Lysosomal storage diseases (LSDs) are a group of diseases caused by defects in single genes. Enzyme defects cause nearly seventy percent of the LSDs, and the rest are defects in enzyme activator or associated proteins (1). A deficit in any of these enzymes will result in progressive accumulation of materials in affected organs and tissues, which will result in an increase in the size and number of these organelles and finally in cellular dysfunction and organ failure(2). Though as a group, LSDs are with an estimated incidence of 1/5,000 to 1/5,500(2), individual LSDs are usually recognized as rare diseases with estimated incidences ranging from 1/50,000 to 1/250,000 live births(3). There have been seventy LSDs reported so far, while only 7 of them have approved therapies on the global market (4), most therapies are enzyme replacement treatments (ERTs). Though there are approved treatments for the 7 LSDs, but the cost for these treatments is extremely high (5)(6). Some of the Western countries have already published policies regarding rare diseases(7)(8), and a few have further designed reimbursement measures for patients with LSDs with high costs. For example, the National Institute for Clinical Excellence raised the concept of ultra-orphan drugs(9) and designed the highly specialized technology (HST) appraisal process to recommend on the use of new and existing highly specialized medicines and treatments, which are usually very expensive within the National Health Service (NHS) in England. The HST guidance has recommended the use of Eliglustat and Migalastat for Gaucher disease (GD) type1 and Fabry disease (FD), respectively (10)(11). The Australian government initiated the Life Saving Drugs Program in 1994 to reimburse expensive and life-saving drugs for life threatening and rare diseases. Now, the program provides fully subsidized access to 16 drugs for patients with 10 indications, including GD, FD, Pompe Disease (PD), Mucopolysaccharidosis (MPS) type I, type II, type IVA, type VI and Neuronal ceroid lipofuscinosis type 2 (CLN2), which are LSDs (12).
With the development of socio-economic and universal health coverage in China(13), the attention on rare disease has turned from the provincial and city level to the national level. The first batch of National Rare Diseases List (NRDL) was published in 2018(14). After that, the Chinse government has published a series of policies to improve comprehensive healthcare security of rare diseases, including constructing the diagnosis and treatment network, registering rare disease patients, publishing guidelines for diagnosis and treatment, improving the accessibility, reducing the import tax, accelerating the market authorization process of drugs for rare diseases, and bring the drugs for rare diseases into the National Drug Reimbursement List (NDRL) (15) .
There are 16 different approved therapies for 7 LSDs in the world(4), while there are only altogether 8 available therapies in China for 5 LSDs, which are GD, FD, MPS, PD, and Niemann-Pick disease (NP), in the NRDL. However, only Miglustat for NP type C is now included in the NDRL, while the other seven ERTs are not. See Table 1 for the details. Recently, the National Healthcare Security Administration claimed that it has basically included all the drugs for rare diseases meeting certain criteria and could not include some drugs into the NRDL due to the extremely high cost, which is far beyond the payment capacity of the basic medical insurance fund and the patients(16). The newly updated NDRL (2020 version, published on Dec 28, 2020) did not contain these extremely expensive drugs for rare diseases(17). Theoretically, there are no healthcare security measures on the national level in China for patients with the mentioned four LSDs, which are GD, PD, FD and MPS.
Table 1 Marketed and reimbursed drugs for LSDs in China
NRDL code
|
Disease
|
Approved name
|
Brand name
|
Approved date in China
|
Included in NDRL
|
27
|
Fabry disease
|
Agalsidase betaa
|
Fabrazyme
|
2009/12
|
No
|
31
|
Gaucher disease
|
Imiglucerase
|
Cerezyme
|
2008/11
|
No
|
|
|
Velaglucerasea
|
Vpriv
|
No
|
—
|
|
|
Taliglucerasea
|
Elelyso
|
No
|
—
|
|
|
Miglusta
|
Zavesca
|
No
|
—
|
|
|
Eliglustata
|
Cerdelga
|
No
|
—
|
35
|
Pompe disease
|
Alglucosidas alfa
|
Myozyme
|
2017/12
|
No
|
|
|
Agalsidase alfa
|
Replagal
|
2020/8
|
No
|
|
|
Migalastata
|
Galafpld
|
No
|
—
|
73
|
MPS
|
|
|
|
|
|
Type I
|
Laronidasea
|
Aldulrazyme
|
2020/6
|
No
|
|
Type II
|
Idursulfasea
|
Elaprase
|
2020/9
|
No
|
|
Type IVA
|
Elosulfasea
|
Vimizim
|
2019/6
|
No
|
|
Type VI
|
Galsulfase
|
Naglazyme
|
No
|
—
|
82
|
Niemann–Pick disease type C
|
Miglustat
|
Zavesca
|
2017/9
|
Yes
|
|
Wolman disease
|
Sebelipase
|
Kanuma
|
No
|
—
|
|
Neuronal ceroid lipofuscinosis type 2(CLN2)
|
Cerliponase
|
Brineura
|
No
|
—
|
a: Drugs included in the List of Urgently Needed New Drugs from Overseas for Clinical Use.
Current studies regarding LSDs patients in China are mainly from the clinical aspect, while few are not. Chen et al. introduced the demographic characteristics and distribution of all 322 diagnosed patients LSDs in Eastern China, including Shanghai and other six provinces(18). Zhao et al. studied the characteristics of 59 Chinese PD patients from the Pompe Registry(19). Yang et al. described the cost-sharing mechanism for Imiglucerase in Qingdao, Shandong province(20). Except for the mentioned three literatures, there are some large-scale surveys focusing on living conditions of patients with rare disease in China. Some surveys on LSDs did report the cost of illness while the usage of ERTs remained unknown. (21)(22) (23) (24). Furthermore, some of these reports are not able to access the full texts.
Shanghai, as one of the most developed cities in China, has over 242 million residents, with an average GDP of 134,982 CNY(25). It is one of the first cities that reimbursed Imiglucerase for GD patients. In 2011, Shanghai Children's Hospitalization Assistance Fund, managed by the Red Cross Society of China Shanghai Branch decided to reimburse the ERTs for patients with the mentioned four LSDs, with a maximum reimbursement amount of 100,000CNY per patient per year (26). In 2013, Imiglucerase could be paid by the basic medical insurance in Shanghai and reimbursement level was ranging from80%-85% depending on the dosage. In 2017, the Shanghai Foundation for Rare Disease established a special assistance fund for LSD patients supported by enterprises(27). The assistant amount was decided based on the income level of patients, ranging from 70% to 100% of the Out-of-Pocket (OOP) part, who were receiving ERTs treatments. The outcomes of these policy intervention on patients with LSDs in Shanghai are little unknown except that Cai et al. reported the numbers of inpatient and outpatient visits of GD and FD patients in Shanghai, but the direct medical costs of these patients were not reported separately(28). Our study aimed to explore the characteristic and usage of ERTs of patients with GD, PD, FD and MPS in Shanghai and then evaluated the economic burden and quality of life (QoL) of these patients.