Questionnarie of physicians
A total of 224 physicians participated in this study. The demographic information of these physicians are summarized in Table 1. Out of 224 physicians, 104 (46.4%) were male and 120 (53.6%) are female. Thirty-four physicians (15.2%) were under the age of 30, 132 (58.9%) were between 30 to 45, 52 (23.2%) were between 46 and 60, and only 6 (2.7%) were over 60 years old. Hospitals in China are organized according to a 3-tier system that recognizes a hospital's ability to provide medical care, medical education, and conduct medical research. Based on this, hospitals are designated as Primary (< 100 beds), Secondary (100–500 beds), or Tertiary institutions (> 500 beds). Further, based on the level of service provision, size, medical technology, medical equipment, and management and medical quality, these 3 grades are further subdivided into 3 subsidiary levels: A, B and C. Out of 224 physicians, 163 (72.8%) were from Tertiary A (the highest level), 16 (7.1%) from Tertiary B, 8 (3.6%) from Tertiary C, and only 35 (15.6%) from Primary or Secondary hospitals. Out of 222 physicians responded, 81 (36.5%) practiced between 5 and 15 years, 71 (32.0%) practiced between 16 and 30 years, 49 (22.1%) under 5 years, and 21 (9.5%) over 30 years.
Table 1
Demographic information of participants of the questionnaire for physicians. Only specialties with more than 4 participants were shown. Hospitals in China are organized into a 3-tier system: Primary (< 100 beds), Secondary (100–500 beds), or Tertiary institutions (> 500 beds). Moreover, based on size, medical equipment, medical technology, management, service provision, and medical quality, each tier are further divided into 3 levels: A, B and C.
Gender | Male (n = 104, 46.4%) |
| Female (n = 120, 53.6%) |
Age (years) | < 30 (n = 34, 15.2%) |
| 30–45 (n = 132, 58.9%) |
| 46–60 (n = 52, 23.2%) |
| > 60 (n = 6, 2.7%) |
Hospital | Tertiary A (n = 163, 72.8%) |
| Tertiary B (n = 16, 7.1%) |
| Tertiary C (n = 8, 3.6%) |
| Secondary A (n = 22, 9.8%) |
| Secondary B (n = 1, 0.4%) |
| Primary A (n = 4, 1.8%) |
| Primary B (n = 4, 1.8%) |
Career length (years) | < 5 (n = 49, 22.1%) |
| 5–15 (n = 81, 36.5%) |
| 16–30 (n = 71, 32.0%) |
| > 30 (n = 21, 9.5%) |
Specialty | Pediatrics (n = 13, 6.3%) |
| Radiology (n = 22, 10.6%) |
| Surgery (n = 18, 8.7%) |
| Orthopedics (n = 10, 4.8%) |
| Internal Medicine (n = 10, 4.8%) |
| Dermatology (n = 10, 4.8%) |
| Cardiology (n = 9, 4.3%) |
| Nephrology (n = 5, 2.4%) |
| Neurology (n = 5, 2.4%) |
| Obstetrics and Gynecology (n = 8, 3.9%) |
| Oncology (n = 9, 3.9%) |
| Other (n = 88, 42.5%) |
As to self-evaluated level of rare disease awareness, one hundred and sixteen physicians (51.8%) were ‘aware of, but did not know much about’ rare diseases, 85 (37.9%) ‘knew a little bit’ about rare diseases, and 11 (4.9%) were ‘not aware of’ rare diseases. Only 11 (4.9%) ‘moderately aware of’ rare diseases, and 1 (0.4%) ‘well aware of’ rare diseases. A previous study in Spain showed that 15% of physicians have a good knowledge about rare diseases [7], significantly better than a total of 5.3% in this study. These results indicated a significant lack of awareness of rare diseases among physicians in China. Considering the fact that most physicians were from Tertiary hospitals with > 500 beds and located in big cities, the rare disease awareness among average physicians in China would be even worse. On the question ‘Have you ever suspected that a patient suffered from a rare disease?’, 91 of 221 respondents (41.2%) chose ‘once or twice’, while 86 (38.9%) chose ‘never’. Only 44 (19.9%) chose ‘over three times’. Out of 220 respondents, 121 (55%) thought that less than 10% of their patients had rare diseases, while 79 were not sure. Only 20 (9.1%) thought over 10% of their patients had rare diseases. Out of 218 respondents, 203 physicians (93.1%) thought rare disease patients were more difficult to manage. Out of 221 respondents, 133 thought their hospitals had not paid enough attention to rare disease patients. Out of 222 respondents, 119 (53.6%) physicians encountered one to five types of rare diseases, and 66 (29.7%) never encounter any. Only 17 (7.7%) encountered more than 10 types, while 20 (9.0%) encountered six to nine types. The combined total of physicians who encountered rare disease patients at least once was 83.3%, similar to the number among physicians in Spain (90%) [8]. Out of 182 respondents, 89 physicians (48.9%) had no rare disease patients in the past year, 44 (24.2%) had one or two rare disease patients, and 27 (14.8%) had three to five rare disease patients. Only 10 (5.5%) had six to ten rare disease patients, and 8 (4.4%) had over ten rare disease patients. Four physicians were not sure which diseases were rare diseases. Out of 177 respondents, 112 physicians (63.3%) had not treated any rare disease patients, 35 (19.8%) treated one to two, 19 (10.7%) treated three to five, 8 (4.5%) treated six to ten, while 3 (1.7%) treated over ten. Out of 222 respondents, 131 physicians (59%) ‘strongly’ supported special legislations for rare diseases, and 84 (37.8%) ‘moderately’ supported. Only 7 (3.2%) were neutral or negative on legislations for rare diseases. These results highlighted the urgent need and wide support for special legislations for rare diseases. Out of 219 respondents, 126 physicians (57.5%) ‘strongly’ supported special legislations for orphan drugs, and 80 (36.5%) ‘moderately’ supported. Only 13 (5.9%) were neutral or negative on legislations for rare diseases. Out of 222 respondents, 103 physicians (46.4%) supported special insurance programs for rare diseases, 95 (42.8%) suggested inclusion of rare diseases into the Critical illness insurance program, a national insurance program in China. Only 8 (3.6%) thought that the Basic Medical Insurance Systems for Urban and Rural Residents is sufficient, and 4 (1.8%) suggested special subsidies from the government (Figure.1A). Out of 222 respondents, 114 physicians (51.4%) rate newborn screening as ‘essential’, 80 (36%) as ‘very important’, 25 (11.3%) as ‘important. Only 3 (1.4%) rated it as ‘not that important’, and none c selected ‘useless’ (Figure.1B). Out of 216 respondents, 107 physicians (49.5%) rated the availability of orphan drugs as ‘moderate’, 39 (18.1%) selected ‘good’, and 29 (13.4%) selected ‘very good’ (Figure.1C). Only 29 (13.4%) selected ‘poor’ and 12 (5.6%) selected ‘very poor’. As to the affordability of orphan drugs, 116 physicians (53.0%) selected ‘mediocre’, 49 (22.4%) selected ‘bad’, and 21 (9.6%) selected ‘very bad’ (Figure.1D). Only 14 (6.4%) and 19 (8.7%) selected ‘very good’ and ‘good’, respectively. Out of 222 respondents, 195 (87.8%) selected ‘yes’ to the question ‘do you need information about rare diseases?’ This number is similar to a previous study in Belgium (83–97%) [9]. As to the question ‘does your previous education and training did not provide sufficient information about rare diseases?’, out of 222 respondents, 77 (34.9%) selected ‘moderate’, 72 (32.4%) selected ‘not sufficient’, and 13 (5.9%) selected ‘useless’. Only 45 (20.3%) and 15 (6.8%) selected ‘very useful’ and ‘sufficient’, respectively.
As to organizations of rare disease patients, 96 physicians heard about China-Dolls Center for Rare Disorders, a non-government organization established in 2008 for patients with osteogenesis imperfecta. Forty-nine physicians heard about the Seven Pansy Rare Diseases Community, a national organization in China dedicated to raise rare disease awareness and provide scientific information and support. As shown in Figure.2A, international sources, e.g., NORD (10.7%), Orphanet (11.6%), Global Genes (8.5%), EURORDIS (4.5%), were not as well-known in China. It has been shown that among pediatricians in Australia, the percentage of awareness of Orphanet, NORD, and EURORDIS was 50%, 35%, and 21%, respectively [10]. This discrepancy may be partly due to the language barrier. Eighty-five physicians (37.9%) have not heard about none of the listed organizations. As to ‘What kind of information do you need?’, 186 respondents (83.0%) chose ‘diagnosis’, 167 (74.6%) for both ‘screening’ and ‘treatment’ (Figure.2B). Interestingly, 106 out of 220 respondents (48.1%) only wanted to know information about rare diseases that can be possibly cured. As to the information source, 163 (72.8%) selected academic conferences, 152 (67.9%) chose the internet, 141 (62.9%) selected medical school education (Figure.2C). Interestingly, only 61 (27.2%) selected patients, and 46 (20.5%) selected patient organizations.
To identify parameters that have impact on rare disease awareness and perspectives, the correlation between Q1-6 and Q7-15 were analyzed. First, in Q4, hospitals were categorized into 9, and 72.8% of physicians were in the Tertiary A hospitals. Therefore, hospitals were re-categorized into Tertiary A and non-Tertiary A hospitals to ensure that each category has sufficient samples. Then, age (Q3) and career length (Q5) was correlated (R2 = 0.79). To avoid collinearity, only gender (Q2), hospital (Q4), and career length (Q5) were analyzed as parameters. Finally, multinomial logistic regression (MLR) was used to determine whether hospitals, gender, and career length has an impact on perspectives and awareness (results summarized in Table 2). As to rare disease awareness, although age is better predictor with an Akaike information criterion (AIC) value of 456.604, no factors had a significant impact. This may be because few physicians were moderately or well aware of rare diseases, which would affect assumptions of MLR. As to Q11 (does your hospital pay enough attention to rare disease patients?), only career length has a significant impact with an AIC value of 289.4388, and p value of 0.0009. The longer their career length is, the more likely physicians have a positive response. As to Q12 (how many rare disease patients have you met?), gender has significant impact (AIC = 491.425, p = 0.02). Specifically, compared to ‘>10’, female physicians were more likely to respond ‘none’. As to Q13 (do you support special legislation for rare diseases?), no factors had a significant impact. Similarly, no factors had a significant impact on Q16 (do you support special legislations of orphan drugs?), Q17 (perspectives on medical insurance), Q18 (the availability of orphan drugs), and Q21 (do you need rare disease information?). Interestingly, hospitals had a significant impact on Q19 (affordability of orphan drugs) with an AIC value of 570.3079 and a p value of 0.017. Physicians from Tertiary A hospitals were more likely to rate the affordability of orphan drugs high. This may be explained by the fact that Tertiary A hospitals had more resources and insurance subsidies from the government. As to perspectives on newborn screening (Q20), gender and career length had significant impact (AIC = 442.2492, p < 0.05). Female physicians were less likely to think newborn screening is important. Notably, very few respondents believed newborn screening to be useless, which may affect assumptions of MLR. As to Q22 (does your previous education and training provide sufficient information about rare diseases?), career length was a good predictor (AIC = 612.4972, p < 0.05). The longer the career length is, the less likely they believe previous education to be useful. This may be explained by the fact that the amount of information about rare diseases in medical school education and job training had gradually increased over time. As to Q25 (do you only want information about rare diseases that can be possibly cured?), career length was also a good predictor (AIC = 290.00995, p < 0.01). Interestingly physicians with less than 5 years or over 30 years of experience were more likely to respond positively, while physicians with 5–30 years of experience had no preference.
Table 2
Impact of demographic information on rare disease awareness and perspectives. First, in Q4, hospitals were initially categorized into 9, and 72.8% of physicians were in the Tertiary A hospitals. Therefore, hospitals were re-categorized into Tertiary A and non-Tertiary A hospitals to ensure that each category has sufficient samples. Then, age and career length were correlated (R2 = 0.79). To avoid collinearity, only gender, hospital, and career length were analyzed as parameters. Then, a MLR analysis was performed with SPSS. Akaike information criterion, AIC.
Rare disease awareness | No factors with statistical significance |
Does your hospital pay enough attention to rare disease patients? | Career length (AIC = 289.4388, p = 0.0009 |
The longer their career length was, the more likely physicians had a positive response |
How many rare disease patients have you met? | Gender (AIC = 491.425, p = 0.02) |
Compared to ‘>10’, female physicians were more likely to respond ‘none’. |
Do you support special legislation for rare diseases? | No factors with statistical significance |
Do you support special legislation of orphan drugs? | No factors with statistical significance |
Perspectives on medical insurance | No factors with statistical significance |
Availability of orphan drugs | No factors with statistical significance |
Do you need rare disease information? | No factors with statistical significance |
Affordability of orphan drugs | Hospital (AIC = 570.3079, p = 0.017) |
Physicians from Tertiary A hospitals were more likely to rate the affordability of orphan drugs high. |
Perspectives on newborn screening (AIC = 442.2492, p < 0.05) | Gender (AIC = 442.2492, p < 0.05) |
Female physicians were less likely to believe newborn screening to be important. |
Does your previous education and training provide sufficient information about rare diseases? | Career length (AIC = 612.4972, p < 0.05) |
The longer the career length was, the less likely they believe previous education to be useful. |
Do you only want information about rare diseases that can be possibly cured? | Career length (AIC = 290.00995, p < 0.01) |
Physicians with less than 5 years or over 30 years of experience were more likely to respond positively, while physicians with 5–30 years of experience had no preference. |
Interviews of rare disease experts
A total of 9 experts in the field of rare diseases were interviewed with exploratory questions. Notably, all of these experts were from Tertiary A hospitals located in big cities, such Beijing, Shanghai and Chengdu. As to how rare disease awareness facilitates fast and accurate diagnosis, most experts (7/9, 77.8%) agreed that such an awareness will point physicians to the right direction and then with additional information they may be able to reach a diagnosis. Even realizing the possibility of rare disease will help them refer patients to larger hospitals where patients are more likely to be diagnosed. Sometimes, physicians without rare disease awareness may neglect crucial evidence that can help diagnosis. Consequently, some patients were misdiagnosed as other common diseases with similar symptoms for long before a correct diagnosis was made. All experts agreed that physicians generally lacked the rare disease awareness, which was a major reason of misdiagnosis. Three experts (33.3%) suggested to establish a rare disease referral hub in each hospital, which collects potential rare disease patients and refer them to larger hospitals. The majority of Chinese population do not live in big cities that have large hospitals and experts. Also, it is unrealistic to provide comprehensive rare disease information to all physicians in smaller hospitals. Such a rare disease referral hub is not expected to incur significant burden to hospitals, therefore, it is feasible and should significantly help the diagnosis and treatment of rare diseases.
All experts believed that current medical school education had not provided enough information about rare diseases. The French National Plan for Rare Diseases stipulated that medical school curriculum should include education in rare diseases [11]. Such stipulations do not exist in China, but all experts recommended inclusion of rare disease topics in medical school curriculum. Five experts (55.6%) recommended that in medical school education and continuing training, topics about a specific type of pathology and related common diseases should also mention potential related rare diseases. Also, case studies of the diagnosis pathway of a rare disease were suggested by seven experts. All experts believed that it would not be practical to include each rare disease in medical school education or continuing medical education. Therefore, the consensus is to adopt a method based on principles and organization of knowledge. Instead of solely teaching students the knowledge of rare diseases, more focus should be put on the ability to exclude common diseases and collect relevant information for diagnosis, as well as the knowledge of how to find information about treatment options upon diagnosis.
As to information sources of rare diseases, seven experts listed medical literature as the major source. Alternative sources included academic conferences, the internet, and patients. Interestingly, all experts mentioned the concept of ‘learning from the patients’, while only 20.7% of physicians listed patients as their information source in the questionnaire. These experts believed that rare disease patients were extremely active in learning about their conditions and scientific breakthroughs in the field, and thus sometimes could teach physicians much. One expert mentioned the experience of one patient explaining the relative strength and weakness of AAV gene therapy versus gene editing for Pompe disease. In general, these experts believed that current information source is not comprehensive and mainly targets experts instead of front line physicians. Six experts (66.7%) expressed that an ideal information source would be a search engine that one can submit symptoms and test results, and obtain possible diseases and treatment options in return. The output could also be recommendations on additional tests and evidence one should look for. Contact information of potential experts or hospitals for referral would be beneficial as well. Another feature of this search engine is a review system that other users can upvote, downvote, and comment on the output so that it can be optimized. Additionally, the search engine should be fully accessible to at least physicians with or without a cost.
All experts expressed the concern for the high cost of orphan drugs, especially gene therapy. Nevertheless, all of them acknowledged the cost involved for developing and manufacturing an orphan drug. In 1983, the United States passed the Orphan Drug Act which provide tax incentives, enhanced patent protection and marketing right, and clinical research subsidies to pharmaceutical companies that develop orphan drugs. The number of orphan drugs significantly from 38 before 1983 to over 600 in 2019. Many other countries and districts pass similar laws to stimulate orphan drug development. All experts believed that legislation of an orphan drug act in China will remarkably accelerate orphan drug development and potentially lower the cost. Similar to the 224 physicians in the questionnaire, most experts (7/9, 77.8%) believed that a special rare disease insurance program would be the best option. One expert mentioned the Orphan Reinsurer and Benefit Manager (ORBM), a program being proposed in the United States to address the ultra-high cost of orphan drugs. Under the ORBM, payment is carved out by the primary insurer, which may be vulnerable to financial challenges of orphan drugs. ORBM aims to address the issue of payment timing, therapeutic performance risk, and actuarial risk [12].
Experts also commented on the biggest challenge when handling rare disease patients. One common issue is the lack of rare disease awareness among patients, families, and many frontline physicians. Symptoms of many rare diseases are non-obvious and even difficult to explain, which are thus often ignored, resulting in significant delay in diagnosis and management. Another difficulty is the lack of reliable, up-to-date, and accessible information source. Most experts (8/9, 88.9%) believed that the language barrier creates much challenge while physicians searching for relevant information. Although international organizations, such as Orphanet, NORD, established systems of reliable and comprehensive information about rare diseases, it is not readily accessible for Chinese physicians, most of whom do not speak English. Further, although only 19% of physicians the questionnaire rated the availability of orphan drugs as ‘poor’ or ‘very poor’, all experts expressed the concern over the lack of treatment options. As to the discrepancy, seven experts believed that it was because ‘most physicians do not know the existence of orphan drugs in Western countries’.