Abstract
Objective
large-scale multicentre clinical trials conducted by cooperative groups have generated a lot of evidence to establish better standard treatments. The Clinical Trials Act was enforced on 1 April 2018, in Japan, and it has remarkably increased the operational burden on investigators, but its long-term impact on cancer cooperative groups is unknown.
Methods
a survey was conducted across the nine major cooperative groups that constitute the Japan Cancer Trials Network to assess the impact of Clinical Trials Act on the number of newly initiated trials from fiscal year (from 1 April to 31 March) 2017 to 2022 and that of ongoing trials on 1 April in each year from 2018 to 2023.
Results
the number of newly initiated trials dropped from 38 trials in fiscal year 2017 to 26 trials in fiscal year 2018, surged to 50 trials in fiscal year 2019, but then gradually decreased to 25 trials by fiscal year 2022. Specified clinical trials decreased from 32 trials in fiscal year 2019 to 12 trials in fiscal year 2022. The number of ongoing trials was 220 trials in 2018, peaked at 245 trials in 2020, but then gradually decreased to 219 trials by 2023. The number of specified clinical trials has been in consistent decline. By April 2023, of the 20 ongoing non-specified clinical trials, nine adhered to Clinical Trials Act and 11 followed the Ethical Guidelines for Medical and Health Research Involving Human Subjects.
Conclusion
the number of multicentre clinical trials in oncology gradually decreased after the Clinical Trials Act’s enforcement, which underscores the need for comprehensive amendment of the Clinical Trials Act to streamline the operational process.
Keywords: Clinical Trials Act, cancer cooperative group, good clinical practice, clinical trial registry, international clinical trial
The number of clinical trials in Japanese cancer cooperative groups gradually decreased after the enforcement of the Clinical Trials Act, which underscores the need for comprehensive amendment of the Act.
Introduction
In April 2018, the Clinical Trials Act (CTA) was enacted in Japan. Before that, there had been two major regulations on clinical research: Pharmaceuticals and Medical Devices Act (PMD Act) for registration-directed trials and the Ethical Guidelines for Medical and Health Research Involving Human Subjects (Ethical Guidelines, hereafter) for non-registrational clinical studies. CTA has become the third major regulation specifically on academic interventional clinical studies for medical products or medical devices (1). Since CTA was established in response to several scientific misconduct such as the Valsartan case (2,3), more strict procedures were imposed for clinical trials under CTA. For example, it was mandated to receive a single ethics review by a certified review board (CRB), perform rigorous conflict of interest (COI) management, submit a so-called ‘trial plan’ to the Ministry of Health, Labour and Welfare (MHLW) and enrol the information to a new clinical trial registry, the Japan Registry of Clinical Trials (jRCT) (4). These enhanced procedures have augmented both the administrative and financial burdens on clinical investigators. Thus, there were concerns that it would lead to a reduction in the number of academic clinical trials (5).
After the implementation of CTA on 1 April 2018, clinical trials that were conducted under the Ethical Guidelines had a transition period of 1 year (up to the end of March 2019) to be categorized either as a specified clinical trial, a non-specified clinical trial or continue under the Ethical Guidelines. For those transitioning to specified or non-specified clinical trials in compliance with CTA, they had to undergo several procedural changes such as undergoing a single review by a CRB, submitting a Trial Plan to MHLW and registering in the new jRCT system. Given these new requirements, a decline in the number of both newly initiated and ongoing trials was anticipated in the year following the CTA’s implementation. In fact, existing reports showed the decline of interventional clinical studies immediately after the enactment of CTA (6–8). However, the analysis was conducted based on the data up until September 2020, and the long-term impact of the CTA on the number of clinical trials remained uncertain.
In addition, there have been few studies investigating the number of clinical trials after the implementation of CTA specifically focusing on the oncology field, where academic cooperative groups play an important role in establishing better standard treatment. The Japanese Clinical Trials Network (JCTN) is a consortium of nine Japanese cancer cooperative groups for standardizing clinical trial operations, sharing the latest information on the clinical trial environment and making a policy proposal. JCTN has issued three common guidelines to standardized operational procedures in academic clinical trials conducted in Japan: central monitoring, site visit audit and adverse events reporting (9). JCTN has also conducted several surveys to elucidate difficulties in clinical trial regulations and operations, and published proposals to MHLW for drastic amendment of CTA (10) and jRCT system (10).
CTA is to be reviewed for necessary amendments five years after its implementation. MHLW has already indicated some plans for potential amendments (11), but actual amendments have yet to be realized and investigators still suffer from a huge operational burden at least as of October 2023. This paper undertakes a survey of the annual number of interventional clinical studies within the JCTN both before and after the introduction of CTA and assesses its long-term effect in the cancer field.
Patients and methods
Survey design and data collection
A structured questionnaire was distributed to the nine cancer cooperative groups that constitute JCTN. The surveys were conducted annually via email from fiscal year (FY)2017 to FY2022, with responses collected from all groups each time. A sample of the questionnaire is shown in Supplementary Fig. 1. Additional surveys on observational studies were conducted in January 2024. These groups are representative cooperative groups in Japan, each equipped with a central headquarters to conduct multiple multi-institutional clinical trials in the oncology area. Their primary objectives are the establishment of standard treatments and the development of novel therapeutic approaches. The nine groups constituting JCTN are listed in Table 1.
Table 1.
Nine cancer cooperative groups in JCTN
| JALSG: Japan Adult Leukemia Study Group |
| JCOG: Japan Clinical Oncology Group |
| JGOG: Japanese Gynecologic Oncology Group |
| JCCG: Japan Children’s Cancer Group |
| HGCSG: Hokkaido Gastrointestinal Cancer Study Group |
| KSCC: Kyushu Study Group of Clinical Cancer |
| LOGIK: Lung Oncology Group in Kyushu |
| TORG: Thoracic Oncology Research Group |
| WJOG: West Japan Oncology Group |
The primary aim of this survey was to collect detailed information on the number and types of interventional clinical studies conducted by these groups before and after the enactment of the CTA.
First, the number of newly Initiated trials was examined in each FY (from 1 April to 31 March), starting from the FY2017 and extending up to the FY2022. The number of newly initiated trials in each FY is counted as follows: for investigator-initiated registration-directed trials (IIRDT), the submission date of the clinical trial notification to the regulatory authority is within the FY; for clinical trials under CTA, the date of first release of jRCT is within the FY; for trials under the Ethical Guidelines, the date of patient accrual start is within the FY.
Second, the number of ongoing trials on 1 April in each year was examined, starting from 1 April 2018, up to 1 April 2023. Here, ‘ongoing’ refers to trials that are either in the patient registration phase or in the follow-up phase, extending up to the date of the final analysis.
Third, the number of newly initiated observational studies in each year was examined. The proportion of translational research amongst the observational studies was also investigated, where translational research was defined as those involving the analysis of biological samples.
Fourth, for specified clinical trials, trends by reasons for classification as specified clinical trials were shown for both newly initiated and ongoing trials. The reasons for being classified as specified clinical trials were categorized into three: (i) the use of unapproved or off-label products, (ii) funding received from pharmaceutical industries and (iii) both of the above.
Classification of trial types
Clinical trials were categorized into four types based on their nature and regulatory requirements:
IIRDT under the PMD Act.
Specified clinical trial obliged to comply with CTA.
Non-specified clinical trial required to make effort to follow CTA.
Clinical trial conducted under the Ethical Guidelines.
Whilst detailed classification criteria have been provided in a separate paper (4), a brief overview is as follows: trials aiming to establish clinical data for new pharmaceutical applications or expanding indications are classified as IIRDT and governed by the PMD Act. Clinical trials with the objective to elucidate the efficacy or safety of pharmaceuticals, medical devices or regenerative products in humans fall under the CTA. If such trials utilize unapproved/off-label products or receive research funding by a manufacturer with marketing approval for pharmaceuticals, the clinical trial is called a specified clinical trial and investigators must comply with CTA. Conversely, if they do not meet these conditions, they are termed non-specified clinical trials. Investigators for these trials are encouraged to comply with the CTA, but because of the CTA’s soft application, some are conducted under the Ethical Guidelines. Lastly, clinical trials not aiming to clarify the efficacy or safety of products, such as surgical or simple radiotherapy trials, are conducted under the Ethical Guidelines.
Statistical analysis
Data were analyzed using descriptive statistics. Trends in the number of newly initiated and ongoing trials were plotted over the years to visualize the impact of CTA on interventional clinical studies.
Results
Trends in newly initiated trials
Figure 1 illustrates the trend in the number of newly initiated trials. The number of new trials decreased from 38 trials in 2017 to 26 trials in 2018. There was a significant drop in the number of trials initiated in 2018. Although the number of new trials rebounded to 50 trials in 2019, but the number gradually declined to 25 trials by 2022, which was even lower than that in 2017. Notably, the number of specified clinical trials decreased from 32 trials in FY2019 to 12 trials in FY2022. The number of new trials in each group is shown in Supplementary Fig. 2. Although the number of trials was small, no particular trend was observed in the changes in the number of new trials across any of the groups.
Figure 1.
The number of newly initiated trials in each fiscal year (FY).
Trends in ongoing trials
Figure 2 depicts the trend in the number of ongoing trials. The number of ongoing trials was 220 trials in 2018, and there was a slight decrease in 2019, after the enactment of CTA. The number recovered to 245 trials in 2020 but then reduced to 219 trials in 2023, which reached levels comparable to those before the CTA’s enactment. Whilst the number of IIRDT has gradually increased, the number of specified clinical trials has been steadily decreasing. Non-specified clinical trials, whilst not as numerous as specified clinical trials, have also shown a decline. As of April 2023, out of the 20 ongoing non-specified clinical trials, nine were conducted in accordance with CTA, whereas 11 were conducted under the Ethical Guidelines. The number of ongoing trials in each group is shown in Supplementary Fig. 3. It appeared that the number of ongoing trials was increasing in JGOG and KSCC, whereas in other groups, it was either stable or decreasing.
Figure 2.
The number of ongoing trials on 1 April in each FY.
Trends in observational studies
Figure 3 shows the trend in newly initiated observational studies and the proportion of translational research within them. Observational studies are generally on an increasing trend, and the proportion of translational research has been around 30–40% in recent years.
Figure 3.
The number of newly initiated observational studies and the proportion of translational research in each FY.
Reasons of specified clinical trials
Figure 4 illustrates the trend in the number of newly initiated and ongoing trials classified as specified clinical trials by the reason for their classification. When looking at the trend of ongoing specified clinical trials, the proportion of trials classified as specified clinical trials because of the use of unapproved or off-label products is the highest, although this proportion is slightly declining. On the other hand, there is a gradually increasing trend in the proportion of trials classified as specified clinical trials for both reasons: the use of unapproved or off-label products and receiving funding from pharmaceutical industries.
Figure 4.
The trend in the number of specified clinical trials by the reasons being classified.
Discussion
After the implementation of CTA, there has been a gradual decline in both the number of newly initiated and ongoing trials in the oncology multicentre clinical trials. There was a significant drop in the number of trials initiated in 2018, possibly because the transition to CTA is required for ongoing clinical trials at that time. Clinical trials planned during this transition period began in FY2019 and FY2020, leading to a recovery in the number of new trials. However, the number of both newly initiated and ongoing trials has decreased in FY2021 and FY2022 possibly because of the complexity of CTA procedures, the preference for observational studies, difficulties in securing research funding especially for specified clinical trials and a decline in interest amongst young physicians towards clinical trials. Given the pivotal role that multicentre clinical trials play in establishing standard treatments in oncology, a continued decline in the number of new trials could potentially lead to a critical situation in the advancement of cancer treatments.
The primary reason for this decline can be attributed to the intricate procedures introduced by CTA (12). In response to these challenges, MHLW took some countermeasures such as the digitization of submissions for trial plans and the reduction of items listed in jRCT (10). However, there remains a substantial burden for investigators (13). For example, even when non-essential changes to a trial plan become necessary (e.g. changes in the hospital director of participating sites), they must be reported to the CRB and the trial plan must be re-submitted to MHLW. In addition, some system malfunctions occurred in jRCT when the system was modified to reduce the items, leading to even more workload on investigators (10). Moreover, the intricate procedures for COI declarations remain unaddressed, although the nationwide COI management database is being developed. The decline in the number of new trials, as revealed in this survey, suggests that investigators might escape from specified clinical trials because of the complexity of procedures, unclear regulations (e.g. the ambiguity in the definition of trials falling under the scope of CTA) and the cost for specified clinical trials, emphasizing the need for comprehensive amendment of CTA to streamline the operational process.
Another significant challenge is the lack of international alignment. Whilst the CTA has incorporated many elements of ICH-GCP, it lacks the concepts of ‘sponsor’ and ‘investigator’ as defined by ICH-GCP. In the current CTA, every physician or dentist in the participating institutions bears the responsibilities of both the sponsor and investigator. This complicates the contract with foreign sponsors and furthermore makes it difficult to keep consistency in monitoring and the judgement of causality in adverse event reporting across institutions. Although the introduction of the sponsor concept is being considered in the upcoming amendment to CTA, the unique structure of multiple regulations including the PMD Act, CTA and the Ethical Guidelines, along with the peculiar categorization of specified clinical trial and non-specified trial, remains perplexing to international counterparts. This poses challenges for international collaborative trials. In the long run, considering international harmonization, it would be prudent to establish basic rules covering all clinical research, with pharmaceutical intervention studies adhering to ICH-GCP, whereas separate regulations are set for medical device intervention studies.
Beyond the administrative burdens induced by CTA, several other factors may have contributed to the decline in clinical trials in Japan. Notably, the COVID-19 pandemic has played a role in reshaping the landscape of clinical trials. The pandemic’s economic instability has strained hospital finances, compelling clinicians to prioritize immediate patient care over research endeavours. In addition, because of restrictions on attending academic conferences and the necessary shift towards virtual platforms, there has been a notable decrease in young investigators’ interest in clinical trials. This reduction in enthusiasm is concerning, as these individuals are essential for the future of clinical trials. Despite these challenges, our survey indicated that the overall number of clinical trials was not significantly impacted by COVID-19, suggesting that factors such as the introduction of CTA and its associated costs and procedural complexities have had a more pronounced effect. To revitalize the clinical trial activities in Japan, it is indispensable not only to streamline the operational process through the amendment of CTA but also to nurture young investigators who have a keen interest in clinical trials and enough skills to negotiate directly with global industries.
Contrary to the downward trend in interventional studies, there has been a notable increase in the number of observational studies. This shift can be attributed to several key factors. First, the procedural complexities of CTA and difficulties in obtaining funding have pushed investigators towards choosing observational studies. Advances in genomic medicine have also contributed to a greater interest in observational translational research. Furthermore, the pharmaceutical industry’s aim to reduce costs whilst seeking market insights or promotional benefits may lead to a preference for funding observational studies. In light of these factors, there has been an increase in studies that are being designed as observational, although they should ideally have been planned as interventional clinical trials. It underscores the need for a balanced approach to study design, ensuring that the choice between observational and interventional studies is driven by scientific objectives rather than procedural or financial constraints.
One limitation of this study is that, whilst it includes most of Japan’s major cancer clinical trial groups, it does not cover all of them. Because of Japan’s lack of a national system to manage and support clinical trial groups, comprehensively tracking all groups poses a challenge. Clinical trial groups such as North East Japan Study Group, Gynecologic Oncology Trial and Investigation Consortium and Japan Clinical Cancer Research Organization were not included in our survey. However, according to their websites as of February 2024, the number of new trials initiated from FY2018 to FY2022 was 10, 8 and 3, respectively. Including these groups in our analysis is not believed to alter the conclusions of this study essentially.
Conclusion
The number of multicentre clinical trials in oncology gradually decreased after the CTA’s enforcement, which underscores the need for comprehensive amendment of the CTA to streamline the operational process. Whilst MHLW has tried to simplify some procedures, it is crucial to focus on more substantial amendments to essentially alleviate the burdens on investigators. Additionally, aligning with international standards will not only streamline processes but also foster international collaboration, which is crucial for advancing global oncology research.
Abbreviations
COI: conflict of interest; CRB: certified review board; CTA: Clinical Trials Act; IIRDT: investigator-initiated registration-directed trial; JCTN: Japanese Cancer Trials Network; jRCT: Japan Registry of Clinical Trials; MHLW: Ministry of Health, Labour and Welfare; PMD Act: Pharmaceuticals and Medical Devices Act
Supplementary Material
Acknowledgements
We thank the members of the JCOG Operations Office for their administrative support.
Contributor Information
Kenichi Nakamura, Japan Clinical Oncology Group, Clinical Research Support Office, National Cancer Center Hospital, Tokyo, Japan.
Koji Takeda, West Japan Oncology Group, Department of Sectretariat, Osaka, Japan.
Akiko M Saito, Clinical Research Center, Japan Children’s Cancer Group, NHO Nagoya Medical Center, Nagoya, Japan.
Miho Kato, Japan Children’s Cancer Group, Department of Childhood Cancer Data Management, National Center for Child Health and Development, Tokyo, Japan.
Shinya Sato, Japan Adult Leukemia Study Group, Department of Hematology, Nagasaki University, Nagasaki, Japan.
Satoshi Nakagawa, Japanese Gynecologic Oncology Group, Department of Study Management, Translational Research Center for Medical Innovation, Kobe, Japan.
Yasuyuki Kawamoto, Hokkaido Gastrointestinal Cancer Study Group, Division of Cancer Center, Hokkaido University, Sapporo, Japan.
Eiji Oki, Kyushu Study Group of Clinical Cancer, Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Isamu Okamoto, Lung Oncology Group in Kyushu, Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Hiroaki Okamoto, Thoracic Oncology Research Group, Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen’s Hospital, Yokohama, Japan.
Hiroshi Katayama, Japan Clinical Oncology Group, Clinical Research Support Office, National Cancer Center Hospital, Tokyo, Japan.
Junki Mizusawa, Japan Clinical Oncology Group, Clinical Research Support Office, National Cancer Center Hospital, Tokyo, Japan.
Harumi Kaba, Japan Clinical Oncology Group, Clinical Research Support Office, National Cancer Center Hospital, Tokyo, Japan.
Taro Shibata, Japan Clinical Oncology Group, Clinical Research Support Office, National Cancer Center Hospital, Tokyo, Japan.
Haruhiko Fukuda, Japan Clinical Oncology Group, Clinical Research Support Office, National Cancer Center Hospital, Tokyo, Japan.
Conflict of interest statement
None declared.
Funding
This work was conducted under a National Cancer Center Research and Development Fund (2023-A-13).
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