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There are many differences between Asian regions in terms of the regulatory requirements and operational procedures in conducting international academic clinical trials for the approval of new drugs. The National Cancer Center Hospital in Japan has launched an international investigator-initiated registration-directed trial (IIRDT) in Japan, Korea, Taiwan, and Singapore, aiming at obtaining pharmaceutical approval in participating regions. Differences in regulatory and operational procedures were identified while coordinating the trial. In Japan, regulatory authority reviews should be performed after approval by institutional review boards for IIRDT, whereas in other regions these can be done in parallel. There were disparities in Good Manufacturing Practice-related documents between regions. Several differences were found regarding investigational product (IP) management, specifically concerning labeling, import/export procedures, and customs clearance costs. On the other hand, safety reporting procedures were relatively well-harmonized in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (ICH-E2A). Regions also differed in per-patient costs, due to varying regulations for academic registration-directed trials. In conclusion, the observed differences among Asian regions should be harmonized to facilitate international academic trials in Asia and thus resolve unmet patient needs worldwide. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? International clinical trials have become common because they make it possible to accrue patients faster and obtain new drug approval in wider areas. However, pharmaceutical regulatory differences hinder the efficient conduct of international clinical trials, especially in academia. WHAT QUESTION DID THIS STUDY ADDRESS? We conducted an academic international clinical trial on new drug applications in four Asian countries and clarified pharmaceutical regulatory differences and operational difficulties. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The study identified differences between countries in terms of regulatory affairs, institutional review board (IRB) review processes, investigational new drug (IND) dossiers, investigational product (IP) management procedures, and clinical trial costs, while safety reporting procedures were relatively harmonized. Japan utilizes investigator-initiated registration-directed trials, an advanced regulatory system for new drug application by academia, but the other countries do not. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Harmonization of pharmaceutical regulations and trial initiation procedures, and regulatory reform of clinical trial costs are important to accelerate academic international clinical trials for new drug applications., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

The registration process for new drugs is crucial in the clinical application of medicines. Previously, the registration of imported novel therapeutic agents in Taiwan depended considerably on their approvals in developed countries. The Taiwanese government enacted Article 38-1 of the Regulations for Registration of Medicinal Products in September 2009. According to the new submission criteria, approvals may be exempted if the number of Taiwanese participants in the clinical trials fulfills the required threshold. The present study compared the profiles of clinical trials of novel therapeutic agents before and after the enactment of this regulation in terms of over-threshold trials, structural types, and therapeutic areas across phases. The outcome-whether the liberalization of the submission criteria functioned as an incentive to launch clinical trials in Taiwan-was also evaluated. The results revealed that the number of clinical trial applications increased after the reformed regulation was enacted, even after the over-threshold criteria were considered; however, the increase disappeared for phase III trials. Most clinical trials were for chemical products and antineoplastic agents across all phases and study periods before and after the enactment of Article 38-1. Furthermore, the increase in the number of international clinical trials conducted in Taiwan was not directly caused by the regulation reform because the percentage of investigational products fulfilling the exemption criteria did not increase. These paradoxical results were interpreted in several aspects, referring particularly to the well-established infrastructure for launching clinical trials as well as the integral environment of medical services in Taiwan.

Current status of oncology drugs approved in Japan without supporting Japanese Phase 2 and 3 clinical trial (J-P2/3) data and potential factors correlating to the decision of Japanese health agency Pharmaceuticals and Medical Devices Agency (PMDA) to waive J-P2/3 data were investigated. Approximately 15 % of 61 investigated recently-approved oncology drugs were granted a J-P2/3 waiver. Drugs that were designated as Fast Track in the United States tended to be granted a J-P2/3 waiver. The orphan drug designation in Japan was also suggested to be correlated with the decision of J-P2/3 waiver, even though the trend was not significant. Specific factors related to the clinical importance, such as the designation of US Fast Track status, may have a correlation with the likelihood of J-P2/3 waiver, suggesting that the clinical importance of the drug is common in both countries. If the key criteria used to determine the waiving of Japanese clinical trial data were clearly disclosed by the regulatory agency, the development of some clinically important oncology drugs could be further expedited.

The history of drug/vaccine development has included major advances guided primarily by risk/benefit analyses concerning the innovative agent, not by evidence-based clinical trials (Phase I-IV). Because the approval for new drugs is hindered under the present process, the system requires restructuring. The Phase I/II study period should be more flexible, using the "environment of knowledge" about the new agent, plus risk/benefit assessments. Phase III, as presently constructed, does not add new adverse events data, it provides a narrower profile of drug efficacy than properly done Phase II studies, and placebo-controlled trials continue to raise unresolved ethical and social issues. Phase III studies should be abandoned for most drugs, and substituted with properly powered Phase II dose-ranging studies plus careful post-marketing surveillance. Phase III should be a penalty for poor drug development, not a regulatory requirement. To accomplish efficient drug development, greater cooperation between pharmaceutical companies and governments in developing clinical trials is needed rather than over-regulation. These changes will synchronize the drug development and regulatory process with the current rapid drug discovery process, reduce drug development time and cost, and improve patient care.

Current Indian drug regulations do not allow for toxicology testing and clinical trials in India with compounds or molecules discovered abroad, except for treatments of tropical, cancer and cardiovascular diseases as part of global studies. The number of GCP Phase II/III trials by foreign sponsors has increased dramatically since 1995, attesting to the potential of India for lower cost trials and reduction in drug development costs and time, due to rapid patient recruitment. However, there have been problems with regard to intellectual property protection and adherence to informed consent guidelines. Starting in 2005, a series of regulatory reforms and patent protection will be instituted that are designed to address many of these concerns; the nature of these reforms are presented and discussed. However, sponsors need to pay close attention to informed consent and other ethical issues in Indian trials, which enroll mainly poor and uneducated patients.