General characteristics of discontinued trials in mainland China
A total of 10234 drug clinical trials were registered on the Drug Trial Registration and Information Publication Platform as of March 31, 2020. Among the registered trials, 316 were recorded as terminated, no trials were stopped by the administration department, and 4 terminated trials due were excluded due to registration errors. Thus 312 (3.0%) discontinued trials were selected for inclusion and data analysis (Fig. 1). After data collection, we found that more than half [181(58.0%)] of the trials did not record the date of termination. In this study, we recorded the date of first ethical approval of the trials as the trial year and calculated the annual number. The first ethical approval date of the trials ranged from July 19, 2004 to November 5, 2019. The annual number of discontinued trials increased significantly over time, with an average annual growth rate of 23.6% (p = 0.000). A notable increase occurred in 2017 with 64 trials discontinued, corresponding to an increase of 266% relative to the number of trials initiated in 2016 (Fig. 2). The majority of the studied drugs were chemical drugs [229(73.4%)], followed by traditional Chinese drugs [57(18.3%)] and biological drugs [26(8.3%)] (Fig. 2). Regarding the geographical location of the principal investigator, the trials were carried out in 24 different cities and were mostly in north and east China (Fig. 3), as most clinical trials in China are carried out in these regions. The distribution of the indications for the studied drugs is shown in Fig. 4. Bioequivalence studies accounted for the largest proportion [97(31.1%)] of the studies, followed by phase III trials (86[ 27.6%]), phase II trials (52 [16.7%]), phase I trials [48 (15.4%)], and phase IV trials [4 (1.3%)]. The remaining 25 trials were studies on safety/efficacy and pharmacokinetics/pharmacodynamics of new drugs without a definitive phase (Fig. 5). Other general characteristics of the 312 discontinued clinical trials are shown in Table 1. Further retrieval and trial information analysis found that 90 trials restarted and re-registered, and 42 of those trials had enrolled participants.
Table 1
General characteristics of 312 discontinued clinical trials in China
Characteristic
|
n, (%)
|
Research institute
|
|
Tertiary hospital
|
285 (91.3)
|
Secondary hospital
|
5 (1.6)
|
Scientific research institutions
|
4 (1.3)
|
other
|
18 (5.8)
|
Study design
|
|
Parallel assignment
|
169 (54.2)
|
Crossover assignment
|
109 (34.9)
|
Single group assignment
|
34 (10.9)
|
Randomization status
|
|
Randomized
|
282 (90.4)
|
Non-randomized
|
30 (9.6)
|
Blinding status
|
|
Open label
|
178 (57.1)
|
Single blind
|
13 (4.2)
|
Double blind
|
121 (38.8)
|
No. of centers
|
|
Single-center trial
|
142 (45.5)
|
Multiple-center trial
|
170 (54.5)
|
Control type
|
|
Active drug
|
154 (49.4)
|
Placebo control
|
105 (33.7)
|
Black control
|
2 (0.6)
|
Uncontrolled
|
51 (16.3)
|
Planned sample size
|
|
< 100 participants
|
156 (50.0)
|
100–499 participants
|
106 (34.0)
|
> 500 participants
|
37 (11.9)
|
Unclear
|
13 (4.2)
|
Has enrolled participants
|
|
Yes
|
135 (43.3)
|
No
|
177 (56.7)
|
DMC has been establish
|
|
Yes
|
53 (17.0)
|
No
|
259 (83.0)
|
Insurance has been purchased
|
|
Yes
|
151 (48.4)
|
No
|
161 (51.6)
|
Abbreviations: DMC, data monitoring committee. |
Reasons for trial discontinuation
Reasons for discontinuation of the trials are shown in Table 2. In total, we identified 15 different reasons for discontinuation which were classified into four categories: trial issues, sponsor issues, administrative issues and research centre issues. Trial issues were the leading cause of discontinuation, and the most common reason was negative results [69(22.1%)]. Negative results were mostly due to the disappointing interim results for the study drug and results of fasting tests not meeting expectations. Protocol issues were mainly related to an unreasonable clinical trial protocol the need for protocol revisions. The main reasons for poor recruitment were slow enrolment of subjects, strict inclusion and exclusion criteria, and low incidence of subjects. Security issues were mainly drug-related adverse effects or serious adverse event (leading to death) in the subjects. The main reason for quality issues was because the sponsor carried out self-inspection and verification of the trial with reference to the Key Points for On-site Verification of Drug Clinical Trial Data released by NMPA on November 10, 2015 [14], and judged that the trial was unlikely to pass the NMPA's on-site verification and review.
Table 2
Reasons for discontinuation of 312 clinical trials in China
Reasons
|
n, (%)
|
Trials' issues
|
177 (56.7)
|
Negative results
|
69 (22.1)
|
Protocol issues
|
41 (13.1)
|
Poor recruitment
|
35 (11.2)
|
Security issues
|
21 (6.7)
|
Quality issues
|
9 (2.9)
|
Poor compliance of volunteers
|
2 (0.6)
|
Sponsors' issues
|
95 (30.4)
|
Company/business decision
|
68 (21.8)
|
Insufficient preparation
|
11 (3.5)
|
Inadequate supplies/lack of study drug
|
9 (2.9)
|
Lack of funding
|
7 (2.2)
|
Research centres' issues
|
15 (4.8)
|
Schedule was too full
|
11 (3.5)
|
Experimental conditions failed to meet the requirements
|
2 (0.6)
|
Poor management ability of the principle investigator
|
2 (0.6)
|
Administration issues
|
26 (8.3)
|
Update of relevant regulations
|
23 (7.4)
|
Trials were exempted
|
3 (1.0)
|
No reason given
|
5 (1.6)
|
Note that some trials cited multiple reasons for discontinuation and as a result have been coded multiple times.
|
Company/business decisions were the main sponsor issues and were mainly due to the company's research and development strategy changing or the market prospects of the studied drug not being wide enough. Insufficient preparation was mainly related to the biological sample testing company being unable to complete the planned sample testing or the partner of the producer or the reference product not qualifying as the national announcement. In terms of research centre issues, the most common reason for trial discontinuation was because the schedule of the centre was too full [11(3.5%)], as the principal investigators conducted too many trials simultaneously or were unable to conduct bioequivalence trials due to full schedule of the phase I trial ward. Additionally, poor management ability of the principle investigator and the laboratory testing items of the research centre not being certified by external quality assessment were also reasons for discontinuation. For administration issues, updates to some relevant regulations led to discontinuation of 23 clinical trials. In addition, 11 trials were terminated according to the DMC's suggestions, and the main reasons were that the risk to the participants involved in the trial outweighed the benefits and the statistical results showed that the main therapeutic indexes could not be achieved. For the 90 trials that had restarted and re-registered, the most common reason for discontinuation was trial issues [67.8% (61/90)] mainly due to protocol issues [35.6% (32/90)]. For the other 222 trials that had not restarted, the most common reason for discontinuation was trial issues [50.9% (113/222)] mainly due to negative results [24.8% (55/222)].
The number of neoplasm drug trials in mainland China grew remarkably over the years studied herein, and improving outcomes of patients with neoplasms by encouraging biopharmaceutical research and development has become a government priority all over the world, including in China [15]. In our study, neoplasm drug trials accounted for the largest number of discontinued trials. Thus, we further explored the reasons for discontinuation in neoplasm clinical trials and found that the majority were trial issues (74.0%) including negative results, poor recruitment, clinical trial protocol issues and security issues (Fig. 6).
Influencing factor analysis for trial discontinuation
Analysis of the association of trial characteristics and the different reasons related to trial discontinuation are shown in Table 3. Compared with parallel trials and single-group trials, crossover design trials showed a significantly higher rate of trial discontinuation associated with research centre issues. The crossover design of clinical trials is thought to have some methodological advantages; however, it may be more prone to problems when the data are incomplete or improper analysis methods are used [16, 17]. Thus, researchers should pay special attention when carrying out crossover design trials. In addition, open-label trials also showed a significantly higher rate of trial discontinuation associated with research centre issues, as most of the open-label trials were bioequivalence trials and phase I trials. Research centre issues, such as whether the schedule of the centre is too full, should be considered before starting the trials.
Table 3
Association of trial characteristics with different issues that related to trial discontinuation
Items
|
Trials' issues
|
Sponsor's issues
|
Research centers' issues
|
Administrative issues
|
Study design
|
|
|
|
|
Parallel assignment (n = 169)
|
100(59.2%)
|
49(29.0%)
|
4(2.4%)
|
13(7.7%)
|
Crossover assignment (n = 109)
|
54(49.5%)
|
32(29.4%)
|
11(10.1%)
|
12(11.0%)
|
Single group assignment (n = 34)
|
20(58.8%)
|
11(32.4%)
|
0(0)
|
1(2.9%)
|
p
|
0.268
|
0.925
|
0.006
|
0.300
|
Blinding status
|
|
|
|
|
Open label (n = 178)
|
98(55.1)
|
50(28.1%)
|
14(7.9%)
|
14(7.9%)
|
Single blind (n = 13)
|
7(53.8%)
|
4(30.8%)
|
0(0)
|
1(7.7%)
|
Double blind (n = 121)
|
69(56.6%)
|
38(31.1)
|
1(0.8%)
|
11(9.0%)
|
p
|
0.935
|
0.822
|
0.014
|
0.928
|
No. of centers
|
|
|
|
|
Single-center trial (n = 142)
|
70(49.3%)
|
47(33.1%)
|
10(7.0%)
|
14(9.9%)
|
Multiple-center trial (n = 170)
|
104(61.2%)
|
45(26.5%)
|
5(2.9%)
|
12(7.1%)
|
p
|
0.035
|
0.201
|
0.092
|
0.373
|
Planned sample size*
|
|
|
|
|
< 100 participants (n = 156)
|
58(37.2%)
|
34(21.8)
|
4(2.6%)
|
9(5.8%)
|
100–499 participants (n = 106)
|
28(26.4%)
|
6(5.7%)
|
0(0)
|
1(0.9%)
|
> 500 participants (n = 37)
|
7(18.9%)
|
5(13.5%)
|
0(0)
|
1(2.7%)
|
p
|
0.042
|
0.002
|
0.256
|
0.091
|
Has enrolled participants
|
|
|
|
|
Yes (n = 135)
|
96(71.1%)
|
20(14.8%)
|
1(0.7%)
|
10(7.4%)
|
No (n = 177)
|
78(44.1%)
|
72(40.7%)
|
14(7.9%)
|
16(9.0%)
|
p
|
0.000
|
0.000
|
0.003
|
0.605
|
* We excluded trials that did not state planned sample size.
Note that some trials cited multiple reasons for discontinuation and as a result have been coded multiple times.
|
Multicentre trials showed a significantly higher rate of trial discontinuation associated with trial issues. It is known that heterogeneity among subject characteristics, clinical practice and management requirements in different centres can lead to heterogenous interpretations of research results, which is called the centre effect. When the results show serious centre effects, the evidence regarding effectiveness and safety is unreliable [18]. Electronic management systems such as clinical trial management systems and electronic data capture help improve the efficiency and accuracy of management, improve the timeliness of data collection, and make the information exchange and sharing between centres more convenient in the implementation stage[19].
Trials with sample sizes of less than 100 participants showed a significantly higher rate of trial discontinuation associated with trial issues and sponsor issues. Unsurprisingly, poor recruitment was the most common reason for trial discontinuation[ 20, 21]. Trials with limited numbers of patients, such as rare disease trials or those with a sample that is too small for meaningful analysis, consume financial and material resources, and the competitiveness of the sponsors should be considered.
Compared with trials that had not enrolled participants, trials that had enrolled participants showed a significantly higher rate of trial discontinuation associated with trial issues and a lower rate of trial discontinuation associated with sponsor issues and research centre issues. Identifying potential problems before starting clinical trials is very important for success of the trials. In this study, we found that 135 trials had enrolled participants before discontinuation, and this may lead to more waste of human and financial resources and related patient safety issues.