This is the first comprehensive article on the status of rare disease clinical trials in China. The annual number of clinical trials indicates that certain progress has been made in the R & D of rare diseases in China from 2013 to 2020. Some results, such as the number of clinical trials for different rare diseases, the proportion of insurance and DMC, and the geographical distribution of participating institutions in clinical trials of orphan drugs, can be used as important guidelines for future research and development of rare disease drugs in China. However, there are still some shortcomings in the development, such as the limited number of clinical trials of some types of rare diseases, the low coverage of insurance and DMC in domestic trials, the uneven geographical distribution of participating institutions and the large gap in participation in clinical trials. These problems may provide future improvement goals for decision makers and stakeholders involved in drug development for rare diseases.
A total of 246 clinical trials of orphan drugs were extracted from the database, covering 22 diseases and 90 drugs. There is a large gap in the number of clinical trials among various rare diseases. Parkinson' s disease (young type, early-onset), hemophilia, homozygote familial hypercholesterolemia have the most clinical trials in operation. Data on incidence/prevalence of rare diseases in China are limited13. Thus, only a few data can be used to explore the comparison between the epidemiology of rare diseases and the number of clinical trials in China. Up to March 25th, 2021, the number of rare diseases registered on the National Rare Diseases Registry System of China (NRDRS) has reached 63438, the top 3 of which are hemophilia, rare pulmonary hypertension and Duchenne/Becker muscular dystrophy, followed by spinocerebellar ataxia, pituitary adenoma, autosomal dominant polycystic kidney disease, primary dystonia, myasthenia gravis, Alport syndrome, and early onset muscular dystrophy. Among the top 10 rare diseases in the number of clinical trials, the number of actual registered cases of 6 rare diseases ranked in the top 26. In contrast, even though the reported cases of familial hypercholesterolemia and Gaucher's disease are lower, ranking 122nd and 74th, but they attracted a great portion of clinical trials. In addition, 98 out of the 121 rare diseases need drug treatment 14. Among them, there are only one clinical trial for 10 rare diseases, and the remaining 77 clinical trials for rare diseases have not been carried out in China,indicating an unmet and demanding needs for these patients. Notably, this situation also occurs in other countries. For example, it has been shown that the EU does not have orphan products for certain rare diseases6. And the orphan drugs under clinical trials cannot fully meet the clinical needs in the future.
Another critical issue is that a great portion of clinical trials covers only a small number of orphan drugs. Many pharmaceutical companies invest money in the same drug, especially in the clinical trials of Parkinson' s disease and homozygous familial hypercholesterolemia. Furthermore, bioequivalence studies account for a great portion and innovative drugs are rare. This phenomenon is also a reflection of the lack of innovation in China ' s pharmaceutical industry. The situation of lacking treatable drugs for some rare diseases in China will not be alleviated in the near future. However, available treatment might be obtained from imported drugs for these rare diseases.
The gradual growth of the annual number of clinical trials indicates that some progress has been made in the R & D of orphan drugs in China from 2013 to 2020. A steady growth can be observed for the number of orphan drug clinical trials since 2013, especially since 2016, the total amount has increased rapidly, benefiting from the reform of drug review and approval system in China, and the promotion policy for the research and development of orphan drugs 151617.
In recent years, the number of phase I and II clinical trials has increased significantly, consistently with an increase of orphan drugs at pre-clinical stage. Although 45 % of clinical trials are bioequivalence trials, its proportion is gradually decreasing each year. Many pharmaceutical companies tend to develop generic drugs, instead of original drugs, mainly due to the following reasons. First of all, there is a lack of epidemiological data on rare diseases in China, and the number of patients and market capacity, which increase the risk of R & D in companies. Secondly, since the pool of eligible patients of rare diseases is quite small, it is also a problem whether enterprises can make a profit of the new drug in a certain period of time. The development of new drug from laboratory to clinic is an extremely risky, and time- and money-consuming business. Finally, the development of generic drugs is also encouraged by the government while supporting the development of innovative drugs. In October 2019, the National Health Commission issued the first batch of 33' National Encouraging Catalogs of Imitation Drugs', including 6 orphan drugs for the treatment of 4 rare diseases18.
The clinical trials of rare diseases in China are mainly domestic trials. The international multicenter trials only accounts for a small portion, and are mainly carried out by global pharmaceutical companies. While many rare disease phase III clinical trials are international multicenter studies, it is also encouraged that the international multicenter trials should not be constrained in phase III clinical trials, but also expanded to other phases of clinical trials.
The proportion of DMC and trial injury insurance for subjects in international multicenter trials were significantly higher than those in domestic trials (DMC, 72 % v.s 3 %; Insurance, 96 % v.s 59% ). A study showed that, the appointment of data monitoring committee (DMC) was more common in rare disease trials as compared other clinical trials (53% v.s 41 %) 19. Patients with rare diseases are a special and vulnerable group, so clinical trials involving these patients should be carried out with more caution. Trial insurance is highly recommended to be purchased to not only protect the rights and interests of subjects, but also these of enterprises. Apparently, the Chinese enterprises have not yet realized its importance. Although the number of orphan drug clinical trials in China is increasing, the insurance coverage is quite low, partially due to the incomplete clinical trial insurance system in China..
The extent of participation in orphan drug clinical trials varies greatly among different hospitals. Most of the institutions participating in rare disease clinical trials are tertiary hospitals with strong research background. Peking Union Medical College Hospital has the highest number of clinical trials, and the hospitals in Beijing have the largest portion of orphan drug clinical trials. In 2019, Peking union medical college hospital lead in the establishment of a rare disease diagnosis and treatment cooperation network in China. In addition, Peking Union Medical College hospital is also responsible for building a national rare disease registration research platform. Beijing takes a leading role in guiding the development of rare diseases in China, which is reflected by its largest share of orphan drug clinical trials (twice more than that of Shanghai) in China.
The number of orphan drug clinical trials varies greatly in different regions in China. Further analysis showed that the regions with highest number of orphan drug clinical trials were consistent with the regions with highest number of registered cases on NRDRS. As of March 25th ,2021, Shandong had the largest number of registered cases on NRDRS, followed by Sichuan, Hebei, Zhejiang, Beijing, Henan and Jiangsu. In general, orphan drug clinical trials in China are mainly distributed in the developed regions, such as the northern and eastern China. However, this also reflects some problems. The distribution of medical resources for rare disease clinical research in China is quite uneven, which is partially due to the leading role of large clinical trial units required by the government 20. In the future, the government should also consider the problem of regional imbalance, so that more institutions, greater areas can be involved in clinical trials for orphan drug.
To solve these problems, we should first pay attention to the unmet needs of the research and development of orphan drugs and promote drug development in related diseases. Secondly, we need to improve the rare disease clinical trial registration database and rare disease diagnosis and treatment cooperation network. Thirdly, a systematic, comprehensive and timely rare disease clinical trial recruitment platform, new recruitment methods, and international collaboration are expected to be applied to promote rare disease clinical trial recruitment. Besides, we should improve the coverage of insurance and DMC in rare disease clinical trials to provide protection for R & D enterprises and subjects. Finally, we should encourage the participation and improve the quality of orphan drug clinical trials in medical institutions across a wider region in China.
The limitation of the current study is listed below. Firstly, this database is input by enterprises themselves, and there is the possibility of missing or mis-recording of data. In addition, part of the input is not standardized, which can possibly result in potential data deviation. Secondly, this study collected orphan drug clinical trials data solely registered on the drug clinical trial registration and information disclosure platform, and did not include clinical trials initiated by investigators. Thirdly, only 121 rare diseases were retrieved, which did not take into account of clinical trials for other rare diseases.