Multiregional Clinical Trials Research Articles

Comparison of efficacy outcomes of anticancer drugs between Japanese patients and the overall population.

It is important to recognize regional and racial differences in drug efficacy and safety when performing multi-regional clinical trials (MRCTs). To understand regional differences, we compared the efficacy results in Japanese patients and the overall population in the MRCTs of anticancer drugs. All new approvals of oncology drugs in Japan from January 2009 to December 2018 were searched using the Pharmaceuticals and Medical Devices Agency web site to find phase 3 MRCTs for the analysis. As the supporting data source, a literature search was performed in PubMed and Google Scholar. Linear regression analysis was performed and Pearson correlation coefficients (r) were calculated to compare the overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) between Japanese patients and the overall population. Seventy MRCTs were identified. The correlation of hazard ratios (HRs) for OS between Japanese patients and the overall population was moderate (r = 0.45), and OS was 1.31 times longer in Japanese patients than in the overall population, although the correlation of median OS was strong (r = 0.91). The HRs for PFS were moderately correlated (r = 0.70) and the correlation of median PFS was strong (r = 0.90). The correlation of ORR was very strong (r = 0.96). The PFS and ORR were consistent between Japanese patients and the overall population. A longer median OS was observed in Japanese patients. Our results would be a useful reference when planning and conducting MRCTs that include Japan for global simultaneous drug development.

Analysis of Pediatric Drug Approval Lag in Japan.

Drugs should be made available to all patients in a timely manner regardless of whether they are adults or children. In contrast to the United States (US) and the European Union (EU), no laws mandating pediatric drug development have been established in Japan. The objective of this study was to examine the current status and characteristics of pediatric drug development in Japan using information on the approval lag for pediatric indications between Japan and the EU. Drugs approved for pediatric indications between January 2007 and December 2018 in Japan were studied. The approval lag for pediatric indications between Japan and the EU was calculated and analyzed by approval time and the Anatomical Therapeutic Chemical (ATC) classification. Factors potentially affecting the approval lag, such as orphan drug status, company nationality, and clinical data package, were examined. The median approval lag for 105 drugs with pediatric indications in both Japan and the EU was 1017days (Japan was behind). The lag for ATC category B improved significantly after 2011, and for category L after 2015; the medians were less than half a year. The lag for drugs developed globally via multi-regional clinical trials was significantly shorter compared with drugs developed regionally. Global clinical trials are the most effective means of shortening approval lag time in pediatric drug development. Global development is making rapid progress for many adult diseases, thereby creating an environment for proactive participation in global clinical trials even for pediatric drugs. For further improvement, more active drug development for pediatric indication is recommended in tandem with the US and the EU.

The progression of clinical trials in Indonesia: an observational study of records from clinical trial registries databases

This report presents an overview on the progress of clinical trials in Indonesia based on database assessment from clinical trial registries. Study records that were registered up to December 26, 2018, were extracted from three clinical trial registries (ClinicalTrials.gov, ISRCTN registry, and EudraCT) and a clinical trial register (WHO International Clinical Trials Registry Platform (ICTRP)) with the keyword “Indonesia”. A total of 505 records comprised of 402 interventional studies and 103 observational studies were found and analyzed. The top five noncommunicable diseases (NCDs) studied were cancers, diabetes, cardiac diseases, hypertension, and gastrointestinal diseases, while the top five infectious diseases (IDs) were malaria, tuberculosis, vaccines for IDs, HIV, and dengue. Remarkably, the proportion of regional studies (within Indonesia only) was higher than that of multiregional studies (including areas outside of Indonesia) in general. This trend became most apparent after the issuance of national regulations on Material Transfer Agreements (MTA) and other rules. Upon closer scrutiny, regional clinical trials and multiregional clinical trials (MRCTs) in Indonesia differed in terms of sponsorship, target population and size, interventions, and study phases. The total number of clinical trials in Indonesia is increasing and is mainly attributed to the growing number of regional clinical trials sponsored from within the country. Interrelated factors have shaped the characteristics of these as compared to the dwindling number of MRCTs. Establishment of a national level of management is an option that can better facilitate both MRCTs as well as regional clinical trials, to better address the national health issues, and to cope with the regulations.

Regional consistency and sample size considerations in a multiregional equivalence trial.

The main objective of a confirmatory multiregional clinical trial (MRCT) is to demonstrate the overall efficacy of test drugs in all participating regions as well as to evaluate the possibility of extrapolating the overall results to each region. With the emergence of the demands of biosimilar drugs development, some guidelines recommended using equivalence design to demonstrate the comparability of efficacy between biosimilar and reference drugs. Previous discussions about assessing regional consistency in MRCT are mainly focused on superiority or non-inferiority designs, while the extensions to equivalence designs were limited. In this work, we proposed a flexible regional consistency criterion for the MRCT with equivalence design. Based on this criterion, sample size determination and sample allocation were also discussed.

Bridging Strategies for In Vitro Diagnostic Clinical Trials in a New Region

The need for multiregional clinical trials for <em>in Vitro</em> diagnostic devices and extrapolating results in a new region is increasing in recent years. In this paper we are providing strategies for consideration of bridging studies for the two most common types of clinical trials for <em>in Vitro</em> diagnostic, method comparison and diagnostic clinical performance trials.

961-P: Efficacy and Safety of Once-Weekly Semaglutide vs. Once-Daily Sitagliptin as Add-On to Metformin in Subjects with Type 2 Diabetes (SUSTAIN China MRCT): A 30-Week Double-Blind, Phase 3a, Randomised Trial

A total of 868 subjects of which 70% were Chinese and 13% Korean were randomised to once-weekly subcutaneous semaglutide 0.5 mg (n=288), 1.0 mg (n=290) or sitagliptin 100 mg (n=290) in a multiregional clinical trial. Both doses of semaglutide were superior to sitagliptin in reducing HbA1c (primary endpoint, Figure 1) and body weight (Table 1) after 30 weeks of treatment. The odds for achieving target HbA1c, weight loss of ≥5% or ≥10% and a composite endpoint were all significantly higher with both semaglutide doses compared to sitagliptin (Table 1). The safety profile of semaglutide was consistent with the previously established profile. Consistent efficacy and safety findings were seen in the Chinese population. Disclosure L. Ji: None. D. Xiaolin: None. F. Eliaschewitz: Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Bayer AG, GlaxoSmithKline plc., Novo Nordisk A/S, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company. Y. Li: None. Y. Li: None. S. Lim: None. M. Liu: None. N. Zu: Employee; Self; Novo Nordisk A/S. S. Rasmussen: Employee; Self; Novo Nordisk A/S. T.V. Skjoeth: Employee; Self; Novo Nordisk A/S. G. Yuan: None. Y. Huang: None. Funding Novo Nordisk A/S

US, EU, and Japanese Regulatory Guidelines for Development of Drugs for Treatment of Alzheimer's Disease: Implications for Global Drug Development.

Drug development guidelines from regulatory authorities provide important information to sponsors on requirements for clinical evidence needed to support approval of new drugs. In the field of Alzheimer’s disease (AD), recently published guidelines are available from EU, US, and Japanese regulatory authorities. In this review, these three guidelines are compared and discussed with emphasis on the recommendations provided for demonstration of efficacy in pivotal clinical trials conducted in predementia stages of AD. Similarities and differences are highlighted, and impact for global drug development is discussed in the context of the new International Conference on Harmonization E17 guideline on multiregional clinical trials. The AD field is characterized by significant challenges as, to date, no drug approval precedence exists in predementia AD despite numerous and ambitious efforts to slow the progression of the disease by pharmacologic intervention. Despite these uncertainties regulatory authorities across regions have blazed a trail for proactive multistakeholder collaboration, involvement, and continuous dialogue, setting a positive example on how to foster a supportive environment for development of new and meaningful treatments for patients with AD globally.

Perspectives on Adopting the Guideline for Multi-regional Clinical Trials in Korea: A Multi-stakeholder Survey

Perspectives on Adopting the Guideline for Multi-regional Clinical Trials in Korea: A Multi-stakeholder Survey

A Phase III Multi Regional Clinical Trial (MRCT) of Tricaprilin in Mild to Moderately Severe Probable Alzheimer's Disease

A Phase III Multi Regional Clinical Trial (MRCT) of Tricaprilin in Mild to Moderately Severe Probable Alzheimer's Disease

Current Landscape of Late-Phase Clinical Trials for Alzheimer's Disease: Comparing Regional Variation Between Subjects in Japan and North America.

Over the last few decades, numerous late-phase multi-regional clinical trials have been conducted to develop a novel treatment for Alzheimer's disease (AD), with no effective results. To inform the design and interpretation of future clinical trials, the aim of this study was first to examine the current landscape of late-phase clinical trials to determine key study design characteristics, and then assess the regional variation between Japan and North America for the most utilized clinical efficacy endpoint in the most targeted stage of the disease. The study design and the mechanism of action of the interventional drugs tested in the late-phase clinical trials initiated in the last 5years (2014-2018) were assessed based on the records in ClinicalTrials.gov database. The regional variation of the most utilized clinical efficacy endpoint in the most targeted population was assessed using data from two similarly designed observational studies conducted in Japan (Japanese Alzheimer's Disease Neuroimaging Initiative, J-ADNI) and North America (Alzheimer's Disease Neuroimaging Initiative, ADNI). For the most utilized clinical efficacy endpoint, the change from baseline (CFB) at Month 6, Year 1 and Year 2 was estimated using the growth curve model with a random intercept and slope, including gender as a fixed factor and age, apolipoprotein E ε4 genotype and years of education as covariates. Of 48 Phase III trials that were initiated during the study period, 25 were disease-modifying treatment trials in which individuals with early AD were the most studied (56%) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) was the most frequently utilized primary clinical efficacy endpoint (64%). The baseline characteristics of the early AD population between J-ADNI and ADNI were generally comparable, except for years of education. When comparing CDR-SB in early AD, J-ADNI had generally better baseline scores and the overall progression was similar (CFB at Year 2, ADNI 2.7 and J-ADNI 2.3, p = 0.190), despite slower progression in functional domains (CFB at Year 2, ADNI 1.4 and J-ADNI 1.0, p = 0.031). Over the years, the target population has shifted toward early stage of the disease, wherein the clinical progression is slower and difficult to measure. Moreover, our results suggest that regional variation could have an impact on functional measurements due to cultural differences in pivotal clinical trials. Therefore, caution should be exercised according to the characteristics of the endpoint used.

Hierarchical Linear Models for Multiregional Clinical Trials

Data observed in multiregional clinical trials are structurally hierarchical in the sense that the patient population consists of several regions and patients are nested within their own regions. To reflect such hierarchical structure, in this article, we propose two-level hierarchical linear models in which the level-1 model is based on patient-level data such as treatment indicator and age, and the level-2 model is based on region-level data such as medical practices. The fixed effect model and the continuous random effect model are shown to be special cases of hierarchical linear models. We conducted simulation studies to investigate the empirical Type I error rates of three methods for testing the overall treatment effect. The performance of the testing method with sample ratios as weights and the empirical Bayes estimator for between-region variability is better than that of the other two testing methods.

CYP2D6 genotyping analysis and functional characterization of novel allelic variants in a Ni-Vanuatu and Kenyan population by assessing dextromethorphan O-demethylation activity

While CYP2D6 allele and phenotype frequencies have been extensively studied, currently, very little ethnically specific data is available regarding the East African and South Pacific region, including Kenya and Vanuatu. The absence of information regarding gene polymorphisms and their resulting clinical effects in these populations may hinder treatment strategies and patient outcome. Given the scarceness of CYP2D6 related data in these populations, the purpose of this study was to perform a pharmacogenomic analysis of the Kenyan and Ni-Vanuatu population and ultimately characterize the enzymatic properties of eight novel CYP2D6 variant proteins expressed in 293FT cells in vitro using dextromethorphan as a substrate. Our study revealed a prevalence of functional alleles in both populations a low frequency for decreased function defining genotypes in the Ni-Vanuatu population, with approximately 36% of our Kenyan subjects presenting substrate-dependent decreased function alleles. Additionally, 6 variants (P171L, G306R, V402L, K1, K2, and K3) showed significantly reduced intrinsic clearance compared to wild-type CYP2D6.1. Our findings aid in efforts to bridge the gap between pharmacogenomic analysis and clinical application, by providing useful information in the development of ethnic-specific strategies as well as stressing the importance of population-specific genotyping when conducting multi-regional clinical trials and designing therapeutic strategies.

Application of Ethical Tool Kit in writing clinical trial protocols

Objective To analysis the necessity, feasibility and route of introducing Harvard Ethics Tool Kit into China. Methods Translated and edited The Ethics Tool Kit of Multi-Regional Clinical Trials (MRCT) Center of Harvard. Analyze the necessity and feasibility of introducing Ethical Tool Kit into China from the perspective of researchers and ethics committees. Explore the ways to introduce ethical toolkits into China from clinical trials and clinical research projects. Results Harvard MRCT Center developed Ethical Tool Kit in 2014 and proposed incorporating ethical principles into clinical research protocols. The Ethics Tool Kit includes 11 essential elements: addressing relevant question, choice of control and standard of care, choice of study design, choice of subject population, potential benefits and risks, informed consent, community engagement, return of research results and incidental findings, post-trial access, payment for participation, study related injury. The Ethics Tool Kit is helpful not only for researcher to develop their protocols, but also for ethical committees to conduct efficient review. From the perspective of researchers and ethics committees, it is necessary and feasible to introduce ethical toolkits into China now. From the ways of introduction, the clinical trial is proposed to be led by the government and the medical association, and the clinical research project is proposed to be explored by the institutions. Conclusions The Harvard Ethical Tool Kit has great practical value for researchers writing protocols and ethics committee reviewing protocols. It is recommended that introducing ethics tool kits to China for improving the overall quality of clinical research. Key words: Ethics committee; Investigator; Clinical trial; Protocol; Ethics Tool Kit

Population/regional differences in efficacy of 3 drug categories (antidiabetic, respiratory and psychotropic agents) among East Asians: A retrospective study based on multiregional clinical trials

This study aimed to identify population/regional differences in drug efficacy and the influencing factors among East Asians to be considered when planning multiregional clinical trials (MRCTs) to facilitate rapid drug approval in Asians. A retrospective analysis of efficacy (intergroup difference in endpoint between control and study drug treatment) among East Asian populations for 3 drug categories, antidiabetic, respiratory and psychotropic agents, was conducted in collaboration with pharmaceutical companies using their MRCT data. Common endpoints by drug category were selected; background factors that commonly affected the endpoints among regions were analysed first; then the population/regional differences were evaluated by the interaction term region-by-treatment using an analysis of covariance model after adjusting for background factors. Among 17 endpoints for eight pharmaceutical products from 3 drug categories, no substantial population/regional differences were detected in the 3 drug categories examined (P>.05), except for haemoglobin A1c change between Japan and Korea for an antidiabetic drug, insulin glulisine (P=.0068). However, no such regional differences were evident in patients with clinically important higher haemoglobin A1c baseline values (majority subgroup). Variability in disease severity at baseline and concomitant drugs were determined to be potential influencing factors for regional differences. This study suggests that the regional variability in efficacy of these 3 drug categories is not large among East Asians, and reveals the importance of considering background factors when planning MRCTs. Further studies are needed to evaluate regional variability in the efficacy of other drug categories and clarify the factors leading to regional differences in East Asians.

Investigation of the Study Characteristics Affecting Clinical Trial Quality Using the Protocol Deviations Leading to Exclusion of Subjects From the Per Protocol Set Data in Studies for New Drug Application: A Retrospective Analysis.

The concept of the risk-based approach has been introduced as an effort to secure the quality of clinical trials. In the risk-based approach, identification and evaluation of risk in advance are considered important. For recently completed clinical trials, we investigated the relationship between study characteristics and protocol deviations leading to the exclusion of subjects from Per Protocol Set (PPS) efficacy analysis. New drugs approved in Japan in the fiscal year 2014-2015 were targeted in the research. The reasons for excluding subjects from the PPS efficacy analysis were described in 102 trials out of 492 in the summary of new drug application documents, which was publicly disclosed after the drug's regulatory approval. The author extracted these reasons along with the numbers of the cases and the study characteristics of each clinical trial. Then, the direct comparison, univariate regression analysis, and multivariate regression analysis was carried out based on the exclusion rate. The study characteristics for which exclusion of subjects from the PPS efficacy analysis were frequently observed was multiregional clinical trials in study region; inhalant and external use in administration route; Anti-infective for systemic use; Respiratory system, Dermatologicals, and Nervous system in therapeutic drug under the Anatomical Therapeutic Chemical Classification. In the multivariate regression analysis, the clinical trial variables of inhalant, Respiratory system, or Dermatologicals were selected as study characteristics leading to a higher exclusion rate. The characteristics of the clinical trial that is likely to cause protocol deviations that will affect efficacy analysis were suggested. These studies should be considered for specific attention and priority observation in the trial protocol or its monitoring plan and execution, such as a clear description of inclusion/exclusion criteria in the protocol, development of training materials to site staff, and/or trial subjects as specific risk-alleviating measures.

Interethnic scaling of fraction unbound of a drug in plasma and volume of distribution: an analysis of extrapolation from Caucasians to Chinese.

Prospective prediction of pharmacokinetic properties for individuals of different ethnic groups could provide useful information for the design of multiregional clinical trials. The accuracy of interethnic scaling of fraction unbound (fu) of a drug could determine in large part the predictive capability of volume of distribution as well as renal clearance. As such, exploring the interethnic extrapolation of fu from healthy Caucasian to Chinese subjects and associated effect on the scaling of volume of distribution is highly warranted. This study assessed the interethnic scaling of fu from healthy Caucasians to Chinese by using physiologically based principles and verified the approach after examining with experimentally determined fu values of a variety of reference compounds with differing binding characteristics. Moreover, the fundamental assumption of interethnic extrapolation of volume of distribution (Vd), namely the equivalency of unbound Vd (Vd,u) across different ethnic groups, was tested on the basis of observed Vd data derived from comprehensive literature analysis and scaled fu values through qualified extrapolation method. The interethnic extrapolation approach of fu provided a high accuracy with 94.7% scaled Chinese fu values (n = 19) being within a 1.25%-fold error range. Specifically, 100% of scaled Chinese fu values for the albumin-bound compounds and 90% for those bound to alpha 1-acid glycoprotein fell within the 1.25%-fold error range. All the percentage prediction errors of scaled Chinese fu values were ≤ 30%, with a majority of those ≤ 20%. Additionally, correlation between the prediction errors and the observed fu levels was not observed. Regarding interethnic scaling of Vd, the bodyweight-normalized Vd,u instead of Vd was similar across ethnic groups. The current study verified for the first time the ability to scale Chinese fu from Caucasian values after examining with experimentally determined fu values of a variety of reference compounds. Similarities in bodyweight-normalized Vd,u between non-obese Caucasians and Chinese have also been shown for the first time. This investigation could greatly enhance the confidence in the interethnic extrapolation of fu and Vd from healthy non-obese Caucasian to Chinese subjects.

The New Landscape of Checkpoint Inhibitors in China

On June 15, 2018, the first checkpoint inhibitor (CPI) was approved by the CFDA and will be commercially available in China by fall. It is anticipated more CPIs will be approved in the near future. In contrast, six CPIs have been approved in the U.S. for various diseases and stages since 2014. Consequently, PD-1/PD-L1 clinical trials have become the most active area of clinical research in China.Using ClinicalTrials.gov with the criteria of “recruiting/active/interventional”, I analyzed opened trials in China; I compiled data and cross-checked with domestic public domain information in China (http://www.chictr.org.cn/). As of July 8, 2018, a total of 134 protocols were identified in PD-1 (112 as China sites [CN], 22 as multi-regional clinical trials [MRCT]), 36 protocols in PD-L1 (9 CN, 27 MRCT) and 13 protocols in anti-CTLA-4 (ipilimumab) (4 CN, 9 MRCT) categories covering both malignant hematology and solid tumors over 20 different disease types. Trials of FDA approved agents in China include nivolumab (n=21), atezolizumab (19), pembrolizumab (12), Durvalumab (10), avelumab (2) and ipilimumab (13). They are predominantly MRCT and in combination with chemotherapy, second CPI or a targeted agent. Trials of domestic PD-1 agents are essentially conducted only in China, with exception of SHR-1210 and BGB-A317 which are also registered for ex-china trials. The majority of early phase trials (>95%) are conducted by a short list of centers in Beijing, Shanghai, and Guangdong, and Zhejiang.Among domestic PD-1 trials, 36 combine PD-1 with various cell therapy technologies, including CAR-T, DC, PD-1 knockout T cells, or CSR T cells; this indicates such combinations are an area of active investigation. The number of registered trials for each PD-1 biologic agent are SHR-1210 (n=34), JS001 (15), BGB-A317 (8), GB226 (2) and IBI308 (1).PD-L1 trials have essentially the same broad disease indications as PD-1 agents, and are open for advanced solid tumors. The number of PD-L1 trials is fewer than for PD-1 agents, including Atezolizumab (n=19), Durvalumab (10), Avelumab (2), KN035 (2), CS1001 (2), and SHR-1316 (1).While majority of CPI trials in China are designed for a single category of cancer, 30% of PD-1 trials, 20% of PD-L1 trials and 7% of ipilimumab trials are opened to advanced solid tumors including lymphoma. In addition, there are more than 20 PD-(L) 1 inhibitors that are in various stages of clinical development in China.In reality, patients in China have been obtaining CPI agents for cancer treatment outside of clinical trials from overseas. Patients who meet clinical trial eligibility criteria might not represent real world population for efficacy and adverse events. After the first CFDA approved nivolumab, which has a very specific label indication (advanced stage lung cancer after failing platin-based regimen) and other CPIs to be approved soon, the off-label use of these CPI agents could be widespread for various advanced stage cancers.Judging from the multiple FDA-approved indications of CPIs, the potential demand in China could reach millions of cases. Currently, there are policies to limit total formulary drug expense in public hospitals, so with the high cost of these medications, hospitals may not be able to provide timely treatment to necessary patients, which could create wait list issue.For care providers, the complexity of managing immune-related adverse events (irAE) and recognizing phenomenon such as pseudo-progression, poses critical need for systemic training and education for physicians, nurses, and patients as well.It is crucial for policy makers, medical societies, and hospitals to implement policies, and treatment guidelines for all immuno-oncology drugs according to the best evidence-based practice to meet potential demand and safe guard societal and patient benefits.In collaboration with Massachusetts General Hospital (Boston, USA), the Cancer Center of Jiahui International Hospital (Shanghai, China) has developed comprehensive clinical pathways and practice guidelines locally in China in order to deliver safe, effective and patient-centered care. We have implemented telemedicine to support multidisciplinary care models to manage treatment criteria and treatment complications. Going forward, post-market clinical studies will be conducted for data collection and in collaboration with pharmaceutical companies. DisclosuresNo relevant conflicts of interest to declare.

Strategic inclusion of regions in multiregional clinical trials.

With the recent publication of the International Conference on Harmonisation E17 guideline and major reforms in China underway, the platform for clinical trial conduct is expected to change. This study aims to assess the strategic inclusion of regions in clinical trials and its change in trends over the past decade. The ClinicalTrials.gov registry was searched for clinical trials registered by the top 10 pharmaceutical companies between 1 January 2008 and 31 December 2017. Extracted data included phase, disease type, intervention, study start year, and region. Trial type was classified as either a local study or a multiregional clinical trial as per the International Conference on Harmonisation E17 guideline. Of 2488 phase I, 1855 phase II, and 1999 phase III trials included, the majority of phase I trials were local studies (76.8%), while the majority of phase II (66.0%) and phase III (72.2%) trials were multiregional clinical trials. The proportion of multiregional clinical trials showed an increasing trend for all phases ( p < 0.01). Although North America and Europe remained the main locations, increasing trends of inclusion of other regions, such as East Asia, were noted. Globalization of drug development is evident with the increasing trend of multiregional clinical trial. Regulatory authorities as well as the pharmaceutical industry should prepare for the evolving setting of clinical research and problems that can arise from these changes.

What Drives Adoption of National Labels as Global Reference Labels? A Case Study With the JPI.

Pharmaceutical labeling describes the safe and effective use of an approved product. Such information may be provided to consumers and/or health care physicians, and available online or in the pack in a variety of different formats according to local or regional regulations. Depending on the Health Authority (HA), content within a nationally approved label is generally reliant on two primary sources, a Company Core Data Sheet (CCDS), and the text approved by the Health Authority. Content in the nationally approved label may differ from the CCDS for a variety of reasons. In some countries, HAs require the Marketing Authorization Holder (MAH) to base their national label on an already approved label in a "major market" economy, only approving changes to the label when there is evidence that the major market has already approved. In this paper, we examine recent steps taken by the Ministry of Health, Labour and Welfare (MHLW) and Pharmaceuticals and Medical Devices Agency (PMDA) to change labeling regulation in Japan in the context of the recently communicated national strategy, and assess whether this may impact on uptake of the J-PI as a reference label. Decreases in approval times by PMDA for new products, development of basic principles on multiregional clinical trials, greater transparency of content on the PMDA website, and increasing outreach to other Asian Agencies in recent years are highlighted. Labeling harmonization across regions, particularly of safety-related information, represents a key factor in promoting patient safety and risk communication, and is a worthy topic for future ICH consideration.

AOJS-3 - Practical issues and future perspectives on early phase development in Asia- competition, collaboration and harmonization

In changing of landscape at drug development process, the nature of oncology early phase 1 drug development has changed substantially in recent years, with key changes in multiple areas of trial design, implementation and interpretation. Two of these trends-increased sample size and increased use of expansion cohorts. Changes in phase 1 trials have evolved as the knowledge of molecular biology accumulates and as molecularly targeted and immuno-oncology agents have become more important parts of the oncology therapeutic strategy. In addition to changing nature of recent early phase oncology new drug development, Asia needs to take the initiative in developing drugs to treat cancers prevalent in the region, especially in Asian specific cancers from the initial-early stage of development. The National Cancer Center (NCC) of Japan signed a memorandum of understanding with key oncology phase 1 centers in Asia including China (HKSAR : Hong Kong Special Administrative Region), Korea, Singapore and Taiwan, to form the Asian Oncology Early Phase 1 Consortium (AsiaOne), to drive the momentum towards international collaborative phase 1 clinical trials across Asia, and to realize efficient clinical development of early phase oncology drugs serving the region since September 2017. By promoting multinational collaborative clinical trials across Asia initiated by global pharmaceutical companies utilizing this platform efficiently, multinational investigator-initiated clinical trials coordinated by Asian investigators, collaboration with early-late phase drug development divisions of pharmaceuticals, and already established accelerated review pathways as well as progress and implementation of the ICH E17 guideline for planning and designing multiregional clinical trials including Asian countries, advancing suitable style of drug development including treatments for unmet needs in Asia and genome-driven drug development need to be accelerated.