Characteristics of Asian Participation in Multi-regional Clinical Trials Reviewed for Drug Approval in Japan: Opportunities for Collaboration Between South-East Asia, East Asia, and Japan.

Although the percentage of multi-regional clinical trials (MRCTs) submitted for drug approval in Japan increased significantly since the 2007 publication of the regulatory guideline, "Basic principles on global clinical trials", strategic collaborations between Asian countries will be important to promote MRCTs in accordance with the ICH E17 guideline published in 2017. In this study, characteristics of MRCTs reviewed for drug approval in Japan, especially those with participation by South-East Asia and East Asia, were investigated to explore opportunities for collaborations on global drug development in Asia. More than 90% of reviewed trials were conducted as global MRCTs. In addition to Japan, South-East Asia has participated in various types of MRCTs in terms of total numbers of subjects and countries. However, South-East Asia participation was lower in large-size MRCTs (total sample size ≥ 1000) than in middle- (500 ≤ total sample size < 1000) and small-size MRCTs (total sample size < 500). Furthermore, similar clinical trials for the same indications to the MRCTs without South-East Asia were rarely conducted separately in South-East Asia. Participation of other Asian countries did not affect the percentage of Japanese subjects enrolled in an MRCT, but did significantly increase the percentage of participating Asian subjects. These results suggest that additional opportunities for collaboration on MRCTs may be possible between Japan and other Asian countries, especially more collaborations with South-East Asia in the large-size MRCTs. More data of Asian populations from MRCTs will be useful for exploring an important ethnic factor affecting drug response, and will provide a sound scientific basis in considering the application of the pooled data concept in Asia, as described in the ICH E17 guideline.

Points to Consider for Implementation of the ICH E17 Guideline: Learning from Past Multiregional Clinical Trials in Japan.

We identified the major points that are described in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guideline but have not been considered in the past multiregional clinical trials (MRCTs) used for drug approval in Japan to elucidate potential challenges in the implementation of the ICH E17 guideline in Japan. Based on the analysis of 167 MRCTs of 130 drugs, several points, such as the same dose setting and consistency between the overall and Japanese populations, in addition to good clinical practice compliance, have been well considered in ≥ 75% of MRCTs. In contrast, the use of relevant guidelines for disease and primary end point definitions, standardization of efficacy/safety information, sample size allocation, as well as training/validation on subject selection and primary end point, have been addressed less adequately and may need to be considered when planning future MRCTs. This study provides useful information for the implementation of the ICH E17 guideline in Japan.

Clinical study designs and patient selection methods based on genomic biomarkers: Points-to-consider documents.

Recently, genomic biomarkers have been widely used clinically for prediction of the efficacy and safety of pharmacotherapy and diagnosis and prognosis of pathological conditions. Therefore, genomic biomarkers are anticipated to accelerate not only precision medicine for pharmacotherapy but also development of molecularly targeted drugs. Because the design of clinical studies involving biomarkers may differ from conventional clinical study designs, a concept paper focused on clinical studies and patient selection methods based on genomic biomarkers is desired to prompt innovative drug development. Thus, this concept paper aimed to compile and present current scientific information from the related guidelines regarding application of genomic biomarkers to clinical trials and studies for drug development. We hope that this concept paper will prompt the development of guidelines for biomarker application to drug development by industry, regulatory authorities, the medical profession, and academia.

Factors Affecting Drug-Development Strategies in Asian Global Clinical Trials for Drug Approval in Japan.

We assessed the current status of Asian global clinical trials (GCTs) and factors, such as therapeutic areas, main metabolic enzymes targeted, approval status in the United States or the European Union, development strategies, influencing drug-development strategies in Asian GCTs and in general GCTs for drug approval in Japan. The findings suggested that region-specific diseases in Asia, intrinsic and extrinsic ethnic differences between Japanese/Asian and Caucasian populations, and the status of the drugs' development in the United States or the European Union all affected Asian GCTs. These factors may influence the drug development process in Asian GCTs. Furthermore, we found that pharmacokinetics data in Asian GCTs comparing similarities between Japanese and other Asian populations were mainly obtained from late-phase trials, which may delay the identification of potential differences in ethnic factors.

Use of a toxicity factor to explain differences in nephrotoxicity and myelosuppression among the platinum antitumour derivatives cisplatin, carboplatin and nedaplatin in rats.

The platinum antitumour drugs cisplatin, carboplatin and nedaplatin differ in their toxicity. The relationships between the pharmacokinetics of these drugs and developed parameters for predicting their nephrotoxicity and myelosuppression were investigated. The drugs were administered to male Wistar rats by intravenous bolus or infusion, and linearity of pharmacokinetics, total clearance and the apparent ratio of tissue concentrations of unchanged drug to plasma concentration (Kp app) at steady state were determined. Apparent hydrolysis rates of each drug were determined in-vitro. Nephrotoxicity and myelosuppression were estimated by blood urea nitrogen (BUN) and platelet count, respectively. Tissue exposure to platinum was estimated as the product of the area under the plasma concentration-time curve for unchanged drug (AUC p), Kp app and the apparent hydrolysis rate constant (k hydrolysis), and toxicity factor was defined as the product of Kp app x k hydrolysis as an intrinsic drug parameter. The relationship between AUC p x toxicity factor and BUN fitted well to an Emax model. In bone marrow, this function was also correlated with platelet count. In summary, the product of AUC p x toxicity factor is a factor determining the pharmacokinetics of platinum drug-induced nephrotoxicity and myelosuppression in rats, and this toxicity factor may be a useful parameter for predicting the degree of toxicity of platinum antitumour compounds.