Purpose: Levodopa plasma concentrations are variable, and drug‒drug interactions affect the pharmacokinetics of levodopa. However, examination of the diurnal variation in levodopa plasma concentrations of patients with Parkinson's disease (PD) is insufficient. The effects of antacids on the pharmacokinetics of levodopa remain unclear. Thus, we examined the diurnal variation in the pharmacokinetics of levodopa in patients with PD to clarify the types of variability. The effects of antacids (magnesium oxide) on the pharmacokinetics of levodopa were also investigated.

Methods: We retrospectively investigated the data of patients with PD who had taken levodopa/carbidopa（100/10 mg) tablets three times a day after meals and for whom data on levodopa concentrations every 2 h from the morning to the evening were available.

Results: Altogether, 102 patients with PD were included in this study. The mean maximum levodopa concentrations (Cmax) was 7.42μM. An 8.2-fold difference in Cmax was observed among the patients. Approximately 64.7％ of the patients demonstrated seven different patterns of the “delayed absorption” in the diurnal fluctuation of levodopa concentrations. Approximately 46.1％ of the participants demonstrated “delayed absorption” in the morning. This proportion was higher than those in the afternoon（27.5％）and evening（30.4％）. The median of the area under the curve of plasma levodopa concentrations in the neither antacids nor gastric acid secretion inhibitors (GASIs) group, antacids-only group, and antacids plus GASIs group was 45.93μM・h, 47.72 μM・h h, and 39.29μM・h, respectively. No significant differences were observed among the three groups.

Conclusions: The “delayed absorption ” in the morning was observed in approximately half of the patients with PD. Antacids had no effect on the pharmacokinetics of levodopa.

Background/Aims: Many physician-initiated clinical trials not for approval have been conducted in Japan, but vulnerable quality management was unmasked with the finding of misconduct in trials. While monitoring has become mandatory with the implementation of the Clinical Research Act of Japan, the errors occurring in such trials were not fully recognized. The aim of the present study was to clarify errors through early, risk-adapted, on-site monitoring of physician-initiated clinical trials involving patients with cardiovascular diseases.

Methods: Early, risk-adapted, on-site monitoring was undertaken at 15 hospitals where 3 multicenter, randomized, controlled trials that enrolled 884 patients were conducted. The selection of facilities was based on the results of early central monitoring. Monitoring items were selected according to the risk assessment of each trial. The errors detected including their effects on the quality of trials were described.

Results: Of the 176 cases monitored, 71 procedural and 13 recording errors, including 32 in the process of informed consent, 17 in the selection of patients, 17 in randomization, 6 in the trial intervention, 3 in the outcome measures, and 2 in reporting serious adverse events (SAEs), were identified. Nine of the procedural errors regarding informed consent, selection of patients, and randomization were considered serious, whereas all recording errors were not serious. The steering committee revised the study protocol and the standard operation procedure of one study to prevent these errors.

Conclusion: This risk-adapted, early monitoring triggered by central monitoring showed that a number of errors occurred in physician-initiated clinical trials, particularly, during patient enrolment, and such early monitoring might help investigators detect and address serious errors to improve the quality of ongoing clinical trials before they become uncorrectable.

Clinical trials have become increasingly electronic and digitalized, and electronic informed consent has begun to gain importance. In order to picture the current situation of eConsent in Japanese medical institutions, we asked research assistants, including CRCs, to answer a questionnaire survey. Responses were obtained from 1403 persons. The experience with eConsent was low; 128（9.1％）had used in informing process and 71（5.1％）in consent process. Of those with eConsent experience, 94（73.4％）had experience in in-person only study and 13（10.9％）in remote only study. In cases where eConsent was considered but abandoned, respondents reported that medical institution did not have sufficient SOP, tablet devices, and/or internet network. Many also expressed concern about the ability of elderly patients to use electronic methods. The importance of eConsent is expected to increase, as clinical trials are anticipated to become diverse, including those requiring remote access, non-contact manner, or virtual conduction. Accordingly, we should consider an appropriate eConsent that is beneficial to all the stakeholders ‒ the sponsor, medical institution, and the subject ‒ and it should become a natural option in the future, in situations where eConsent is necessary.

Based on the position that human specimens should not be subject to trading from an ethical standpoint, we examined the legal issue of “paid-for sharing” in which research biobanks provide human specimens to companies for money. According to the 1998 report of the Health Sciences Council, “the cost” of collecting, transporting, examining, and providing surgically removed tissue in appropriate conditions should be borne by the user. The history of the Wholesale Market Act reveals the problems of fee merchanting and resale due to bankruptcy, and the actual situation of NPOs that are outsourced to provide services raises the issue of the composition of “actual costs” and operating costs. To solve these issues, we examined the legal relationships between participants and biobanks and between biobanks and other institutions. The assumption of a transfer agreement between the participant/biobank and the biobank/company makes it difficult to impose legal restrictions on the resale of samples. In the case of a delegation contract between the participant and the biobank, the delegation contract terminates upon the death of the parties （Article 653 of the Civil Code）；similarly, in the case of a purpose trust between the participant and the biobank, the duration is limited to 20 years （Article 259 of the Trust Law）. We propose the application of the “Act on Charitable Trusts （to be revised）” in biobanks as a trust without beneficiaries in order to solve such problems including those between biobanks/companies. The Act on Charitable Trusts stipulates that trust assets are not limited to money and can last indefinitely, which is in line with the scheme of the biobank. Due to the cost of operation, we decide that national biobanks, in particular, should become independent trustees as a type of incorporated association.

In clinical trials, the need for an audit should be determined using a risk-based approach as part of a quality assurance process. However, it is difficult to define clear evaluation criteria because various risks are associated with investigator-initiated clinical trials. For example, while several Japanese standards for the conduct of clinical trials suggest that an audit should be performed “as needed,” the exact meaning of “needed” is unclear. Therefore, this study aimed to define indications that can be used by a principal investigator to determine the need for an audit.

We first examined prerequisites to simplify our risk evaluation. They were, 1）it is to be performed for individual clinical trials, rather than to act as a systems audit to examine facilities or functionalities, and 2）it is to be performed for clinical trials that satisfy quality control measures above a certain level. Based on these prerequisites, we then examined the risk factors that are generally considered in investigator-initiated clinical trials. The results revealed that the need for an audit increases when the outcomes of the trial can be biased by conflicts of interest, and when the study intervention is highly invasive, posing a safety concern to the participants. Other situations, such as the study design and quality management level, affect the need for an audit to a lesser extent. It should be noted that the need for an audit shall be appropriately determined for each actual particular trial with reference to these ideas.

Current clinical research is planned and pursued in accordance with the following three laws: “ GCP Ordinance,” “Clinical Trials Act,” and “Ethical Guidelines for Medical and Health Research Involving Human Subjects.” Recently, there has been an increase in studies that classify and explain laws related to clinical research.

In the domain of law information in natural language processing, calculating similarity and visualizing relationships between multiple laws is useful for managing legal costs and promoting comprehension. Similarly, it is expected that enough comprehension by simplifying and visualizing relation of laws related clinical research.

The aim of this study is to visualize the similarities between ministerial ordinances, laws, and guidelines related to clinical research. In this paper, based on the hypothesis that “the higher the degree of matching of a word, the higher the similarity between articles containing those words,” we proposed a method for measuring the relationships among possible combinations of law “articles” using “word matching,” i.e., the number of common words.

The results of performance evaluation indicated that word matching could identify the combinations of the articles with “consistence/high similar” for some items. Furthermore, high-degree word matching was observed with less meaning as a clinical research related legal word, the combinations of the articles with the “low similar/inconsistence” were acquired.

Neurocognitive complications such as leukoencephalopathy after high-dose intravenous methotrexate therapy （HD‒MTX） are important for childhood cancer survivors, because these neurocognitive complications affect the quality of life of patients. We identified Protein A in cerebrospinal fluid （CSF） as an MTX-related neurotoxicity-associated protein by proteomics analysis. In a series of CSF samples obtained during MTX-containing chemotherapy of 17 pediatric patients with hematological malignancy, Protein A was elevated at onset and just before onset of neurocognitive complications associated with HD‒MTX or intrathecal MTX therapy in the patients. The concentration of MTX in CSF was higher in the 5 g/m² HD‒MTX group than the 2 g/m² HD‒MTX group. We will evaluate the significance of Protein A in CSF as a biomarker for leukoencephalopathy in a larger cohort. We will also study the association between Protein A and MTX in CSF and leukoencephalopathy by pharmacogenetic approach.