PHWR Public Health Weekly Report

The term “rare diseases” refers to diseases with an extremely low prevalence, many of which are difficult to diagnose early due to a lack of basic disease information and have no effective treatment options. Furthermore, actively investing in the research and development for their diagnosis and treatment is challenging owing to low profitability; therefore, national intervention is needed to promote related research and support projects. The Korea Disease Control and Prevention Agency (KDCA) designates national managed rare diseases through discussions with medical experts in each field and deliberations by special committees in accordance with the Rare Disease Management Act [1]. Once designated, the economic burden on patients and their families is relieved in conjunction with national support policies such as the National Health Insurance Service’s (NHIS) special exemption system of co-payment for rare diseases (special exemption system for rare diseases) and KDCA’s medical expense support projects for patients with rare diseases. In addition, KDCA has officially established a framework for the rapid initiation and scale-up of research surrounding the diagnosis and treatment of rare diseases, which are characterized by a lack of information and underinvestment [2].

This report describes the definition of national managed rare diseases, criteria and procedures for their designation, and progress and achievements of the national managed rare disease designation project over the past 5 years since the first designation in 2018.

1. Definition of National Managed Rare Diseases

While there is no single definition of rare diseases around the world, countries define rare diseases in different ways, taking into account characteristics such as prevalence, severity, and diagnosis. In the US and Europe, the definition is based on prevalence/affected population [3,4], while Japan considers prevalence, diagnosis, and treatment [5]. In Republic of Korea (ROK), "rare disease" is defined as a disease that affects fewer than 20,000 people or for which the number of carriers is unknown owing to difficulty in diagnosis, considering prevalence and diagnosis according to Article 2 of the Rare Disease Management Act [1].

2. Criteria for Designation of National Managed Rare Diseases

Since the enactment of the Rare Disease Management Act (2015), the criteria for the designation of rare diseases have been established through the enactment of Rare Disease Management Act Enforcement Decree (2016), and detailed criteria for the designation of rare diseases according to Article 2 of the Enforcement Decree have been established by the Rare Disease Management Committee to ensure fairness and clarity in the deliberation of rare disease designation (Table 1) [1]. Unlike countries such as the US and Europe, which consider the prevalence/affected population of the disease, the criteria for rare disease designation in ROK considers the socioeconomic burden because rare diseases are supported and managed under the national insurance system.

Table 1 Designated criteria of rare disease for national management

Designated criteria	Detailed criteria
	Designation	Undesignation
1. Disease prevalence population	Disease that affects fewer than 20,000 people (based on statistics of the National Health Insurance Service or the Health Insurance Review and Assessment Service)	- Disease with a population of more than 20,000 people
2. Technical level for disease diagnosis	Disease that can be diagnosed specifically and independently	- Disease in which diagnostic criteria are not established or specific independent diagnosis is not possiblea)
3. The possibility of a cure for disease	Severe and difficult disease	- Transient or acute diseases, diseases that can be cured by surgery etc., or diseases diseases of relatively low severity
4. The level of socioeconomic costs for diagnosis and treatment of diseases etc.	Disease with a high burden of diagnosis and treatment etc.	- Diseases with relatively low co-payment for diagnosis and treatment, etc. (based on co-payment of costs for health care benefits per person)
5. Otherb)	Primary disease	- Diseases eligible for other projects or acceptable as designated rare diseases
		- Secondary diseases due to infection or drug trauma etc., or tumor
		- Lack of information, such as the absence of reporting cases in domestic academia, or the need for supplementation of the opinions of the specialists · relevant academic societies (re-deliberation of the following year after request for supplementation)

^a)Ex: nephrotic syndrome (×), NPHS1-related congenital nephrotic syndrome (O). ^b)Other criteria deemed necessary by the Commissioner of the Korea Centers for Disease Control and Prevention in consideration of the cause, characteristics, type, etc. of the disease..

3. Procedure for Designation of National Managed Rare Diseases

Because the population affected by rare diseases is extremely small, there is a general lack of information regarding the disease itself, including diagnosis and treatment. Thus, to allow anyone, including doctors and patients, to apply for designation as a rare disease, the threshold for demand surveys has been lowered, while efforts are being made to collect information concerning each disease and deliberate on whether to designate it through multiple stages (Figure 1) [6].

Figure 1. Designated procedure of rare disease for national management
KDCA=Korea Disease Control and Prevention Agency; HIRA=Health Insurance Review and Assessment Service; NHIS=National Health Insurance Service; KCD=Korean Standard Classification of Disease

1) Demand survey for deliberations regarding the designation of national managed rare diseases

The KDCA opened a Rare Diseases Helpline website (2006) to provide information about the characteristics of rare diseases occurring in ROK, the status of occurrence, and national support projects, and to listen to the voices of patients with rare diseases and their families [7]. Anyone, including patients and doctors, can apply for rare disease designation at any time of the year through this website. Since the deliberation process for rare disease designation is held once a year, the deliberation timing may differ depending on the application period. The diseases eligible for deliberation in the current year are all diseases that were applied for from March of the previous year to the last day of February of the current year (“Rare Disease Day”).

2) Disease deliberation process

To collect a wide range of information concerning rare diseases, information on rare diseases is to be collected through international rare disease information media such as Orphanet and Omim and related domestic scientific societies. Data from the NHIS and the Health Insurance Review and Assessment Service are also collected to understand the economic burden of such diseases. To review characteristics of diseases in detail, the four Rare Disease Specialized Committees, including the Genetic and Neurological Diseases Specialized Committee, review and discuss whether or not to designate a rare disease on the basis of the collected disease data, following which the Rare Disease Management Committee makes a final deliberation and decision.

In accordance with Article 7 of the Rare Disease Management Act and Article 4 of Rare Disease Management Act Enforcement Decree, the Rare Disease Management Committee has been organized and operated.

The Rare Disease Management Committee is composed of no more than 15 members, including one chairperson, and deliberates on essential matters concerning the formulation and evaluation of comprehensive plans and registration.

The Rare Disease Specialized Committees are comprised of no more than 20 members, including one chairperson per field, and deliberates matters that the Rare Disease Management Committee considers in a specialized manner.

3) Consultation among competent authorities

Diseases designated as national managed rare diseases are linked to the special exemption system for rare diseases operated by the NHIS. The NHIS participates in the deliberation process for the designation of national managed rare diseases and provides its opinions and consultations in order to promptly offer support according to the purpose of the special exemption system for rare diseases, which is to support severe and high-cost diseases.

In addition, KDCA publishes disease codes and disease names of national managed rare diseases according to the Korean Standard Classification of Disease (KCD) of Statistics Korea. Disease codes are used to categorize diseases in the healthcare system, including prescriptions, which are revised by Statistics Korea every 5 years. However, some of the national managed rare diseases have no disease code due to the nature of rare diseases affecting an extremely small number of individuals. In summary, Statistics Korea reviews the disease codes and names of newly designated diseases based on the KCD every year, following which the KDCA notifies of the newly designated rare diseases. When Statistics Korea revises the KCD (every 5 years), KDCA presents its opinions and discusses requests for the inclusion of diseases that have no disease codes in the KCD.

4) Notice of national managed rare diseases

After completing the entire deliberation process and finalizing the list of newly designated rare diseases, the entire list of national managed rare diseases, including newly designated diseases and new diseases, are notified on the KDCA website and the Rare Diseases Helpline, and published in the official gazette at the end of each year, which entails notification of the deliberation results of each application received on the Rare Diseases Helpline website.

4. Progress and Achievements in Designation of National Managed Rare Diseases

1) Status of rare diseases in the Republic of Korea before the enactment of the Rare Disease Management Act

In the ROK, medical expense support projects for rare incurable diseases began in 2001 for four diseases, including hemophilia. In 2015, however, the Rare Disease Management Act was enacted to provide a legal basis for promoting comprehensive and systematic support projects for rare diseases.

2) Expansion of eligible diseases according to continued promotion of national managed rare disease designation

Since the implementation of the Rare Disease Management Act in 2016, KDCA has established criteria and procedures for the designation of rare diseases. Since 2018, KDCA has been deliberating the designation of rare diseases every year to expand the number of national managed rare diseases (Table 2) [8,9].

Table 2 Status of rare disease for national management by year

2018	2019	2020	2021	2022	2023
926	1,014	1,086	1,123	1,165	1,248

For diseases designated as national managed rare diseases, KDCA provides guidelines along with basic information such as causes, symptoms, diagnosis, and treatment of each rare disease through the KDCA Rare Diseases Helpline website for patients, guardians, and healthcare providers. In addition, these are linked to projects for supporting the exemption system for rare diseases and medical expenses of patients with rare diseases, thereby helping to reduce medical expenses for the treatment of rare diseases and the rare disease diagnosis support projects that enable timely treatment through early diagnosis.

With the increasing demand for medical expense support related to rare diseases and the advancement of diagnostic technology and medicine for rare diseases, national managed rare diseases are expected to continue expanding in scale.

The KDCA Rare Diseases Helpline provides disease-related information, including symptoms, causes, diagnoses, and treatments for diseases designed as national managed rare diseases.

Enables designation of new rare diseases and application for support projects for medical expenses of patients with rare diseases. Allows introduction of other resources such as online counseling and disease-specific patient support groups.

3) Improvements to rare disease designation process

With the diversification of the national support projects for rare diseases and increase in the demand for the designation of new rare diseases, we sought to improve the reliability, fairness, and efficiency of the system, including the criteria and procedures for the designation of rare diseases, and to make the process transparent to the public.

(1) Improvements to the rare diseases redeliberation system

During rare disease deliberation, undesignated diseases are redeliberated to reflect medical advancements in the diagnosis and treatment of such diseases. With increased demand for deliberation for designation, the number of diseases to be redeliberated has also increased; therefore, the redeliberation process has been streamlined in an attempt to shorten the waiting time of patients for redeliberation.

In the past, there was a blanket rule that undesignated diseases and pending diseases would be redeliberated after 2 years and 1 year, respectively. Currently, undesignated diseases are redeliberated only in the following year without distinguishing between undesignated and pending, and the undesignated diseases finally remaining in redeliberation are terminated from deliberation. However, a disease with deliberation termination may be eligible for reapplication for designation at any time if additional evidence becomes available to address the reasons for the original failure to be designated.

Following improvements to the redeliberation system, the waiting time for redeliberation of undesignated diseases was shortened from 3 years to 1 year, and the undesignated diseases that remained before such improvement were decided to be redeliberated together for a faster deliberation, thereby resolving public inconvenience.

(2) Enhancing expertise of deliberations for rare disease designation

Owing to the lack of information regarding rare diseases, there is also a scarcity of relevant healthcare professionals and experts. For this reason, Rare Disease Specialized Committees have been formed involving healthcare professionals who treat rare diseases in clinical practice, thus enabling them to thoroughly evaluate diseases during the deliberation of rare disease designations.

To further strengthen the expertise of rare disease deliberation, the Rare Disease Specialized Committees were restructured in 2023 from four Specialized Committees to four subcommittees and six Specialized Committees (Table 3).

Table 3 Reorganization status of Rare Diseases Specialized Committees

Field (person)	Composition detail of sub-divisions (person)
1. Subcommittee (13): Genetic∙neurological disease	1-1.. Genetic (8). 1-2.. Neurology (5).
2. Subcommittee (17): Internal medicine disease	2-1.. Immunology∙cardiology∙respiratory∙allergy∙hematological tumor (9). 2-2.. Nephrology∙endocrinology∙gastroenterology (8).
3. Subcommittee (8): Surgical∙etc. disease	Ophthalmology∙otolaryngology∙orthopedics∙dermatology∙ dentistry (8)
4. Subcommittee (11): Rare diseases statistics	Health statistics∙epidemiology∙statistics∙applied statistics (7). Related public institutions (4).

4) Enhanced transparency in rare diseases designation by establishing rare diseases designation guidelines

To increase the credibility and transparency of the national managed rare diseases designation project, the Rare Diseases Designation Project Guidelines were established in 2022 to disclose details of the rare disease designation deliberation to the public, including the definition of rare diseases, criteria, and detailed explanations of each process. These were also published on the Rare Diseases Helpline website, making it more accessible for anyone to check the guidelines [6].

Approximately 70% to 80% of rare diseases are genetically inherited, and early diagnosis and timely treatment are difficult due to a lack of relevant information. In this regard, the national managed rare disease designation project increases access to basic medical information such as diagnosis and treatment of rare diseases by officially announcing rare diseases that occur in the ROK and plays an important role as the first gateway in reducing the economic burden of patients with rare diseases through government support, including the special exemption system of co-payment for rare diseases and medical expense support projects.

In future, KDCA will continue to identify and promote the designation of national managed rare diseases, thereby contributing to the activation of research, policy establishment, and support projects for the diagnosis and treatment of rare diseases in the country.

Ethics Statement: Not applicable.

Funding Source: None.

Acknowledgments: None.

Conflict of Interest: The authors have no conflicts of interest to declare.

Author Contributions: Conceptualization: JYJ. Project administration: JYJ. Supervision: JYK, CHC. Writing – original draft: JYJ. Writing – review & editing: JYJ, JKC, JYK, CHC.