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Trends in new drug application approvals and related pivotal clinical trial data. The numbers of newly approved drugs whose pivotal clinical trial data were collected from global clinical trials between FY2007 and FY2015 are shown. The bars denote the number of drugs approved based on specific types of clinical trials. Squares, triangles, and circles denote the percentages of drugs approved based on specific types of clinical trials.
Source publication
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 suggeste...
Contexts in source publication
Context 1
... aim of the 2007 Japanese guideline was to offer points to consider in planning and conducting GCTs, and to encourage Japanese participation in such trials. To exam- ine the effect of the guideline, we assessed the yearly trends of new drug applications (NDAs) that received GCT-based approvals and bridging studies that included Japanese sub- jects between FY2007, when the guideline was issued, and FY2015 (Figure 2). We found that the absolute numbers and percentage of GCTs increased greatly after FY2009 (i.e., 2 years after the publication of the guideline), although the absolute numbers and percentage of drugs approved based on bridging studies were greater than those of drugs approved based on GCTs in FY2007 and FY2008. ...
Context 2
... 2014, 20% or more of new drugs approved in Japan were GCT-based approvals (FY2014: 27.7% (33/119 drugs); FY2015: 20.0% (23/115 drugs)). The percentage of GCTs conducted only in Asian regions has also increased over the past few years, and the pivotal clinical trial data of ß5% of new drugs approved in Japan were collected from Asian GCTs (Figure 2). Figure 3 shows the number of Asian regions participating in GCTs by study initiation time. ...
Citations
... Multiregional clinical trials (MRCTs) help decrease the lag in drug development and approval that often occurs in Asian countries compared with those in Europe and North America. 1,2 For example, delays due to country-specific requirements for submission of local patient data can be mitigated if the MRCT is designed to enroll local patients. 1 The International Conference on Harmonisation of Technical Requirement for Registration of Pharmaceuticals for Human Use (ICH) E5 guidelines provide a framework for evaluating the impact of ethnic factors on the efficacy and safety of a particular study drug dose and regimen. ...
... 3 Global MRCTs are on the rise, notably in oncology and rare disease/orphan drug development. 2 In 2017, the ICH issued E17 guidelines, which describe general principles for the planning and design of MRCTs with the aim of generating data that are applicable for global regulatory submissions. 4 The key principles of the E17 guidelines are to: conduct well-designed MRCTs to increase drug development efficiency and support regulatory decision making across regions, understand relevant intrinsic and extrinsic factor effects early in MRCT design, allocate sample size by region to verify consistency in treatment effect while allowing feasibility in recruitment and timely trial conduct, pool prespecified regions based upon similarities, use a single primary analysis supported by structured exploration of consistency, ensure high-quality trial design and conduct, and encourage efficient communication between sponsors and regulatory authorities during MRCT design. ...
The investigational NEDD8‐activating enzyme inhibitor pevonedistat is being evaluated in combination with azacitidine versus single‐agent azacitidine in patients with higher‐risk myelodysplastic syndrome (higher‐risk MDS), higher‐risk chronic myelomonocytic leukemia (higher‐risk CMML), or low‐blast acute myeloid leukemia (AML) in a Phase 3 trial PANTHER. To support Asia‐inclusive global development, we applied multiregional clinical trial (MRCT) principles of the International Conference on Harmonisation E17 guidelines by evaluating similarity in drug‐related and disease‐related intrinsic and extrinsic factors. A PubMed literature review (January 2000–November 2019) supported similarity in epidemiology of higher‐risk MDS, AML, and CMML in Western and East Asian populations. Furthermore, the treatment of MDS/AML was similar in both East Asian and Western regions, with the same dose of azacitidine being the standard of care. Median overall survival in MDS following azacitidine treatment was generally comparable across regions, and the types and frequencies of molecular alterations in AML and MDS were comparable. Dose‐escalation studies established the same maximum tolerated dose of pevonedistat in combination with azacitidine in Western and East Asian populations. Pevonedistat clearance was similar across races. Taken together, conservation of drug‐related and disease‐related intrinsic and extrinsic factors supported design of an Asia‐inclusive Phase 3 trial and a pooled East Asian region. A sample size of ~ 30 East Asian patients (of ~ 450 randomized) was estimated as needed to demonstrate consistency in efficacy relative to the global population. This analysis is presented as an exemplar to illustrate application of clinical pharmacology and translational science principles in designing Asia‐inclusive MRCTs.
Study Highlights
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Azacitidine is the standard of care for myelodysplastic syndromes/low‐blast acute myeloid leukemia (AML) across Western and East Asian patients. The first‐in‐class small‐molecule inhibitor of NEDD8‐activating enzyme, pevonedistat, has been investigated as a single agent in multiple studies of hematologic and nonhematologic malignancies and in combination with azacitidine in elderly patients with untreated AML. WHAT QUESTION DID THIS STUDY ADDRESS?
By applying clinical pharmacology and translational science and International Conference on Harmonisation E17 principles, this study designed an East Asian‐inclusive global pivotal Phase 3 trial of pevonedistat, taking into consideration drug‐related and disease‐related intrinsic and extrinsic factors. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
These analyses provide scientific rationale for Asia‐inclusive globalization of the pivotal, Phase 3 PANTHER trial and for pooling clinical data across the East Asian region for assessing consistency in efficacy. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
We developed a framework to facilitate efficient global clinical development of investigational therapies for rare cancers and orphan diseases in Asia‐inclusive multiregional clinical trials.
... In this study, we used information on MRCTs that were submitted for approval in Japan, because those MRCTs included not only Japan but also many other regions. 3,8 Data from them had been usually submitted to various regulatory agencies, including those in Japan, the United States, and the European Union. Another reason for using the information on those MRCTs was that modules 1 and 2 of the common technical document (CTD) submitted by marketing authorization holders (i.e., pharmaceutical companies) and the Pharmaceuticals and Medical Devices Agency (PMDA; Japanese regulatory agency) review reports for a specific product, including information on MRCTs, are publicly available in Japan. ...
... Conducting subgroup analyses (e.g., analyses to investigate differential treatment effects by sex and age) [ We further characterized the key principles that were usually explained in the official documents. With regard to [3] ethnic PK differences, considerations were actually based on data for interethnic PK comparisons between Japanese and non-Japanese populations, which were derived from two sources: early-phase PK studies (e.g., maximum concentration and area under the curve values) and latephase studies, such as MRCTs (e.g., trough level; Figure 3). Among the 167 studies, the PK data were obtained from both early-phase PK studies and late-phase studies in 84 studies (50.3%, 84/167 studies), from only late-phase studies in 42 studies (25.1%, 42/167 studies), and from only early-phase PK studies in 29 studies (17.4%, 29/167 studies). ...
... In the eliglustat study, 50 mg twice daily was orally administered from day 0 to day 28 in non-Japanese subjects and 50 mg once daily on day 1 and 50 mg twice daily from day 2 to day 28 were orally administered in Japanese subjects. In the benralizumab study, the dose regimens Compliance with GCP standards [1] Conducting scientific consultation meetings related to MRCT with the PMDA [2] Considerations of ethnic differences based on PK data between Japanese and non-Japanese populations [3] The use of relevant guidelines for disease definitions in the inclusion and exclusion criteria [4] Conducting training/validation on the subjective criteria [5] Setting of the same doses in confirmatory MRCTs [6] Conducting dose-response studies for the selection of dose regimens in confirmatory MRCTs [7] The use of relevant guidelines for clinical evaluation at the primary endpoint [8] Conducting training/validation on the subjective primary endpoint [9] Sample size allocation to Japanese population [10] Setting of standardized collection and handling of efficacy information [11] Setting of standardized collection and handling of safety information [12] Conducting a single primary analysis [13] Conducting the evaluation of consistency in treatment effects between the overall population and Japanese population [14] Conducting the evaluation of consistency in treatment effects across regions, race, or variant frequencies [15] Conducting subgroup analyses [16] Uniform placebo or active ingredient of active comparator [ In terms of [7] dose response study, we checked the status of performing dose-response studies to select dose regimens for confirmatory MRCTs (Figure 4). Dose regimens in 139 confirmatory MRCTs were selected based on dose-response studies. ...
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.
... From the industrial perspective, pharmaceutical companies have been implementing effective clinical development strategies globally by utilizing the above guidance issued by the PMDA. Pharmaceutical companies are strategically utilizing Asian global clinical trials [7,103] and bridging strategies [47], aided by Japan's participation in global clinical trials [85,115,104]. As a result, several reports have indicated that the drug lag for anticancer drugs has decreased in Japan, given that the clinical development of oncologic agents, including those for cancer immunotherapy, has been expanded [96,55,121]. ...
The Japanese pharmaceutical market is one of the largest in the world. The Japanese government has increasingly been trying to control rising health care costs, and as a result, pharmaceutical companies are expecting that fewer opportunities will be available to command a higher price based on higher levels of innovation; this will likely lead to decreased interest in research and development (R&D) activities. With this background, the purpose of this article is to review current perspectives for R&D by the Japanese pharmaceutical industry, and to discuss the limitations and challenges for further research from the regulatory science and management perspectives. Given the substantial amount of evidence of regulatory science and management perspectives from the pharmaceutical industry outside of Japan and the limited amount of evidence from inside of Japan, it is important to review perspectives focusing on the Japanese pharmaceutical industry in comparison with those from other countries to understand the complexities of the Japanese pharmaceutical market, as well as the limitations and challenges associated with increasing productivity. https://doi.org/10.21423/jrs-v08shoyo
... 111 drugs were approved between 2005 and 2015 based on data from global studies, 4 and another report showed that of 121 drugs approved between 2007 and 2015 based on data from global studies, 31 were based on Asian studies. 5 Pharmaceutical companies globalize drug-development activities to establish clinical evidence of new drugs for global markets in the most efficient way. As mentioned above, implementing bridging and MRCTs are typical components of globalized development. ...
Recent International Conference on Harmonization (ICH) guidelines provide pharmaceutical companies with regulatory justifications to pursue various global drug‐development pathways, in some of which “local” dose‐ranging and/or pivotal phase III studies are skipped. We examined the association between the clinical development pathway and postmarketing safety in Japan for 177 new molecular entities approved between 2004 and 2013 focusing on dose setting histories for each drug. The risk of drug‐related deaths was higher when companies did not conduct local (i.e., Japanese) dose‐ranging studies and/or pivotal studies. Even when local dose‐ranging studies were conducted, the risk remained higher in some drugs for which the approved dose in Japan was set equal to that in the United States. Drugs developed under a bridging strategy tended to show lower risks. These results suggested that local clinical studies may play a substantial role in achieving optimization of postmarketing drug use in each local target population.
We examined the development strategies of new molecular entities approved during a 10-year period (fiscal years of 2012–2021) in Japan to determine the differences in drug lag between Japan and foreign companies. The results demonstrated a clear difference in development strategies. For example, products were usually developed through a “only-Japan” strategy by Japan companies (51.1% of products), compared to a “MRCT (multi-regional clinical trials)” strategy by foreign companies (54.9% of products). Regarding types of licenses, for Japan companies, the percentage of original products was higher in the category of less drug lag, such as “no approval in the US and EU” (59.1%), whereas the percentage of “license-in” products was markedly higher in the “drug lag ≥ 5 years” category (52.5%). Such differences were not observed for products developed by foreign companies. Of 64 license-in products developed by Japan companies with a drug lag > 5 years, 51 (79.7%) had already been approved in the US or EU at initiation of clinical development in Japan. The origin of approximately half (34) of the products was from the emerging companies (non-member foreign companies of the Japan Pharmaceutical Manufacture Association). These results suggest that more global cooperation of Japan companies, particularly with emerging foreign companies, is necessary in terms of the earlier timing of license-in and development strategies of products to promote drug development without drug lag or drug loss in 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.
What is known and objective:
Regulatory authorities in several regions have introduced a number of expedited programs (EPs) to promote the development of innovative drugs for patients in their own countries. The EPs in the United States (US), alone or in combination, have been successful in shortening the clinical development time in the US. We examined whether US-EPs, as well as other related factors, have an impact on the clinical development time in Japan to obtain new insights for more efficient drug development.
Methods:
In total, 168 drugs approved as new molecular entities (NMEs) in Japan and approved in the US between 2012 and 2019 were surveyed. We compared the clinical development time in Japan for those drugs with or without US-EPs. We also examined the impact of overlapping designations of US-EPs on clinical development time in Japan. Multiple regression analysis was performed to identify associated factors related to clinical development time in Japan, including US-EPs.
Results and discussion:
The clinical development time in Japan was significantly shorter at 37.4 [Interquartile range, IQR, 28.7-48.9] months for Accelerated Approval (AA), 42.2 [30.0-53.6] months for Breakthrough Therapy (BT), 42.3 [29.3-56.4] months for Fast Track (FT), 44.5 [30.7-60.0] months for US Priority Review, and 45.2 [31.3-61.8] months for US Orphan Designation. Multiple regression analysis revealed that AA (p = 0.008), FT (p = 0.013), Japan Priority Review, and the difference in development initiation dates between the US and Japan were significant factors related to a decrease in the clinical development time in Japan, whereas Japan Orphan Designation and the development of anticancer drugs were significant factors linked to an increase in the clinical development time.
What is new and conclusion:
US-EPs were associated with a decrease in the clinical development time in Japan for the drugs that were approved as NMEs in Japan and approved in the US. This association was not restricted to particular therapeutic areas or development strategies. Stakeholders involved in drug development, including the drug developers and regulatory authorities in Japan, should realize these effects for efficient drug development.
Aprocitentan is an orally active dual endothelin receptor antagonist currently in development for treatment of difficult‐to‐control (resistant) hypertension. In phase 1 and 2 studies, aprocitentan has been characterized predominantly in Caucasian subjects. In this bridging, double‐blind study, 20 healthy Japanese and Caucasian male and female subjects received 25 mg of aprocitentan or placebo once daily for 10 days and were monitored until 216 hours after the last dosing. The pharmacokinetics of aprocitentan were similar between ethnicities. At steady state, maximum plasma concentration was reached at 4 and 3 hours, and elimination half‐life was 49.1 and 48.8 hours for Japanese and Caucasian subjects, respectively. The accumulation index was around 3 for both populations. Geometric means ratios for maximum plasma concentration and area under the plasma concentration–time curve during 1 dosing interval were around 1, with 90% confidence interval ranging from 0.87 to 1.30. Aprocitentan was safe and well tolerated in both groups. As no clinically relevant differences were found between Japanese and Caucasian subjects, it is unlikely that the pharmacokinetics of aprocitentan would differ significantly between Caucasian subjects and other ethnicities. Aprocitentan can therefore be administered at a dose level of up to 25 mg in any ethnicity without dose adjustment.
The legacy of male bias within pharmaceutical research, regulation, and commercialisation needs to be rectified, argue Sundari Ravindran and colleagues
Revisions of drug package inserts (PIs) may be made immediately after approval or after considerable clinical experience; however, it is unclear whether there is a relationship between the characteristics of these safety measures and the period since drug approval. Here, we analyzed 209 cases of safety measures (revisions of the PIs) taken in Japan over 5 years (FY2014 to FY2018). The median, minimum, and maximum period from approval date in Japan to PI revision date was 6.29 years (interquartile range 2.68–15.53 years), 0.16 years, and 59.69 years, respectively. The cases were classified into four groups depending on types of adverse reaction and therapeutic category in relation to the national approval date and international birth date, resulting in the grouping together of particular adverse reactions and therapeutic drugs. For example, “Hepatobiliary disorders”, “Blood and lymphatic system disorders”, “Respiratory, thoracic and mediastinal disorders”, “Antineoplastics”, “Chemotherapeutics”, and “Other agents affecting metabolism” were associated with the group of safety measures taken early after approval of a drug soon after the international birth date, suggesting that careful attention at an earlier stage after approval is necessary for these adverse reactions and drugs. Understanding such features of PI revisions makes pharmacovigilance planning more appropriate, contributing to the implementation of rapid and proper safety measures after drug approval.
