in rare diseases and statistics.

Results

1. Major Findings from the Statistics for Rare Disease Patients in 2021

The data collected from five relevant organizations were analyzed according to the data processing procedures, statistical content, and methodologies described above. The major statistical findings for rare disease patients in 2021 [4] are as follows. Detailed statistical findings for each year can also be accessed through the KDCA’s Rare Diseases Helpline (http://helpline.kdca.go.kr) and the national statistics portal (Korean Statistical Information Service, http://www.kosis.kr) [5,6].

1) Incidence statistics

Of the 1,086 rare diseases, a total of 753 rare diseases were registered with new patients. A total of 55,874 new cases (new patients) were registered for these rare diseases, with 27,976 (50.1%) male patients and 27,898 (49.9%) female patients. Of the total cases, 53,967 (96.6%) included rare diseases (excluding ultra-rare and other chromosomal abnormalities), 1,820 (3.3%) included ultra-rare diseases, and 87 (0.2%) included other chromosomal abnormalities.

2) Mortality statistics

Of the 55,874 cases of rare diseases in 2021, there were 1,845 deaths, including 1,826 cases of rare diseases (excluding ultra-rare diseases and other chromosomal abnormalities) and 19 cases of ultra-rare diseases. There were no reported deaths from other chromosomal abnormalities (Table 2).

Table 2. Key finding of 2021 Annual Report on the Rare Disease Patients in Korea.

Category		Total	Rare disease (excluding ultra-rare, other chromosomal abnormalities)a)	Ultra-rare diseaseb)	Other chromosomal abnormalitiesc)
No. of rare diseases	Total (officially annanced)	1,086	783	249	54
	Incident cases	753	525	192	36
	Incident cases (>patient 200)	52	51	1	0
No. of incident cases	Total	55,874	53,967	1,820	87
	Male	27,976	26,880	1,054	42
	Female	27,898	27,087	766	45
	Incident cases (>patient 200)	43,079	42,653	426	0
	Male	21,742	21,440	302	0
	Female	21,337	21,213	124	0
No. of deathsd)	Total	1,845	1,826	19	0
National Health Insurance Service benefite)	Patients	49,772	48,173	1,530	69
	Claims per capita (case)f)	15	15	23	51
	Vsits per capita (day)f)	19	19	26	46
	Days paid per capita (day)f)	214	216	165	107
	Medical expenses per capita (KRW 10,000)f)	617	620	559	242
	Insurance benefit per capita (KRW 10,000)f)	553	555	495	220
	Co-payment per capita (KRW 10,000)f)	64	64	65	23

^a)Rare disease: disease that affects less than 20,000 people or disease by which the number of people affected is unknown because it is difficult to diagnose that disease. ^b)Ultra-rare disease: disease has a specific diagnostic criteria and it satisfies one of the followings; (i) its affected people is less than 200, or (ii) it does not have a specific Korean Standard Calssification of Diseases (KCD). ^c)Other chromosomal abnormalities: new chromosomal abnormalities (deletion, duplication, etc.) which were detected by scientific and medical technology development meeting with the following criteria; (i) the abnormalities do not have a specific KCD, and (ii) it can be classified as a disease, not as a symptom. ^d)It refers to the number of patients who were registered within the same year and reported as deceased between January 1 and December 31, 2021. ^e)The statistics was produced from the information of National Health Insurance Service Benefit within 12 months after the registrations in 2021. ^f)Mean.

3) Healthcare utilization statistics

Of the rare disease cases, a total of 49,772 patients (clinic visits) were treated at least once within 12 months after initial registration for co-pay relief. The mean total medical expenses per patient were 6,170,000 KRW, with co-payments paid by patients amounting to 640,000 KRW (Table 2).

2. Suggestions for Improving Rare Diseases Statistics

The Annual Report on the Rare Disease Patients has been designated as a nationally approved statistic (Approval No. 117106) since 2019, with four editions published up to 2023. The 2019 Annual Report on the Rare Disease Patients published in 2020 included only incidence statistics. In contrast, the 2020 Annual Report on the Rare Disease Patients published in 2021 expanded to include mortality statistics and healthcare utilization statistics, as well as an increased number of statistical indicators for individual categories. However, to accurately report the overall incidence of diseases and improve policies and systems for managing rare diseases, various statistical indicators from a more direct and user-friendly perspective are needed. Additionally, there is a need to revise the statistical production system to account for changes in data sources and calculation methods to produce more accurate rare disease statistics. Moreover, it is necessary to develop a more systematic information system for collecting, managing, and analyzing data than the current information system. Thus, this study proposes the following measures to improve rare disease statistics in ROK [7].

1) Development of new statistical indicators

Currently, the Annual Report on the Rare Disease Patients includes incidence statistics, mortality statistics, and healthcare utilization statistics, with a total of nine statistical result tables for each category. Although the statistical indicators have been improved both quantitatively and qualitatively by incorporating feedback from various internal and external experts since the first publication, there remains a need to enhance and develop statistical indicators that are both direct and highly useful for the development of policies and systems related to rare diseases. Based on a review of Korean and international literature and input from the Statistical Advisory Committee on Rare Diseases, this study proposes the significance and development of key new statistical indicators, as detailed in Table 3 [8]. While the Annual Report on the Rare Disease Patients currently reports the number of rare disease cases in ROK, it is also essential to calculate the total prevalence of these diseases. To address this, several options could be considered: expanding the data from the NHIS and SSIS to include all registrants, not just those newly registered for co-pay relief, and using this data to calculate the overall prevalence of rare diseases; expanding rare disease registries to collect relevant data directly from designated organizations, such as the Cancer Registration and Statistics Program, to calculate the prevalence of rare diseases; or utilizing the incidence statistics from the Annual Report on the Rare Disease Patients, which is currently published, to calculate prevalence at a specific time point (point prevalence). For mortality statistics, the current count refers to the number of deaths within the current year among cases identified within that year. Given that the follow-up period for deaths can range from as short as one day to as long as one year, the current methodology for counting deaths may need to be reconsidered. Additionally, developing a relative survival rate—considering the probability of surviving without death from a rare disease within one year of diagnosis, combined with the life expectancy of the general population—would provide a valuable novel indicator.

Table 3. New statistical indicators for rare disease patients.

Indicators	Description	Method
Number of prevalent cases of rare diseases	Total prevalent cases of each rare disease for the current year Includes individuals diagnosed with rare diseases who are alive after a certain period	Collection of complete data on rare disease patients within the NHI system Implementation of the rare disease registration program Calculation of the point prevalent cases using the Annual Report on the Rare Disease Patients in Korea
Number of deaths	Number of deaths within 1 year of rare disease onset cf) Currently, number of deaths among rare disease patients within the same year	Review of current Statistics Korea cause of death data items and collection process
Relative survival rate for 1 year	Probability of not dying from the rare disease within 1 year of diagnosis Relative survival rate: the ratio of the observed survival rate of patients to the expected survival rate of the general population with the same sex and age group [8]	Linkage with Statistics Korea's cause of death data

2) Advancement in the integrated information management system for rare diseases

In the integrated information management system for rare diseases currently operated by the KDCA, data is transmitted from the KDCA based on five relevant organizations through the administrative information distribution system in text format. These data are then loaded into the integrated information management system for rare diseases, where they are organized into a database that facilitates connections between the different data sets. While the current system supports basic functions such as aggregation, error checking, correction, and deletion of transmitted and received information, it lacks advanced capabilities for data preprocessing and analysis of the integrated information. Therefore, it is necessary to upgrade the integrated information management system for rare diseases to one with more efficient data integration, management, and analysis functions, taking into account future expansion and utilization. The proposed contents and configuration of the information system are outlined below (Figure 1).

Figure 1. Integrated rare disease information management system diagram.

KDCA=Korea Disease Control and Prevention Agency; NHIS=National Health Insurance Service; SSIS=Korea Social Security information Service; HIRA=Health Insurance Review and Assessment Service; KOSTAT=Statistics Korea; SQL=structured query language; ML=machine learning.

(1) Overall system environment

• A system environment that enables automated data preprocessing according to certain predefined rules after staging of data collected from internal and external organizations.

• A system environment capable of advanced computational processing, including integrated analysis mart configuration, data processing and analysis, visualization of results, and machine learning.

(2) Statistical analysis functions

• Basic/advanced statistical analysis, modeling, visualization, unstructured data analysis, etc.

(3) Presenting and utilizing analysis results

• Establishing an environment where analysis results can be provided not only to internal staff and researchers but also to general users (the public) in the long term. The data should be usable even in a limited form, depending on the purpose of its utilization; however, institutional measures for the safe protection of privacy should be prioritized.

3) Actual implementation of the rare diseases registry program

As for rare disease statistics, the “2019 Annual Report on the Rare Disease Patients” was published in December 2020 under Article 10 of the “Rare Disease Management Act” (Projects, etc. for Statistics on Registration of Rare Diseases), which is significant, as it represents the first official data on the incidence of rare diseases in ROK. However, the current Annual Report on the Rare Disease Patients only analyzes new cases, which limits its ability to capture the overall status of all rare disease patients in ROK. Furthermore, the statistical analysis relies on secondary data collected and integrated through administrative procedures, which means the criteria for selecting subjects and conducting overall statistical analysis are based on administrative data processing rather than disease characteristics and clinical judgment. Additionally, the statistics only include co-pay relief registrants from NHIS and SSIS, excluding information on rare disease patients who are not registered. To address these limitations and to collect and manage comprehensive information on disease statistics and progression, it is necessary to implement a rare disease registry statistical program with a “disease registry” and reporting system, similar to the cancer registry in ROK. This initiative could also serve as core information for “establishing an integrated database” among the 10 strategic objectives proposed in the Second Comprehensive Plan for the Management of Rare Diseases (2022–2026) [9].

Discussion

The KDCA has been conducting a national statistics project to monitor the status of patients with rare diseases under national oversight in accordance with the Rare Disease Management Act. Since its initial publication in December 2020, the KDCA has been releasing the Annual Report on the Rare Disease Patients annually. This annual report, which is a nationally approved statistic, provides an annual overview of the status of rare disease patients in ROK.

The statistics on rare disease patients are derived from administrative data collected from five key organizations: the NHIS, SSIS, HIRA, Statistics Korea, and the Ministry of the Interior and Safety. The KDCA collects and integrates this data through administrative procedures aligned with each organization’s purpose and then preprocesses it for analysis to produce rare disease statistics. Initially, the Annual Report on the Rare Disease Patients included only incidence statistics. However, subsequent publications have introduced new statistical indicators, such as number of deaths and healthcare utilization, while expanding the scope of statistical analysis. Ongoing research is conducted to establish and review the criteria for statistical indicators and to develop various data processing methodologies, ensuring the reliability of these statistics.

To improve the policy and social utilization of current rare disease statistics in ROK as a national statistic, continuous efforts are required. From this perspective, this study proposes several key areas for improvement in rare disease statistics. First, it is essential to develop new statistical indicators that focus on the needs of consumers. Second, it is recommended that the integrated information management system for rare diseases of KDCA be advanced, and that a rare disease registry statistical program be promoted. These measures aim to produce more accurate rare disease statistics based on disease characteristics and clinical criteria in the medium to long term.

Rare diseases are often incurable and require lifelong treatment, resulting in high social costs and imposing significant psychosocial and economic burdens on patients and their families. Due to the limited number of cases, active government intervention is essential rather than relying solely on private efforts. Therefore, it is crucial to develop clear and comprehensive statistical information to enhance the efficiency of the current system, develop additional systems, and support various policy decisions. Achieving this requires ongoing support and efforts at the national level.

Supplementary Materials

Supplementary data are available online.