Questionnarie of physicians
A total of 1,802 physicians were contacted, and 224 (12.4% response rate) physicians participated in this study. The demographic information of these physicians is summarized in Table 1. Notably, it is difficult to estimate potential bias because information about physicians who decline to participate in this study and the general population of Chinese physicians is not available. However, the participants may represent a group of Chinese physicians who is more likely to have better rare disease awareness because the social media accounts and websites used to enroll participants have regular coverage of rare diseases.
Out of 224 physicians, 104 (46.4%) were male and 120 (53.6%) are female while 132 (58.9%) were between 30 to 45. 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). Out of 222 physicians responded, 81 (36.5%) practiced between 5 and 15 years, and 71 (32.0%) practiced between 16 and 30 years.
As to self-evaluated level of rare disease awareness, only 11 (4.9%) ‘moderately aware of’ rare diseases, and 1 (0.4%) ‘well aware of’ rare diseases. On the question ‘Have you ever suspected that a patient suffered from a rare disease?’, only 44 (19.9%) chose ‘over three times’. Out of 220 respondents, 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. Out of 182 respondents, 89 physicians (48.9%) had no rare disease patients in the past year. Out of 177 respondents, 112 physicians (63.3%) had not treated any rare disease patients. Out of 222 respondents, 131 physicians (59%) ‘strongly’ supported special legislations for rare diseases, and 84 (37.8%) ‘moderately’ supported. 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. Out of 222 respondents, 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, only 3 (1.4%) rated it as ‘not that important’ (Figure.1B). Out of 216 respondents, 107 physicians (49.5%) rated the availability of orphan drugs as ‘moderate’ (Figure.1C). As to the affordability of orphan drugs, 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?’ As to the question ‘does your previous education and training provide sufficient information about rare diseases?’, out of 222 respondents, 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. 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.
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.
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. 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.
All experts believed that current medical school education had not provided enough information about rare diseases. 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. 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 .
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’.