There is a dearth of evidence on the health service utilization and economic burden of rare disease patients with GD in China. In this study, we performed a comprehensive, analysis and identified a wide range of unmet needs and problems of patients with GD in their health service utilization, cost of illness, and health-related quality of life associated with GD in China. Families of patients with GD often experienced delays in diagnosis and misdiagnosis, enormous economic cost, and caregiving burden. Lack of social support often resulted in deteriorated health related quality of life and other major health issues which deserve great attention of society.
Misdiagnosis or delayed diagnosis is especially detrimental to patients[20]. Although several publications have acknowledged that diagnostic delays or misdiagnosis often occurs in obtaining a definitive GD diagnosis [21], this study further quantified the exact time delay and difficulty in obtaining the correct diagnosis that occurred in 79.6% surveyed patients. 59.2% of them experienced misdiagnosis, of up to 5.0 ± 9.6 times. Besides, patients reported multiple referrals (3.9 ± 3.1) to different hospitals before their disease was accurately determined. Studies indicated the process of continually seeking diagnosis was a traumatic experience for patients with rare diseases[22]. Patients spent 1.2 ± 1.7 years to receive a definitive diagnosis since the onset of symptom, and 44.9% of 40 patients had lived with their rare condition for > 6 months before accurate diagnosis. Due to the frequent misdiagnosis and delayed diagnosis, patients ended up paying $15,250 for the final GD diagnoses. Davari M et al. have shown a patient misdiagnosed with GD had taken medications for ten years at the cost of $207,580[1]. Thus, a rapid precise diagnosis of patients is essential for reducing unnecessary tests or costs[21, 23, 24], and preventing psychological stress for the family[25].
The main reason for the prolonged diagnostic delay most likely is insufficient knowledge on GD[26–28] by the medical community due to its low prevalence, extreme variations in clinical manifestations[23, 29], and severity of symptoms (e.g., bone pain/bone crisis, thrombocytopenia, and splenomegaly) [12, 21, 23]. Nevertheless, a survey revealed that only one of five hematologist-oncologist considers GD in the differential diagnosis of patients with a history of anemia, thrombocytopenia, hepatomegaly, splenomegaly, and bone pain. In this study, 79.6% of patients had visited doctors with obvious symptoms (osteopenia, normocytic anemia, dyskinesia, and obviously enlarged liver) in whom GD was not diagnosed in a timely manner. Therefore, establishing an information center of rare disease symptoms[30] and providing training on diagnostic methods and appropriate clinical guidelines to medical doctors are essential to effectively support early diagnosis of rare diseases. Besides, because most rare diseases are caused by DNA mutations or are recessive genetic diseases[31], family history and genetic screening could facilitate earlier diagnosis, while genetic testing can be used to confirm disease diagnosis[32]. Nine families reported a family history of the same disorder in this study, indicating a need for awareness of genetic disorders to highlight the importance and burden of genetic diseases. Therefore, newborn screening for disorders that meet the criteria for population screening[33], use of reliable diagnostic tools[1, 34–36], raising of awareness on the early signs/symptoms[37] or less severe manifestation [21], and initiation of therapy early for rare diseases[30], are essential.
In particular, long-term treatment with regular monitoring for GD can optimize outcomes[38], alleviate fewer exacerbations[1], and reduce the incidence of complications[39]. A Gaucher outcome survey involved 1209 patients with GD reported the overall treatment (1,209, 73.4%) and different treatment rates in countries [the UK (119, 93.3%), Israel (536, 63.6%), the US (380, 82.6%), rest of the world (174, 69.5%)][40]. In this study, 8 of the 49 patients (16.3%) were never treated, while 83.7% get treated, and 10 (20.4%) of patients undergone splenectomy, which was higher than previous research (8.7%-13.3%) [2, 40]. Besides, other studies also shown a significant proportion of patients (e.g., asymptomatic or mildly affected) never accessed medical attention or required treatment[41, 42]. In this study, even 20 (40.8%) of patients did not clear the type of their GD. Maaswinkel Mooij et al.[43] found that no treatment for type 1 GD with enzyme replacement therapy can worsen the condition at any age in non-Jewish patients[44]. Besides, 4 of 9 patients who took imiglucerase interrupted their treatment in this study. However, Drelichman et al. emphasized the need to avoid interruption of medical treatment of patients with GD because of recurrent organomegaly, growth delays, and skeletal manifestations[45]. Furthermore, a previous study identified association of high immunoglobulin (Ig) A and IgG levels with long-term complications[46]. Therefore, long-term treatment and surveillance are required for improving the efficiency of GD management[47].
To estimate the annual cost of GD, we presented the core components of costs for health care services separately, from the payer’ perspectives, excluding patients’ out-of-pocket costs and informal care. The estimated annual per-patient cost of GD of $49,925 (95% confidence interval [CI]: $29,178, $70,672, which is 5.3 times of GDP per capita of China in 2018($9,377)[48]. The additional time spent by caregivers for providing care reflects an annual productivity loss of $1,980 per patient. In contrast, a recent analysis using the human capital approach showed high costs [e.g., Splenectomy ($13,698), Bone complication ($10,002), Multiple complications ($10,615), and Malignancy ($73,057)] that generated much higher indirect costs than ours[49], whereas we calculated indirect costs with the actual wage of the caregivers. Besides, direct non-medical costs ($4,974), comprised those for accommodation, transportation, meals, and other expenditures, which accounted for 10.6% of direct costs; this indicated a high burden of access to medical services. Moreover, patients with GD required frequent healthcare utilization resulting in an annual direct cost (direct medical/non-medical costs) of $46,791 per patient (95% CI: $26,049, $67,533); that is, 93.7% of total costs. In this study, the mean direct medical costs of $41,816 per patient was about 66.5 times of the average health expenditure per patient ($629) in China in 2018[50]. The direct medical costs included those for pharmaceutical ($29,908, 59.9%), inpatient (14.9%), and outpatient treatments (3.7%). One study in Iran estimated the annual direct medical costs at $20,758 in 2014 and identified drug costs as 95.2% ($19,763) of direct medical costs[1]. These figures clearly show that the pharmaceutical cost encompasses most of the resources used by patients with GD. Recent research has also demonstrated that drug expenditures accounted for almost 90% of rare diseases’ health expenditures[19]. Therefore, further efforts are needed to address the issue of pharmaceutical treatment costs holistically[51].
However, both the availability and affordability of orphan drugs[52] for the treatment of rare diseases in China are low[17]. Poor accessibility to drugs is the most problematic issue for patients with rare disease in China[53]. In this study, 89.8% of patients perceived the availability of therapeutic drugs to be problematic. Furthermore, 35.0% of patients who received pharmaceutical treatment could not take the medication as prescribed. These figures demonstrate poor availability of rare drugs. Several hindering factors contributing to the low availability of orphan drugs in China include the low market availability of orphan drugs in China[17, 54]. Compared with the earliest launch time globally, the average delay in the market authorization of orphan drugs for rare diseases in China was 7.7-9 years[17, 54]. Imiglucerase received China’s marketing authorization in 2008[17]. On May 22, 2018, the Chinese Government officially included GD on the first list of rare diseases[55]. With a low availability of < 30% [17], many Chinese patients currently pay out-of-pocket for international treatments that are currently unapproved in China[56]. Second, lack of research and development and supply incentive policies for orphan drugs are possible reasons leading to low market availability[56]. Under a market-oriented economy, due to a small market share of orphan drugs, most pharmaceutical manufacturers are unwilling to invest in research and development on the production of orphan drugs without an incentive policy[17]. Third, low public hospital availability of orphan drugs is another major issue both for the patients[57] and the Chinese government. In this study, 31 (77.5%) of patients reported purchasing medicine at pharmacies or overseas. Due to the unique market attributes (e.g., low market volume, low profit, low turnover rate, and high price) of orphan drugs, and as the reform of public hospitals in China stipulated (control the share of drug sales in total hospital revenue), hospitals have little incentive to stock and prescribe expensive orphan drugs[58]. Lastly, there are no public national or provincial networks for rare diseases or orphan drugs to share useful information about these diseases, e.g., treatment or supply information. Therefore, it is urgent to improve the availability of rare drugs, e.g., simplify the approval procedure for imported orphan drugs, increase research and development investment, formulate incentive policies, and establish information-sharing platforms.
Furthermore, to recoup research and development costs and for profit, orphan drug manufacturers often adopt a strategy of charging high prices[59]. Miglustat and imiglucerase, which are effective medications for treating GD, had annual costs of $116,800 and $140,200, respectively in 2004[60], and the expenditure share was > 3% of per capita GDP[16]. A study focusing on seven selected rare diseases found that the affordability of treatment was relatively poor, with the health expenditure for GD equivalent to 69.34 years per urban resident’s income in 2014[16]. In this study, 49 (100%) of patients reported the unaffordability of therapeutic drugs. A few cities/provinces are active in creating rare disease lists with a high reimbursement at 80%-95%[61]. However, due to the restrictive reimbursement caps, even with 5% out-of-pocket expenses, few drugs could be afforded by high-income urban residents[62]. The out-of-pocket costs are still unaffordable for many patients. Therefore, the low affordability of orphan drugs may be closely associated with many factors, e.g., high drug prices, lack of insurance coverage, low reimbursement rates, and low-income levels for Chinese residents[17]. Several measures should be taken to improve the affordability of orphan drugs in China including: 1) formulating and implementing incentive policies[59, 63] to promote the development and supply of generic drugs, and to control the price of orphan drugs[64, 65]; 2) developing an orphan drug reimbursement system to increase insurance coverage; and 3) developing government-supported programs for patients with rare disease.
Due to the delayed diagnosis, unavailability, and unaffordability of costly drugs, 79.6% of 49 patients with GD felt poorly confident about future treatment. Moreover, the total social support, sleep quality, and quality of life scores for patients with GD/caregivers were significantly lower than those for normal healthy Chinese people. Thus, patients with GD experience limited access to health services, substantial costs, and low health-related quality of life [66].
Limitations
First, this study is limited primarily by the small sample size. Due to the rarity of GD, data collection was challenging. Second, families who voluntarily participate in the GD patient registry may represent a more compliant and motivated patient cohort in general. Thus, the findings may not be generalized to all. Thirdly, this study relied on responders’ recall of health service utilization and the unit costs to capture a more inclusive set of cost components usually not included in billing data, such as traffic costs, formal care costs, and productivity loss to caregivers. To enhance the accuracy of the estimates reported, patients with GD and caregivers were asked to complete questions regarding the average consumption amount and costs per resource in the past year. However, recall bias may have led to errors. Lastly, utilization and corresponding costs from pharmaceutical use of prescription were not included in the survey. For pharmaceutical costs, we asked for the “annual purchase of imported/ domestic medicines,” which could have resulted in an underestimation of this study’s GD’s financial burden. Hence, appraisal costs using data from health insurance is needed.