Background
Rare diseases are diseases that affect a small number of the population. Although every single rare disease affects only an extremely limited number of patients, which is defined as affects no more than 1 person in 2000 in Europe and affects less than 200,000 people in the United States. There are a total of 7000 rare diseases along with 250 to 280 new additional ones annually [
1,
2]. Rare diseases impact more people than cancer and AIDs, and approximately 30% of patients with rare diseases die before the age of 5 [
3]. Although rare diseases vary in etiology and clinical manifestations, most of them are associated with significant disease burden [
4,
5].
Orphan drugs are intended to treat, prevent or diagnose rare diseases. It was estimated that 95% of rare diseases are lacking drug treatments, demonstrating that the accessibility of orphan drugs is critical [
3]. In addition, the high price of orphan drugs poses challenges for both patients and governments. For example, the annual cost of eculizumab is over $409,500, which is used to treat Paroxysmal nocturnal haemoglobinuria, and the annual cost of idursulfase is over $375,000, which is used to treat Mucopolysaccharidosis II [
6]. Affordability of orphan drugs is a serious public health issue in China, as they are in other countries. A survey made by the Chinese Organization for Rare Disorders with 5810 patients registered in 2019 showed that the employment rate for adult patients was only 40%, and 80% of the income is spent on disease management. Poverty caused by the significant disease burden is a common experience for them and their families [
7]. Orphan drugs, which account for a large proportion of treatment spending, deserves more attention.
The Orphan Drug Act was enacted in 1983 in the US. Only 10 orphan drugs had been approved by the US Food and Drug Administration (FDA) in the decade before 1983, while more than 350 orphan drugs had been approved by 2010. The Orphan Drug Act also inspired similar policies in Singapore, Australia, Japan and Europe [
8]. China's attention to rare diseases started late. However, in recent years, the importance of orphan drugs has gradually appeared in various policy documents. For example, the Compendium of China’s First List of Rare Diseases (2018) (CLRD), which includes 121 rare diseases [
9], first clarified the concept and scope of rare diseases in China. Besides, the CLRD has made China the first country to delineate the boundaries of rare diseases in the form of a catalogue. The National Network to Collaborate on Diagnosis and Treatment of Rare Diseases (NCDTRD) was established in China in 2019, consisting of 324 hospitals nationwide, including 1 leading national institution (Peking Union Medical College Hospital), and 32 leading provincial institutions, achieving rare disease resource sharing [
10]. As the core contents of the national system for rare diseases in China, they played a key role in solving problems of rare diseases.
Improving orphan drugs access is a core priority for China’s policies. There have been studies assessing access to orphan drugs in Europe, the U.S., and South Africa [
11‐
14]. However, very few studies have assessed the availability and affordability of orphan drugs in China, and most of them were made before release of the CLRD and NCDTRD [
15,
16]. In comparison, for the first time on the basis of CLRD and NCDTRD, we evaluated the accessibility of orphan drugs that have been approved for CLRD indication in the U.S. [
17], EU [
18], Japan [
19] and marketed in China in 30 leading provincial institutions of NCDTRD, exploring the concrete effects of the China’s national system from the point of drug access.
Discussion
In this study, we conducted an annual and regional comparative analysis of access to orphan drugs in China, hoping to provide a reference for the development of countries with a late start in rare diseases in the world by taking the national system in China as an example. There were some studies have assessed the accessibility of orphan drugs in China in past few years [
15,
16]. In comparison, this study has some remarkable features. First, CLRD is the first definition of rare diseases in China, and our study delineates the range of diseases with CLRD, which is the first study based on CLRD since its release in 2018, and is more accurate and comprehensive compared with previous studies. Secondly, NCDTRD is the nationally designated institutions for rare disease diagnosis and treatment in each region. PUMCH is the only leading national institution, and there are 32 provincial lead institutions, 30 of which are included in our survey. This is the first study to use provincial lead institutions as data sources, which made the data collected more reliable. Thirdly, our study includes cross-sectional comparisons for three economic disparities and longitudinal comparisons for four years from 2017 to 2020. In addition, the availability and affordability analyses for seven efficacy groups were analyzed, making it the most comprehensive analysis of rare disease drug accessibility in China. Finally, the background and time span of this study was selected around the establishment of the National System for Rare Diseases in China, with the aim of analyzing the effectiveness of the system from the perspective of orphan drug accessibility, which has a more ambitious meaning.
Despite differences in research, all related studies came to similar conclusions: access to drugs for rare diseases in China was still low, but has shown a clear upward trend in recent years. This corroborates the conclusion of this study that the national system of rare diseases in China has achieved significant results in terms of drug access. Specifically, there are four main findings in this study. First, the market availability of orphan drugs in China is still relatively low in 2020. The number of drugs approved between 2017 and 2020 exceeds the number approved in the decade 2007 to 2016, indicating that the implementation of the China’s national system for rare diseases played an important role in the increasement of market availability. Meanwhile, there are thirteen orphan drugs for ten rare diseases of the CLRD were approved in China in 2021, making a huge leap in access to orphan drugs. In addition, it should also be noted that compared with other three countries, the marketing time of surveyed drugs still lagged behind, which is consistent with previous findings, indicating that the R&D of orphan drugs is still the top priority of rare disease management in China. The independent R&D capability of rare disease drugs is the main factor affecting the price of rare disease drugs, and it is also the key to restricting the accessibility of the Chinese market. It is closely related to policy management. The development of rare disease management in China lags behind that of European and the U.S., and this leaves rare disease definition and management policies still to be improved. Definition of rare diseases, which is the cornerstone of R&D, has not been fundamentally resolved for a long time in China [
31]. Considering national conditions, the definition will coexist with the updated list for a period of time to come. Although this way of defining is an adaptive policy in the early stages of rare disease development, our findings suggest that it has yielded optimistic results, at least in terms of drug accessibility. In addition, national policy incentives are the driving force behind independent R&D. There are two barriers to R&D of orphan drugs: first, the number of patients with rare diseases is fairly small, and many diseases have not yet developed accurate diagnosis and treatment level; second, return on investment is an issue that drug institutions must consider, while orphan drugs rely on more advanced instruments, which means greater investment and risks [
32]. In the US, orphan drug clinical research costs can be tax-deductible by 50%, with extended tax-deductible periods and tax relief for orphan drugs. Exempting applicants for orphan drugs from FDA review fees, and a 7-year market monopoly period. In China, it’s better to direct the incentives toward orphan drugs with low availability, and more specific incentives are needed to establish targeted subsidies for orphan drugs. For imported orphan drugs, further promote the use of real-world research, an orphan drug import tariff reduction system and a free public platform for all stakeholders to share information on orphan drugs also need to be developed. International cooperation will play a crucial role in the response to rare diseases [
33]. Besides, the high market accessibility rare diseases (endocrine, nutritional and metabolic diseases, etc.) reflects the morbidity and treatment needs of rare diseases in China (oncology and infectious diseases are not included in the CLRD). Policies should be guided by market demand. There is a certain information block between patients with rare diseases and drug development institutions, and patient organizations can play an important role in this process. The National Organization for Rare Disorders in the US, EURODIS in Europe and Canadian Organization for Rare Disorders have played an vital role in leading the development of orphan drug legislation, supporting patients, raising awareness and sponsoring academic research [
1,
34‐
36].The number of patient organizations in China has grown rapidly in recent years. However, these organizations are lack of training, play no role of promoting legislative agenda, and generally not active in the academic research. It’s hoped that with the implementation of government policies, the awareness of rare diseases can be better deepened in China.
Second, the availability of surveyed drugs increased year by year in three areas and in nationwide. In 2020, the hospital-level availability increased to more than 1.5 times that of 2017, with domestic drugs accounting for more than half, indicating that the China’s national system has achieved significant results. However, seven drugs were absent in the surveyed institutions, five of them were approved 5 years before 2020. Drugs for “endocrine, nutritional and metabolic diseases” and “diseases of the nervous system”, the two efficacy groups with the highest market availability, had the lowest hospital-level availability. This indicated a significant delay of hospital orphan drugs access. The reasons might be related to the low ability of diagnosis and treatment, the immature procurement and management system of orphan drugs. The establishment of the collaboration network is a good demonstration, but the specific resource scheduling of the huge collaboration network still needs to be considered. Doctors' professionalism of rare diseases also needs to be enhanced, especially in primary institutions [
37,
38]. At present, online multi-disciplinary team for rare diseases with primary institutions is a referable approach, but it’s not a fundamental solution [
10]. In addition, there is no clear orphan drugs procurement policies and use of norms, and no special management measures in the hospital pharmacy in China. A study to assess the accessibility of explicit diagnosis of rare diseases in Chinese adults showed that about 72.97% of patients were misdiagnosed, and patients waited an average of 4.30 times and visited 2.97 hospitals before being diagnosed [
39]. In the future, more attention should be paid to the uneven distribution of medical networks for rare diseases and quality medical services. The drug ratio and the government's control over the total amount of medical insurance are important assessment indicators for public hospitals, which need to control the drug ratio at around 30% overall. The procurement of drugs for rare diseases, which cost more but have "less clinical demand", undoubtedly poses a greater challenge for hospital pharmacy management. It's all about drug prices. In addition, the availability at drug level also showed an increasing trend by year and by region, which also confirmed the remarkable effect of the system. However, it should also be noted that the proportion of “high” availability drugs remained low (16.5%), and the availability of high-price drugs was low. By 2020, Alpha-galactosidase A, Imiglucerase and Alglucosidase alfa, the top three most unaffordable orphan drugs for residents under NBMI, were all in the "very low" grade of availability (3.3%). It suggested that improving the availability of high-priced drugs, whether through imports or independent R&D, was the focus of future efforts. Besides, drugs for “endocrine, nutritional and metabolic diseases” and “diseases of the nervous system” also had the lowest drug-level availability. The future policies should be more prioritized towards these two efficacy groups.
Thirdly, the median DDDc increased by year during 2017–2020. It has been reported that the median DDDc of orphan drugs in China showed a decreasing trend from 2010 to 2017, which is different from our finding [
15]. This may be related to the newly approved high-price orphan drugs encouraged by rare disease policies in recent years. Our results show that the average DDDc of newly approved drugs in the four years is $54.0, $56.4, $865.3 and $35.6, respectively. Moreover, these are beyond the affordable range of urban residents in 2020 (equivalent to 2.0–49.0 days of urban residents' income from work) and rural residents' affordable range (equivalent to 5.2–125.4 days of rural residents' income from work), which also confirms our conclusions above. The underlying problem behind this is that patients are not able to take the full course of drugs. According to the Chinese Organization for Rare Disorders, 58% of registered rare disease patients received treatment, but most of them failed to take adequate drugs. It has been shown that the use of high-cost drugs impoverishes most families [
40,
41]. Future rare disease incentives should be pursued simultaneously in terms of both improving availability and reducing the price of high-priced drugs.
Finally, the economic burden of patients with rare diseases is decreasing, but the overall affordability is still not optimistic. By 2020, the affordability rate was 64.6% in rural areas and 74.7% in urban areas, respectively, but the proportion of better availability and affordability drugs was still not unfavorable (39.4% in urban areas after NBMI), this reflected a mismatch between the affordability and accessibility of some affordable drugs. This once again reflects that the provincial and hospital drug procurement and the development of national medical insurance have not been synchronized. Among them, problems such as prescription restrictions, procurement restrictions and the disadvantages of designated hospitals remain to be resolved. The list of Part A and Part B includes 62.6% of the surveyed drugs. The proportion of surveyed orphan drugs included in Part B increased from 27.3% to 42.4% during our survey, and the proportion of imported drugs also increased significantly, further explaining that the NBMI has attached more importance to rare disease drugs. Teriflunomide and other 7 drugs have been included in Part B reimbursement through price negotiation after 2018. After being reimbursed, all 7 drugs have changed from unaffordable to affordable. It further indicated that the price negotiation system and NBMI play an important role in the affordability of orphan drugs, and significantly narrow the affordability gap between urban and rural areas. China has a breakthrough in the guarantee of high-price orphan drugs as of 2020. Nusinersen for spinal muscular atrophy and Alglucosidase alfa for Fabre disease have been included in the National Catalogue of Medical Insurance [
42]. In addition, since 2005, Shanghai, Qingdao, Zhejiang and other places have introduced rare disease drug coverage models with local characteristics, such as Qingdao's supplementary medical insurance system, which has helped patients alleviate payment problems to a certain extent. However, there’s still a lot of room for the improvement in China's payment system for orphan drugs. Multi-criteria decision analysis has recently been considered as a proper tool for orphan drug payment research [
43‐
46]. International experience shows that multi-party healthcare payment is the ideal model for orphan drugs, and China should consider developing matching payment schemes, such as installment payment and efficacy insurance [
47]. In addition, there have been a number of donated drug projects in China, including hemophilia, pulmonary hypertension, multiple sclerosis drugs and so on. These measures will have a meaningful impact on affordability. There is already a wealth of international experience in this area. Defining rare diseases through legislation, encouraging a differentiated registration and approval system for orphan drugs, building a government-led, health insurance-covered, multi-payer drug protection system, and setting up a differentiated health technology assessment system, while reducing or even eliminating out-of-pocket costs for patients, are the mainstream models at present [
48‐
51]. China's orphan drug management system should learn from its reference.
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