A study based on regulatory factors, ethnicity and pharmacokinetic/pharmacodynamic differences on approval dosing regimen in Northeast Asian countries = 동북아시아 국가에서 의약품 허가 용량에 대한 규제적 요소와 민족적/약동력학 차이를 기반한 분석과 고찰

다국어 초록 (Multilingual Abstract)

Introduction: Various studies have highlighted the importance of ethnic differences. The consideration of ethnic differences in the field of individualized pharmacotherapy is imperative. Therefore, various organizations and networks across countries should aim to conduct multi-country and multi-regional clinical trials (MRCTs). If there is solid evidence available to evaluate the existence of ethnic differences between the same regional areas, it will lead to an increase in the efficiency of drug development. This study aimed to compare the approved dosing regimen among Northeast Asian countries (Korea, Japan, China, and Taiwan) and elucidate the readiness and current status of the implementation of the International Conference on Harmonization (ICH) E17 guidelines on MRCTs. Moreover, the purpose was to elucidate the readiness and the current status of the implementation of the ICH E17 guidelines on MRCTs and evaluate if individual studies with single protocols could be conducted, to minimize the frequency of unnecessary multinational clinical trials, among Northeast Asian countries. Additionally, this study evaluated the relationship between the approved dosage regimens and reported adverse events in Korea based on real-world data (RWD), and it appraised the current status of ethnicity sensitivity in various therapeutic areas.
Methods: For data collection, the information on the approved dosing regimen using generic names and ingredients was screened from a list of approved drugs on the official websites of the regulatory agencies of Korea (Ministry of Food and Drug Safety, MFDS) and Japan (Pharmaceuticals and Medical Devices Agency, PMDA) from April 2012 to March 2021. The approved dosing regimens in China and Taiwan were obtained from individual drug labels, which were found by searching several of the top search engines such as Google (https://www.google.com/) and Baidu (https://www.baidu.com/). Each drug was classified by molecule type such as small molecule, monoclonal antibody and others, and by anatomical therapeutic chemical (ATC) criteria.
Results: The approved dosing regimens for some drugs in the four Asian countries were similar; however, some differences might be caused by variations in legislation even though there were no significant ethnic differences.
Conclusion: The results indicates that exploratory MRCTs lead to the accumulation of evidence that would ultimately accelerating the efficiency of drug development in Northeast Asian countries. The exposure of the new treatment to the necessary patients through collaborative research coordination and simultaneous multinational subject recruitment would serve its role in providing Northeast Asia with specific personalized medicine with a high treatment success rates.

국문 초록 (Abstract)

서론: 다양한 연구들을 통하여 인종간 차이의 중요성이 강조되고 있으며, 개별화된 약물치료 분야에서 인종적 차이는 필수 고려 사항이다. 이로 인해 여러 국가들을 대상으로 하는 다양한 네트워크에서 다중 국가 및 다중 지역 임상시험(MRCT) 수행을 통하여, 인종적 차이를 평가하고 있다. 만약 같은 지역 간의 민족적 차이의 존재를 평가할 수 있는 근거가 있다면 그것은 약물 개발의 효율성 증가로 이어질 것이다. 따라서, 본 연구는 동북아시아 국가(한국, 일본, 중국, 대만)간 허가된 용량 용법을 비교하고, MRCT에 대한 International Conference on Harmonization (국제화합회의) E17 지침의 실행 준비와 현재 상태를 설명하고자 하였다. 또한, 동아시아 국가들 간의 다국적 임상시험을 통해 불필요한 임상시험을 줄이고 하나의 연구계획서로 초기 임상 개발 연구가 수행될 수 있는지를 평가하고자 하였다. 더불어 한국에서 보고된 의약품부작용과 의약품의 허가 용량 용법 사이의 연관성을 평가하고자 하였다.
방법: 2012년 4월부터 2021년 3월까지 한국(식품의약품안전처, MFDS)와 일본(의약품안전청, PMDA)의 공식 홈페이지에서 승인된 의약품 목록을 기반으로 하여, 해당 의약품들의 성분을 기반으로 허가 용량, 용법을 조사하였다. 또한, 중국(의약품관리국, NMPA)과 대만(식품의약품안전청)에서 승인된 약물요법은 공식 홈페이지와 상위 검색엔진을 검색하여 정보를 조사하였다. 각 의약품은 소분자, 단일클로항체 등의 약물 계열과 의약품 분류체계 코드(ATC 코드)를 기준으로 분류되었다. 또한, 한국의약품 안전관리원의 의약품부작용보고시스템에 보고된 실제 의약품부작용 데이터들 중 대상자들의 병력과 그들이 투약한 의약품 정보를 병합하였으며, 각 의약품들은 ATC코드를 기준으로 분류하였다.
결과: 연구 결과에 따르면 4개의 아시아 국가에서 약 60% 이상의 의약품에 대한 허가 용량 용법이 비슷하였다. 그러나, 허가 용량 용법의 차이를 보인 의약품 중 대부분이 중요한 인종적 차이가 없었고, 이는 각 국가들의 지침의 차이들에 의해 야기된 것으로 판단되었다. 또한, 한정된 데이터 접근 권한과 수집된 데이터들로 인하여 보고된 의약품부작용 데이터와 승인된 의약품의 허가 용량 용법 사이의 연관성을 찾기 어려웠다. 그러나 본 연구에서는 의약품부작용 투여 전/후의 환자 상태와 의약품부작용 발생 예측 원인 등 의약품부작용 데이터 수집 시 추가 수집을 필요로 하는 정보들을 파악할 수 있었다. 더불어 실사용 증거를 기반으로 한 데이터가 규제기관에서 평가 및 의사 결정을 하는데 좋은 근거가 될 수 있음을 확인하였다.
결론: 본 연구 결과는 궁극적으로 탐색적 MRCT를 통해 동북아시아 국가들에서 약물 개발의 효율성을 가속화 할 수 있는 근거를 제시하였다. 또한, 실사용 증거를 사용한 후향적 연구를 통하여 여러 국가에서 의약품 관련 지침을 평가하고, 개선할 수 있음을 제안하고 있다. 결론적으로 동북아시아 국가 간의 협력적인 연구와 다국적 대상자를 동시 모집하여 진행하는 초기 단계의 연구들이 새로운 치료법을 필요로 하는 환자들에게 신속하고 효율적인 임상 개발을 가능하게 할 것이다. 더불어 이러한 임상 개발을 통하여 인종간의 정보를 포함한 맞춤 약물 요법을 제공할 수 있을 것이다.

목차 (Table of Contents)

• ABSTRACT i
• TABLE OF CONTENTS v
• LIST OF FIGURES vi
• LIST OF TABLES vii
• LIST OF ABBREVIATION viii
• INTRODUCTION 1
• METHODS 7
• Data collection and analysis for approved dosing regimens 7
• Data collection and analysis of adverse drug reaction data 11
• RESULTS 13
• Analysis of approved dosing regimens 13
• Analysis of adverse drug reaction data 39
• DISCUSSION 43
• CONCLUSIONS 54
• ACKNOWLEDGMENT 54
• APPENDICIES 55
• REFERENCES 64
• 국문 초록 70

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