This study conducted a statistical analysis of the clinical registration trials of rare disease and drugs registered on the China Food and Drug Administration Registration and Information Disclosure Platform for Drug Clinical Studies from 2013 to November 2022. The results showed that the total number of clinical trials of rare disease and orphan drugs in China is small compared with the number in the USA (1252, 1332), Europe (250, 172) and Japan (22, 29)[11], and the research and development of innovative drugs only involves around 10 rare diseases.
The numbers of rare diseases with clinical trials and drugs in test account for a small part of the first list of rare disease released in China, and most of them are diseases with high prevalence. The main reason for this phenomenon is that the incidence of most rare diseases is low and there are difficulties in recruiting patients.
In China, overall, the trials and drugs were limited to a small number of rare diseases, and most were stocked in hemophilia. For most of rare diseases, a small proportion of trials are in Phase 3 or Phase 4 (less than 30%) while Phase 3 and Phase 4 trials were considered as promising for drug development, implying there is a huge hurdle to clear on drug development in China.
Of the 481 trials, trials design methods include one-arm trial, factorial design, parallel grouping and crossover design. 45% were trials of crossover design and 27% were one-arm trial and 28% were parallel grouping. The essential feature between a crossover trial and a conventional parallel-group trial is that each patient serves as his/her own control. In crossover trials, each participant would receive all compared treatments in a random order. The effects of two or more treatments can be observed in the same individual, so it can effectively control irrelevant variables and thus reduces the sample size needed[12]. Thus, due to the limitation of the number of subjects, crossover design is applied in most rare disease clinical trials.
Drugs for rare diseases in trials are mainly chemical drugs (312, 83%), followed by biological drugs (64, 17%). Biological drugs are mainly about proteins, which is lacking in nucleic acid preparations, gene and cell therapies and vaccines. Due to the complex pathological process, the treatment of rare diseases should be diversified, rather than limited to small molecule chemical drugs or some simple protein preparations. China is known worldwide for its distinctive TCM theories[13, 14]. In order to diversify the treatment of rare diseases and improve the cure rate, the Chinese government, research institutions and pharmaceutical companies need to pay attention to the advantages of traditional Chinese medicine and combine it with clinical research on rare diseases.
For most rare diseases, imported drugs account for a considerable proportion, which would increase the economic burden of disease treatment and thus, domestic patients have difficulty in using drugs or cannot afford to use them. This shows implicitly that the needed drugs for rare diseases in China market is far greater than the pharmaceutical market could provide, and therefore it is necessary to vigorously develop clinical research on rare diseases.
To fuel the clinical research on rare diseases, China has issued a series of policies for drug research and development and clinical research for rare diseases. One of the policies is to prioritize and accelerate the review and approval of rare disease-related registrations. For example, in 2015, the State Food and Drug Administration issued the "Announcement on Several Policies for Drug Registration, Review and Approval", clarifying that the registration application of innovative drugs for rare diseases can be accelerated on the process of review and approval. In 2017, "Opinions on Deepening the Reform of the Review and Approval System and Encouraging Innovation in Drugs and Medical Devices" put forward clear opinions on encouraging the research and development of drugs for rare diseases and accelerating the registration and approval of rare disease drugs. In 2018, China listed rare disease treatment drugs as data protection objects and granted a 6-year data protection period from the date when the indication was first approved in China. In addition, to improve the level of diagnosis and treatment of rare diseases and safeguard the health rights of patients with rare diseases, China has established a national cooperation network for the diagnosis and treatment of rare diseases. As China and the society paying more and more attention to rare diseases, at the Fourth Session of the 13th National People's Congress, it was officially stated that China would further improve the diagnosis, treatment, and medical security of rare diseases, increase support for the research and development of innovative drugs and generic drugs for rare diseases, and strive to improve the dilemma of domestic rare disease patients drug using difficulties. In the contrary, The Orphan Drug Act of 1983 was passed by US Congress to give financial incentives to pharmaceutical companies including market exclusivity and tax breaks to develop drugs for rare diseases, which is 30 years earlier than China[4]. The drug investigation on rare diseases in the US, EU and Japan is much more promising and vigorous[11].
At present, there is still a certain gap between domestic drug research and development for rare diseases and foreign countries. Through the data analysis of this study, most of the domestic clinical research on rare disease drugs is bioequivalence tests and the drugs about rare diseases in China are non-innovative drugs. Conversely, one study showed that 48% of clinical trials registered on ClinicalTrials.gov about rare diseases were in the United States. The disparity in rare disease research at home and abroad is mainly due to the late start of biomedical research in China, the low level of basic research, the weak ability of independent innovation, and the backwardness of scientific and technology, so the research and development of innovative drugs for rare diseases is also lagging. Nevertheless, in light of the annual growth rate (28.2%) of the number of clinical trial applications for rare diseases, it is apparent that the Chinese government and society are paying more and more attention to clinical research on rare diseases, and the number of clinical trials is showing a steady growth trend year by year.
Based on various policies promulgated by the country, the research environment for rare diseases has greatly improved in recent years. However, due to the complexity of rare diseases, small number of rare disease patients, the difficulty of recruitment, and the high cost of treatment, there are still many obstacles to the clinical research of rare diseases[4]. To boost the more improvement of infant drug clinical trials on rare diseases, it is not enough to depend on the government. The development of specialized centers caring for rare disease patients within academic medical institutions and partnerships between academic institutions, health care providers and the pharmaceutical industry should also be played attention on[8].
This retrospective study still has some limitations. The database is limited and does not include the registration information from other platforms, so it can only reflect the clinical trial of rare diseases research status of the drug clinical trial registration and information disclosure platform. This study only reflects the registered clinical trials from 2013 to 2022, it cannot represent the overall level of rare disease clinical research in the future in China. By integrating the information of clinical trials and drugs on rare diseases in China, this work is expected to boost the drug development in rare diseases and offer the latest research trend in China.