Regular Articles
Comparison of the Speed of Enrollment for Clinical Trials Conducted by Japanese and Global Pharmaceutical Companies
2023 Volume 46 Issue 9 Pages 1289-1295
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2023 Volume 46 Issue 9 Pages 1289-1295
Since the establishment of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), many countries in the world have rapidly improved their clinical trial performance, and the era has come to compare the clinical trial performance of each country. Japan’s clinical trials are considered excellent quality, but costly and slow. In this study, we examined the speed of enrollment period in clinical trials. We surveyed clinical trials from January 1, 2010, to December 31, 2019, covering the top 10 pharmaceutical companies in each global sales ranking (Global 10) and the Japanese sales ranking (Japan 10). Clinical trial data were obtained from ClinicalTrials.gov, a clinical trial registration information database, and the speed of participant enrollment (cases/month) was compared for each phase of the trials. The number of clinical trials conducted during the 10 years was 8938 trials for Global 10 and 1439 trials for Japan 10. Comparing the speed of participant enrollment by phase, Japan 10 was significantly faster in phase 1 for both healthy subjects and oncology patients. [Japan 10: Global 10; 15.1 : 12.0 cases/month (healthy subjects) and 5.5 : 1.8 cases/month (oncology), respectively. p < 0.001]. Global 10 was also significantly faster in phase 3. [Japan 10: Global 10; 12.4: 36.9 cases/month, p < 0.001). No significant difference was observed in phase 2 and phase 4. There was a possibility that the speed of enrollment differed by phase between global companies and Japanese domestic companies.
In Japan, the number of multinational clinical trials (MRCTs) has been increasing every year since the notification of “Basic Principles on Global Clinical Trials” issued in 2007.1,2) MRCTs avoid overlapping clinical trials globally based on the spirit of ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use). As a result, it has allowed for more efficient clinical development, more efficient review of the applications for drug approval, and more efficient post-marketing activities.3) MRCT has also enabled to shorten the drug lag between the US and Japan.4–6) The notification of “General Principles for Planning and Design of Multi-Regional Clinical Trials (ICH-E17)” was issued in 2018.7,8) ICH-E17 has increased the acceptability of MRCT in regulatory agencies worldwide, allowing earlier access to new medicines globally. Also, the drug lag with foreign countries was also shortened in Japan, and it could be said that there was a great merit for Japanese patients as well.4)
However, as the global simultaneous development has become a crucial era, each pharmaceutical company is becoming more able to perform MRCT by selecting countries or regions where clinical trials can be performed more efficiently. In the future, the market size of each country’s medicines and the clinical trial performance of each country seem to influence the selection of the country and/or region in which the clinical trial is conducted.
With regard to the global pharmaceutical market, the average annual growth rate in developed countries from 2017 to 2021 is +4.9%, whereas the pharmaceutical market in Japan has the only negative growth estimate of −0.5%.9) Therefore, the merit of choosing Japan as a participating country for MRCT would be low when considering participating countries and regions from worldwide for MRCT.10) In addition, regarding quality, cost, and speed, which are considered to be parameters of clinical trial performance, although clinical trial in Japan is considered to be a good evaluation of quality, the evaluation of cost and speed is low.11)
In this study, we attempted to compare the benchmark on the speed for clinical trials conducted by Japanese pharmaceutical companies and foreign affiliated-pharmaceutical companies. The patient/participant enrollment speed was investigated from the viewpoint of affecting speed and cost in the clinical trial performance in this study. Specifically, for clinical trials registered in ClinicalTrials.gov, we compared the speed of enrollment between the top 10 companies in global sales (Global 10) and the top 10 companies in Japanese sales (Japan 10). By conducting these studies, we also expected to demonstrate the performance of pharmaceutical companies in Global 10 and Japan 10.
This study investigated clinical trials conducted by Global 10 and Japan 10 among clinical trials registered in ClinicalTrials.gov during the 10 years from January 2010 to December 2019 (based on the study initiation date). We surveyed with ClinicalTrials.gov as of November 1, 2020.
When data-collected from ClinicalTrials.gov, the extracted conditions were as follows:
Funder type: Industry, Study type: Interventional Studies (Clinical Trials), Intervention: Drug, Sponsor: The following pharmaceutical companies
We initially, would like to define representatives of foreign-affiliated pharmaceutical company and Japan domestic pharmaceutical company. As one of the methods for this definition, targeted pharmaceutical companies were selected from the global and Japanese rankings of the top 10 pharmaceutical companies' sales rankings based on the reports and related materials released by each company in fiscal 2019.12,13) In this study, the company which merged for 10 years from 2010 to 2019 was considered. Regarding the sample size, the estimated sample size registered in advance was not used, and the actual sample size registered was treated as the sample size. In this study, we excluded trials that were discontinued, trials in which the speed of participant accrual could not be calculated (date of completion of participant registration not registered, number of patients/participants not registered), trials that were not registered in the phase, and trials in which the trial was registered in duplicate due to the combination. This study was conducted according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.14)
Definition of ClassificationIn this study, analyses were performed by phase. Phase 1/2 was tabulated as phase 2 and phase 2/3 as phase 3. Phase 1 studies were classified into phase 1 healthy volunteer and phase 1 oncology based on the target diseases. We divided the locations into five regions such as Japan, the US, Europe (one or more of UK, Germany, France, Italy, Spain, Switzerland), China, and other countries. In the classification of MRCT and Domestic trial, studies conducted in only of the above five regions were defined as Domestic trial, and studies conducted in two or more locations of the above five regions participated in were defined as MRCT. And clinical trials between other countries were defined as MRCT if they were conducted in two or more countries. In this study, we defined the participant enrollment period (months) = date of completing participant enrollment–date of study initiation, and the rate of participant enrollment (cases/months) = a number of patients/(date of completing patient enrollment–date of study initiation). Calculations were performed as 30 d for 1 month.
Statistical Analysis MethodAll statistical analyses were performed using the analytical tools of JMP Pro 15, with a significance level of 5% two tailed. We used the chi-square test for trend comparisons of characteristics, and used t-test for speed.
Ethical ApprovalThis study did not require institutional review board approval because it was based on publicly available information. Therefore, we did not have ethics approval for this study.
When the top 10 companies in 2019 were investigated, Global 10 was the 10 companies in Roche, Pfizer, Novartis, Merck, GSK, Johnson & Johnson, Sanofi, AbbVie, Takeda, BMS. Japan 10 was 10 companies in Otsuka, Astellas, Daiichi-Sankyo, Eisai, Chugai, Sumitomo Pharma, Mitsubishi-Tanabe Pharma, Shionogi, Kyowa Kirin, Ono Pharmaceutical. Takeda of Global 10 was ranked 1 in Japan ranking at the time of 2020, but it was included in Japan 10 by moving up Ono Pharmaceutical Industry ranking 11 in Japan ranking as 10, and the data were collected.
The number of clinical trials registered during the 10-year period from January 2010 to December 2019 was 8938 in Global 10 and 1439 in Japan 10, respectively. The number of clinical trials to be analyzed for the speed of participant enrollment was 7294 in Global 10 and 1265 in Japan 10 (Fig. 1), respectively, after excluding studies with duplicate registrations and other studies for which the phase of the clinical trial was unknown.
Characteristics of the studies are shown in Table 1. Regarding the implementation region of clinical trials, Global 10 was more prevalent than Japan 10 in MRCT performed in regions with two or more regions. Regarding the study design, there were relatively many single-arm studies in Japan 10. Randomized trials were the most common in both Global 10 and Japan 10. In terms of blinding, open-label studies accounted for more than half in both Global 10 and Japan 10, whereas double-blind studies were conducted in more than 20% of Global 10. The sample size was more than 50% in 10–99 clinical-trials in both Global 10 and Japan 10, and interventional study accounted for more than 70% in study type in both Global 10 and Japan 10.
| N (%) | Total | |||
|---|---|---|---|---|
| Global 10 | Japan 10 | N (%) | ||
| No. | 7294 | 1265 | 8559 | |
| Study phase | Phase 1 healthy volunteer | 2261 (31.0) | 404 (31.9) | 2665 (31.1) |
| Phase 1 oncology | 552 (7.6) | 133 (10.6) | 685 (8.0) | |
| Phase 2 | 1705 (23.4) | 308 (24.3) | 2013 (23.5) | |
| Phase 3 | 2104 (28.8) | 318 (25.1) | 2422 (28.3) | |
| Phase 4 | 672 (9.2) | 102 (8.1) | 774 (9.0) | |
| Study method | Multi-regional clinical trial | 2801 (38.4) | 320 (25.3) | 3121 (36.5) |
| Domestic trial | 3788 (51.9) | 924 (73.0) | 4712 (55.1) | |
| N/A | 705 (9.7) | 21 (1.7) | 726 (8.5) | |
| Study region | Japan | 916 (12.6) | 444 (35.1) | 1360 (15.9) |
| United States | 3561 (48.8) | 541 (42.8) | 4102 (47.9) | |
| Europe* | 2636 (36.1) | 282 (22.3) | 2918 (34.1) | |
| China | 552 (7.6) | 72 (5.7) | 624 (7.3) | |
| Other countries | 4426 (60.7) | 407 (32.2) | 4833 (56.5) | |
| Study design | Single arm study | 1813 (24.9) | 415 (32.8) | 2228 (26.0) |
| Parallel group comparison | 4180 (57.3) | 662 (52.3) | 4842 (56.6) | |
| Crossover study | 1031 (14.1) | 155 (12.3) | 1186 (13.9) | |
| Stratified randomization | 135 (1.9) | 27 (2.1) | 162 (1.9) | |
| Factorial study | 15 (0.2) | 4 (0.3) | 19 (0.2) | |
| N/A | 120 (1.6) | 2 (0.2) | 122 (1.4) | |
| Randomization | Randomized | 4754 (65.2) | 761 (60.2) | 5515 (64.4) |
| Non randomized | 1163 (15.9) | 167 (13.2) | 1330 (15.5) | |
| N/A | 1377 (18.9) | 337 (26.6) | 1714 (20.0) | |
| Blind | Non blinded | 3983 (54.6) | 747 (59.1) | 4,730 (55.3) |
| Single blinded | 209 (2.9) | 21 (1.7) | 230 (2.7) | |
| Double blinded | 1486 (20.4) | 178 (14.1) | 1664 (19.4) | |
| Triple blinded or more | 1602 (21.9) | 312(24.7) | 1914 (22.4) | |
| N/A | 14 (0.9) | 7 (0.6) | 21 (0.2) | |
| Number of participants | 1–9 | 439 (6.0) | 60 (4.7) | 499 (5.8) |
| 10–99 | 3685 (50.5) | 711 (56.2) | 4396 (51.4) | |
| 100–999 | 2818 (38.6) | 453 (35.8) | 3271 (38.2) | |
| 1000–4999 | 308 (4.2) | 40 (3.2) | 348 (4.1) | |
| 5000–9999 | 24 (0.3) | 0 (0.0) | 24 (0.3) | |
| 10000– | 20 (0.3) | 1 (0.1) | 21 (0.2) | |
| Target age | Child (Birth–17) | 510 (7.0) | 63 (5.0) | 573 (6.7) |
| Adult (18–64) | 1721 (23.6) | 323 (25.5) | 2044 (23.9) | |
| Older adult (65–) | 62 (0.9) | 10 (0.8) | 72 (0.8) | |
| Child to Adult | 173 (2.4) | 16 (1.3) | 189 (2.2) | |
| Adult to Older adult | 4519 (62.0) | 827 (65.4) | 5346 (62.5) | |
| All age | 309 (4.2) | 26 (2.6) | 335 (3.9) | |
| Study type | Interventional | 5251 (72.0) | 993 (78.5) | 6244 (73.0) |
| Observational | 690 (9.5) | 27 (2.1) | 717 (8.4) | |
| Patient registry | 576 (7.9) | 104 (8.2) | 680 (7.9) | |
| Expanded access | 25 (0.3) | 4 (0.3) | 29 (0.3) | |
| Other type | 448(6.1) | 55(4.3) | 503 (5.9) | |
| N/A | 304 (4.2) | 82 (6.5) | 386 (4.5) | |
N/A: Not applicable, *: One or more countries with United Kingdom, Germany, France, Italy, Spain, Switzerland.
The number of clinical trials by phase was highest in phase 1 healthy volunteer trials in both Global 10 and Japan 10, followed by Phase 3. A comparison of the number of clinical trials by phase between Global 10 and Japan 10 shows that Japan 10 was significantly more common in phase 1 (p = 0.019), and Global 10 was significantly more common in phase 3 (p = 0.040) (Table 2).
| Global 10 | Japan 10 | Total | p Value* | |
|---|---|---|---|---|
| N (%) | N (%) | N (%) | ||
| Phase 1 | 2813 (38.6) | 537 (42.5) | 3350 (39.1) | 0.019 |
| Phase 2 | 1705 (23.4) | 308 (24.3) | 2013 (23.5) | 0.374 |
| Phase 3 | 2104 (28.8) | 318 (25.1) | 2422 (28.3) | 0.040 |
| Phase 4 | 672 (9.2) | 102 (8.1) | 774 (9.0) | 0.262 |
| Total | 7294 (100.0) | 1265 (100.0) | 8559 (100.0) | — |
*: Chi-square test.
Categorization was performed based on ICD 10 (International Statistical Classification of Disease and Related Health Problems) by area of disease (Table 3).
| ICD 10 | Disease area | Global 10 | Japan 10 | Total |
|---|---|---|---|---|
| N (%) | N (%) | N (%) | ||
| 1 | Infectious or parasitic diseases | 1230 (16.9) | 67 (5.3) | 1297(15.2) |
| 2 | Neoplasms | 1563 (21.4) | 326 (25.8) | 1889(22.1) |
| 3 | Diseases of the blood or blood-forming organs | 110 (1.5) | 41 (3.2) | 151(1.7) |
| 4 | Diseases of the immune system | 118 (1.6) | 6 (0.5) | 124(1.4) |
| 5 | Endocrine, nutritional or metabolic diseases | 688 (9.4) | 94 (7.4) | 782(9.1) |
| 6 | Mental, behavioural or neurodevelopmental disorders | 365 (5.0) | 142 (11.2) | 507(5.9) |
| 7 | Sleep-wake disorders | 27 (0.4) | 18 (1.4) | 45(0.5) |
| 8 | Diseases of the nervous system | 257 (3.5) | 72 (5.7) | 329(3.8) |
| 9 | Diseases of the visual system | 124 (1.7) | 15 (1.2) | 139(1.6) |
| 10 | Diseases of the ear or mastoid process | 2 (0.03) | 0 (0.0) | 2(0.02) |
| 11 | Diseases of the circulatory system | 286 (3.9) | 51 (4.0) | 337(3.9) |
| 12 | Diseases of the respiratory system | 482 (6.6) | 17 (1.3) | 499(5.8) |
| 13 | Diseases of the digestive system | 302 (4.1) | 55 (4.3) | 357(4.2) |
| 14 | Diseases of the skin | 253 (3.5) | 25 (2.0) | 278(3.2) |
| 15 | Diseases of the musculoskeletal system or connective tissue : RA | 336 (4.6) | 38 (3.0) | 374(4.4) |
| 16 | Diseases of the genitourinary system | 179 (2.5) | 94 (7.4) | 273(3.2) |
| 17 | Conditions related to sexual health | 11 (0.2) | 1 (0.1) | 12(0.1) |
| 18 | Pregnancy, childbirth or the puerperium | 27 (0.4) | 0 (0.0) | 27(0.3) |
| 19 | Certain conditions originating in the perinatal period | 2 (0.03) | 1 (0.1) | 3(0.04) |
| 20 | Developmental anomalies | 31(0.4) | 1 (0.1) | 32(0.4) |
| 21 | Symptoms, signs or clinical findings, not elsewhere classified | 141 (1.9) | 19 (1.5) | 160(1.9) |
| 22 | Injury, poisoning or certain other consequences of external causes | 92 (1.3) | 28 (2.2) | 120(1.4) |
| — | Healthy volunteer | 668(9.2) | 154 (12.2) | 822(9.6) |
In a total of 8559 studies conducted during the 10-year period, neoplasms was the most common disease area for 1889 (22.1%), followed by infectious or parasitic diseases for 1297 (15.2%), and 782 (9.1%) in endocrine, nutritional or metabolic diseases.
Comparison of the Speed of Participant EnrollmentTable 4 shows the speed for participant enrollment, number of clinical trials, number of participants per each trial, and duration of participant enrollment by phase in Global 10 and Japan 10. In the phase3 trials, Global 10 was significantly faster compared to 36.9 participants/month and 12.4 participants/month in Japan 10 (p < 0.0001, student t-test). In phase 1 trials, Japan 10 had a significantly faster rate of participant enrollment than Global 10 in both healthy subjects and cancer-treated subjects (phase 1 healthy volunteer: p = 0.0002, phase 1 oncology: p < 0.0001). There was no significant difference in the rate of participant enrollment between Global 10 and Japan 10 for phase 2 and phase 4. Table 5 shows the speed of clinical trials conducted by Global 10 and Japan 10 by region and phase. The regions and phases which Japan 10 was significantly faster than Global 10 were “Phase 1 healthy volunteers,” “Phase 1 oncology” in Japan, “Phase 1 oncology” in the US, “Phase 1 healthy volunteers” in Europe, and “Phase 1 oncology” in other countries. The regions and phases in which Global 10 was significantly faster than Japan 10 were “Phase 3” and “Phase 4” in Japan, “Phase 3” in the US, “Phase 2” and “Phase 3” in Europe, “Phase 2,” “Phase 3,” “Phase 4” in China, and “Phase 3,” “Phase 4” in other countries.
| Phase | Global 10/Japan 10 | Average +/− S.D. (participants/month) | Median [quartile] (participants/month) | p Value t test |
|---|---|---|---|---|
| Phase 1 healthy volunteer | Global 10 | 11.95 ± 17.24 | 7.06 (3.73–13.25) | 0.0002 |
| Japan 10 | 15.05 ± 14.94 | 10.79 (4.99–22.75) | ||
| Phase 1 oncology | Global 10 | 1.77 ± 2.25 | 1.18 (0.70–2.07) | <.0001 |
| Japan 10 | 5.54 ± 7.92 | 2.11 (1.10–6.90) | ||
| Phase 2 | Global 10 | 13.09 ± 27.22 | 4.57 (1.65–12.14) | 0.3221 |
| Japan 10 | 11.43 ± 26.56 | 3.51 (1.52–10.72) | ||
| Phase 3 | Global 10 | 36.90 ± 73.93 | 16.36 (6.57–35.57) | <.0001 |
| Japan 10 | 12.38 ± 27.41 | 3.78 (1.32–11.82) | ||
| Phase 4 | Global 10 | 32.27 ± 85.89 | 9.20 (2.96–26.84) | 0.7821 |
| Japan 10 | 27.81 ± 158.04 | 5.53 (1.57–15.16) |
| Region | Phase | Global 10/Japan 10 | n | Average +/− S.D. (participants/month) | Median [quartile] (participants/month) | p Value t test |
|---|---|---|---|---|---|---|
| Japan | Phase 1 healthy volunteer | Global 10 | 91 | 10.88 ± 9.70 | 7.74 (4.49–14.48) | 0.0060 |
| Japan 10 | 99 | 16.03 ± 15.08 | 12.77 (5.08–23.23) | |||
| Phase 1 oncology | Global 10 | 88 | 1.05 ± 1.14 | 0.75 (0.52–1.15) | <.0001 | |
| Japan 10 | 41 | 7.84 ± 11.33 | 2.22 (1.10–10.69) | |||
| Phase 2 | Global 10 | 210 | 10.28 ± 16.89 | 4.18 (1.62–13.32) | 0.7593 | |
| Japan 10 | 110 | 10.90 ± 17.50 | 3.64 (1.77–11.84) | |||
| Phase 3 | Global 10 | 471 | 23.64 ± 35.75 | 13.50 (5.10–26.98) | <.0001 | |
| Japan 10 | 173 | 8.88 ± 20.26 | 3.41 (1.22–8.62) | |||
| Phase 4 | Global 10 | 56 | 15.18 ± 24.93 | 7.30 (3.26–12.77) | 0.0345 | |
| Japan 10 | 21 | 7.29 ± 7.01 | 4.51 (1.39–13.03) | |||
| United States | Phase 1 healthy volunteer | Global 10 | 1007 | 12.52 ± 19.28 | 7.20 (3.70–13.73) | 0.2260 |
| Japan 10 | 178 | 13.96 ± 13.52 | 9.60 (3.93–19.83) | |||
| Phase 1 oncology | Global 10 | 337 | 1.95 ± 2.29 | 1.36 (0.87–2.27) | <.0001 | |
| Japan 10 | 72 | 4.73 ± 5.98 | 1.83 (1.04–6.87) | |||
| Phase 2 | Global 10 | 1048 | 12.58 ± 26.59 | 4.62 (1.73–12.01) | 0.3326 | |
| Japan 10 | 156 | 10.53 ± 24.24 | 3.25 (1.48–10.12) | |||
| Phase 3 | Global 10 | 955 | 40.38 ± 80.89 | 18.60 (7.96–37.37) | <.0001 | |
| Japan 10 | 116 | 15.15 ± 31.08 | 3.03 (1.25–14.19) | |||
| Phase 4 | Global 10 | 214 | 43.34 ± 119.79 | 14.42 (3.65–46.98) | 0.5656 | |
| Japan 10 | 19 | 92.60 ± 365.31 | 5.92 (1.40–15.17) | |||
| Europe* | Phase 1 healthy volunteer | Global 10 | 403 | 7.19 ± 8.65 | 5.22 (2.50–9.00) | <.0001 |
| Japan 10 | 79 | 13.25 ± 10.68 | 10.00 (4.93–17.42) | |||
| Phase 1 oncology | Global 10 | 234 | 1.88 ± 2.21 | 1.38 (0.81–2.31) | 0.1665 | |
| Japan 10 | 17 | 2.66 ± 2.69 | 1.41 (0.98–3.11) | |||
| Phase 2 | Global 10 | 832 | 10.23 ± 23.82 | 3.86 (1.65–9.03) | 0.0298 | |
| Japan 10 | 82 | 7.12 ± 10.46 | 2.58 (1.01–6.82) | |||
| Phase 3 | Global 10 | 952 | 32.78 ± 57.56 | 16.39 (7.10–34.02) | 0.0001 | |
| Japan 10 | 85 | 16.01 ± 34.79 | 2.99 (1.03–13.95) | |||
| Phase 4 | Global 10 | 215 | 32.50 ± 56.17 | 10.28 (3.24–35.65) | 0.3059 | |
| Japan 10 | 19 | 18.96 ± 40.98 | 3.60 (1.22–15.13) | |||
| China | Phase 1 healthy volunteer | Global 10 | 63 | 17.03 ± 14.22 | 13.04 (6.77–22.98) | 0.6165 |
| Japan 10 | 10 | 14.64 ± 11.98 | 8.94 (4.46–28.18) | |||
| Phase 1 oncology | Global 10 | 24 | 2.77 ± 4.49 | 1.34 (0.90–1.95) | 0.5973 | |
| Japan 10 | 3 | 4.19 ± 1.95 | 3.43 (2.73–6.40) | |||
| Phase 2 | Global 10 | 71 | 8.44 ± 19.14 | 4.28 (2.15–7.49) | 0.0087 | |
| Japan 10 | 10 | 2.17 ± 1.59 | 2.26 (0.61–3.68) | |||
| Phase 3 | Global 10 | 314 | 35.17 ± 59.25 | 16.99 (8.76–33.27) | <.0001 | |
| Japan 10 | 34 | 5.67 ± 7.18 | 2.40 (0.83–8.12) | |||
| Phase 4 | Global 10 | 80 | 38.83 ± 63.95 | 14.94 (5.53–43.94) | 0.0404 | |
| Japan 10 | 15 | 17.95 ± 26.65 | 10.24 (3.53–15.95) | |||
| Other countries | Phase 1 healthy volunteer | Global 10 | 902 | 12.47 ± 20.28 | 6.63 (3.30–12.43) | 0.0971 |
| Japan 10 | 51 | 17.98 ± 22.82 | 10.59 (3.91–23.48) | |||
| Phase 1 oncology | Global 10 | 301 | 1.99 ± 2.27 | 1.34 (0.88–2.42) | 0.0339 | |
| Japan 10 | 32 | 3.61 ± 4.06 | 1.97 (1.28–4.77) | |||
| Phase 2 | Global 10 | 1184 | 13.71 ± 26.99 | 5.34 (2.12–13.06) | 0.3501 | |
| Japan 10 | 125 | 11.08 ± 30.20 | 3.28 (1.50–8.20) | |||
| Phase 3 | Global 10 | 1639 | 35.86 ± 66.93 | 16.93 (7.36–35.56) | <.0001 | |
| Japan 10 | 146 | 16.29 ± 33.57 | 4.07 (1.43–16.20) | |||
| Phase 4 | Global 10 | 400 | 36.18 ± 103.81 | 8.92 (2.86–29.42) | <.0001 | |
| 53 | 10.34 ± 22.34 | 3.77 (1.20–9.79) |
*: One or more countries with United Kingdom, Germany, France, Italy, Spain, Switzerland.
The problem of drug lag, in which drugs approved overseas in Japan were not approved in Japan, has often become a social problem since the beginning of the 21st century. A solution to the drug lag at that time was the globalization of the clinical trial environment.15–17) In 2007, a notification of “Concerning the Basic Concept on Global Clinical Trials” was issued, and the participation of Japan in global MRCT conducted in the United States and EU has led to the simultaneous development of the world, including Japan. Subsequently, the “General Principles for the Plan and Design of Global Clinical Trials (ICH E17)” was issued, and it is obvious that Japan participates in MRCT in the US and EU from the initial clinical development from early phase of clinical development. On the other hand, the required clinical trial performance level for MRCT has been raised due to the increase in the drug market in China and other emerging countries and the improvement of the clinical trial environment,18,19) and contrary to the decline of the Japanese drug market.9)
In this context, research on clinical trial performance in Japan is important, but most studies are conducted within pharmaceutical industry organizations and regulatory agencies. Few studies have been published in English, and there have been few academic studies.20,21) Specific research into the quality, cost, and speed of clinical trial performance has been conducted by the R&D Head Club for many years through a benchmark survey on the cost of clinical trials in Japan, and data have been accumulated.20) The Japan Pharmaceutical Manufacturers Association (JPMA) also calculates the performance and quality of clinical trials in Japan and the proportion of global MRCT in application data.21) On the other hand, few studies have conducted international comparisons on the performance of trial speed. This study focuses on the speed of participant enrollment and provides an international comparison.
From the results of the participant enrollment speed of our study, the possibility of differing by the phase in both Japanese and global companies was indicated. That is to say, the results showed that Japanese companies had faster phase 1 trials, while Japanese companies had slower Phase 3 trials than global companies. In this study, we also compared the speed by region, and we found similar results that Japan 10 was faster in phase 1 trials and Global 10 was faster in phase 3 trials in several regions. These results were comparison of Japan 10 and Global 10. It is not necessarily the case that phase 1 trials conducted in Japan were earlier than phase 1 trials conducted overseas. In the phase 1 study, the Japanese company was found to be faster in both healthy people and cancer patients. To our knowledge, this is the first finding. Phase 1 trials are often conducted with healthy volunteers, and recruitment is typically conducted from a healthy adult panel. Therefore, enrollment speeds may not represent trial performance significantly. We also compared the background, characteristics, and number of clinical trials for Global 10 and Japan 10 as a secondary objective.
It is assumed that the Japanese drug market will shrink in the future, and it may be left behind from the clinical development in the world. In this context, in order for clinical development in Japan to remain, it is necessary to demonstrate clinical trial performance equal to or higher than that in other countries. Or, it seems to have the discrimination point from other countries, and it seems to be necessary to make the characteristic. The results obtained in this study suggest that the speed of participant enrollment in the phase 1 study conducted by Japanese pharmaceutical companies is fast, suggesting one direction for the presence of Japanese pharmaceutical companies in early clinical development from the perspective of pharmaceutical company performance.
This study has the following study limitations:
・The two categories were classified according to the rank based on 2019 sales as representative values of global and Japanese companies, but they may not be considered representative values because other indicators are also considered (e.g., R&D expenses, number of clinical trials).
・Due to the properties of ClinicalTrials.gov, quality assurance of the data may vary among the inputs and needs to be captured as a consequence of using Clinical Trials.gov. Information on the number of sites for each clinical study is not available from Clinical Trials.gov and information on the number of patients/sites/month is not available. Instead, speed was expressed by number of patients/month (/trial) in this study. Also, these data do not represent the performance of the trial in all respects.
・We used ClinicalTrials.gov, the largest database of clinical trials, for international comparisons. There are other databases for clinical trials in Japan, and the results may differ if they are used.
・Though the participant enrollment speed was examined according to the phase, the result which is different from this time may be different by comparing and examining on the basis of other clinical trial background.
・This study investigated differences in speed between Global 10 and Japan 10 and in speed by phases, and stratified analysis by location, study design, blinding, etc. have not been performed.
This study compared the speed of enrollment for clinical trials between the top 10 companies in global sales (Global 10) and the top 10 companies in Japanese sales (Japan 10) in ClinicalTrials.gov during a 10-year period from January 2010 to December 2019. In the comparative analysis of participant enrollment speed by phase, Japan 10 was fast regardless of the type of phase 1, and Global 10 was fast for phase 3. The results of this study suggest that the speed of participant enrollment in the phase 1 study conducted by Japanese pharmaceutical companies is fast, suggesting one direction for the presence of Japanese pharmaceutical companies in early clinical development from the perspective of pharmaceutical company performance.
HM and MY were responsible for the conception and design of the study and MY, YF, and YI were accountable for the analysis of data. All authors drafted the initial manuscript. All authors reviewed and approved the final manuscript.
The authors declare no conflict of interest.
The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request.
