Trend of clinical trials of new drugs for rare diseases in China in recent 10 years

Distribution of types of clinical trials for rare diseases

As shown in Fig. 1, there were 481 clinical trial applications for rare diseases in China from 2013 to 2022 in total. Among them, the top 5 applications were Parkinson Disease (119, 24.7%), Hemophilia (93, 19.3%), Hypercholesterolemia (80, 16.6%), Idiopathic Pulmonary Fibrosis (58, 12.1%), and Multiple Sclerosis (50, 10.4%), which are categorized in nervous system, blood system, respiratory system, and autoimmune system respectively as shown in Table 1. Rare diseases that are undergoing clinical trials account for 18% (22 species) of the first list of rare diseases (121 species) released in China, declining that most rare diseases in China still lack of clinical research. From the number of trials conducted, we saw Parkinson Disease (PD) was a hot spot in clinical trials in rare diseases. This suggested that a large number of trials were conducted for a relatively small number of rare diseases in China and clinical research may be related to the prevalence of diseases [2].

Fig. 1figure 1

Summary chart of the number of clinical trial applications for each rare disease from 2013 to 2022

Table 1 Classification of Diseases included in rare disease clinical trials from 2013 to 2022 Overview of clinical trials for rare diseases

A total of 481 clinical trials related to rare disease was registered on the drug clinical trial registration and information disclosure platform, involving 276 enterprises, of which 67 (24.3%) were multinational enterprises. As shown in Fig. 2A), 52% clinical trials have been completed and 46% were in the process of recruiting, 2% were terminated or suspended automatically. Relevant factors leading to this discontinuation of these trials have been concerned, such as safety or toxicity concerns and mostly related to the difficulties in patient enrolment [9]. This reflects the difficulty of recruiting participants with rare disease, resulting in most clinical trials being unable to enter the trial stage as expected.

Most of the clinical trials were still in BE (203, 42%), while phases I, II, III and IV accounting for 18% (88), 9% (41), 23% (109), and 4% (19) respectively as shown in Fig. 2C). From the perspective of clinical trial scope in Fig. 2B), the number of domestic clinical trials was 420 (87%), while the number of international multi-center trials was 61 (13%). Most of the clinical trials in China were bioequivalence trials, indicating that there was a large space for the development of innovative drugs for rare diseases in China.

The trial types and design distributions of clinical trials were shown in the Fig. 2D. In all trials of analyzed, alternative clinical trial designs for studying treatments of rare diseases applied in included single-arm, factorial, parallel grouping and crossover design. In terms of study design, the most popular was crossover design, with a total of 215 studies (45%), and followed by parallel grouping and single-arm experiment, which accounted for 28% (134) and 27% (131) respectively. There was only one case of factorial design, and the proportion was almost non-countable.

Fig. 2figure 2

Summary of clinical trial characteristics

Clinical trial applications on rare diseases for a total of 481 were submitted from 2013 to 2022, with an average annual growth rate of 28.2% (Fig. 3). Since 2015, the number of clinical trial registrations for rare diseases has gradually increased. In 2016, the number of clinical trial application for rare diseases increased by 80% compared to 2015, which may be related to the fact that China provided a faster process for clinical trials and infant drug approval for rare diseases in 2015. Notably, the number of applications for rare diseases drugs increased by 122% in 2017 compared with 2016, which was consistent with the overall trend of IND applications [10]. The number of rare disease clinical trial registrations in 2021 increased by 63.8% compared to 2020, while the number of rare disease clinical trial registrations in 2022 increased by 22% compared to 2021. To a certain extent, it could be implied that the outbreak of the global coronavirus epidemic in 2020 has little impact on rare disease clinical trials in China. It cannot be ignored that the annual growth trend of rare disease clinical trials was consistent with the overall development trend of clinical trials in China, but in terms of average annual growth rate, it was still lower than average (32%) [10].

Fig. 3figure 3

Annual numbers of clinical trial applications for rare diseases in China

Characteristics of drugs in clinical trials for rare diseases

The characteristics of drugs registered were summarized in Fig. 4. The diseases with the most registered drugs were Parkinson disease, Hemophilia, Hypercholesterolemia, Idiopathic Pulmonary Fibrosis, and Multiple Sclerosis, which containing 91, 73, 71, 44, 44 drugs respectively. However, the number of innovative drugs was not corresponding to that of registration. The new drug registered in Parkinson disease, Hemophilia, Hypercholesterolemia, Idiopathic Pulmonary Fibrosis, and Multiple Sclerosis are 14 (15.4%), 51 (69.9%), 11 (15.5%), 21 (47.7%), and 9 (20.5%). Although the largest number of drugs was for Parkinson disease, most were generics and imported drugs. 69.9% drugs were innovative in the registration of Hemophilia. It was assumed that the research and development of innovative drugs for hemophilia by pharmaceutical companies in the recent 10 years was significantly greater than that for other rare diseases. Among the diseases with number of drug registration less than 10, Neuromyelitis Optica owned the highest number of innovative drugs in 8.

Fig. 4figure 4

The number of drugs in rare diseases registered in drug clinical trial registration and information disclosure platform

In terms of drug types as shown in Fig. 5, of the 481 clinical trials registered, there were 378 drugs in total, and 312 (83%) of which are chemicals and 64 (17%) are biologics. Clinical trials registered in traditional Chinese medicine or natural medicine were the least with only 2 drugs. Drugs for rare diseases were mainly chemical drugs, while biologics accounted for a small part.

Fig. 5figure 5

Drug registration classification for clinical trials in rare diseases

The clinical trials in which the participants were under 18 years old and were in phases II, III, and IV were statistically analyzed and shown in Fig. 6. The total number of applications was 92 (19% of 481), including dramatically 60 for hemophilia. The clinical trials for rare diseases in adolescents were mainly hemophilia, which was consistent with the age of onset of hemophilia. The overall prevalence of hemophilia in China was 2.73/10,0000, and most of the patients were adolescents. Since more than half these diseases begin in childhood [2], the much more applications on hemophilia showed that the country and pharmaceutical companies attached importance to juvenile diseases.

Fig. 6figure 6

Clinical trials with the age of participants younger than 18 and the corresponding number of drugs in diseases

The size and geographical distribution of clinical trials

Clinical trials that had completed subject recruitment were chosen out from the available data, and the target and actual numbers were compared. Table 2 shows the data about number of participants related to scope of trials, which told us that domestic clinical trials not only outnumbered international multi-center trials, but also obtained a higher percentage (74.2% vs. 68%) in trials that the actual number of participants was equal to or greater than the target number. The reason why the recruitment of participants in international multi-center trials was not as successful as in domestic clinical trials was speculated to insufficient collaboration between centers related. The ease of recruitment of participants is related to the prevalence of the rare disease and the scattered geographical distribution of the patients also add difficulty to the enrollment of the subjects. In light of the small size of subjects recruited, study designs must be improved to efficiently use the limited samples available.

Table 2 The number of participants related to scope of trials

In addition, as can be seen from the column of the province where the leading pricinple investigator (PI) of the multi-center clinical trial was located (Fig. 7), most of the leading PIs were from economically developed southeast region of China such as Beijing, Shanghai, Guangdong, and Tianjin. There were 141 (74.2%) leading PIs located in Beijing, Shanghai, Guangdong, and Tianjin. On the one hand, the level of economic development of local regions would affect the development of medical industry, hence to a certain level, the propotion of leading PIs in other provinces in China was smaller. On the other hand, the difficulty of disease treatment and clinical trials conduction of rare diseases is bigger than that of common diseases, which decreased the probability of other provinces to be the leading PIs. The number of rare disease clinical trials conducted in each region shown in Fig. 8. Sites conducting clinical trials of rare diseases were distributed in some coastal cities and economically developed cities, which was consistent with the results of leading PIs. Although there were clinical trials of rare diseases located in western provinces of China, the numbers were dramatically less compared to that in coastal cities, indicating that clinical research on rare diseases still has a lot of space for improvement in these provinces, such as Xinjiang, Ningxia, Inner Mongolia.

Fig. 7figure 7

Geographical distribution of leading PI in multicenter clinical trials

Fig. 8figure 8

The number of clinical trials for rare diseases in each province in China

留言 (0)

沒有登入
gif