法规合规：在中国注册外国药品的关键考虑因素

Mingping ZhangVice PresidentTechnicalRegulatory Consulting The proportion of global clinical trialsinitiated in China has exhibited asubstantial increase, rising from 25% in2019 to 39% in 2023. The guideline,Clinical Data Requirement ofDrug Products Marketed Abroad but Not inChinaissued by China’s Center for DrugEvaluation (CDE) of the National MedicalProducts Administration (NMPA), aimsto facilitateaccess to foreign medicalproducts to address unmet medicalneeds in China.This guideline isapplicable to two main categories: 1.The innovative chemical productsand therapeutic biological productsmarketed abroad 2.Generic domestic and foreignchemical products Regulatory review criteria for foreign medical productsmarketed outside of China For foreign medical products not marketed in China, the technical requirements for clinical trialssupporting their market entry should be formulated in accordance with established clinicalevaluation principles. These requirements should be based on a comprehensive assessment of thefollowing key steps: While the evaluation of unmet medical needs in China and ethnicity-specific sensitivity analysesare critical components in the registration process for foreign drug products, the primary emphasisremains on robust clinical data demonstrating efficacy and safety, aligning with requirements setby health authorities in other countries/regions. These foundational clinical outcomes serve as thecornerstone for regulatory assessment, complemented by China market specific and ethnicity-specificconsiderations. The pharmacokinetic (PK), efficacy, and safety datain the Chinese population are mandatory for NewDrug Application (NDA) or Marketing AuthorizationApplication (MAA) approval, barring exceptionalcircumstances. Inclusion of China in Multi-RegionalClinical Trials (MRCT) may facilitate simultaneousNDA/Biologics License Application (BLA) approval,which is generally regarded as the most cost-effective approach. In 2023, 55% of global clinicaltrials included at least 1 trial location in the Asia-Pacific (APAC) region, and the number of trialsinitiated in APAC has surpassed those initiated inthe rest of the world since 2021. Specifically, theproportion of global clinical trials initiated in Chinahas exhibited a substantial increase, rising from25% in 2019 to 39% in 2023.1The CDE typicallyadvocates for the collection of Chinese PK data priorto initiating MRCTs. Key regualtory considerations for evaluating foreign drugapplications in China According to the new guideline on MRCT (新药全球同步研发中基于多区域临床试验数据进行获益风险评估的指导原则) issued on December 13, 2024, the following critical factors should beconsidered when applying for foreign drug product registration in China: Safety considerations for the Chinese population The potential safety risks for the Chinese population may be elevated compared to other regions,particularly in the following scenarios: 1.Drugs that have demonstrated significant safety concerns in clinical trialsconducted in other regions.2.Drugs with mechanisms of action that are not well elucidated.3.Novel active ingredients without precedent products in the market. Body weight differences The Chinese population generally exhibits lower average body weight compared to the Westernpopulation. Consequently, when applying dosages established in global clinical trials to theChinese population, there may be discrepancies in drug exposure levels. These differences couldpotentially impact both safety and efficacy profiles. Genetic polymorphisms in metabolic pathways As outlined in ICH E5, the drugs metabolized via pathways subject to genetic polymorphisms (e.g.,CYP2D6, CYP2C9, CYP2C19) may exhibit altered drug exposure levels due to the differentialdistribution of metabolizer phenotypes between the Chinese and Western populations.Consequently, this could potentially impact both the safety profile and therapeutic efficacy in theChinese population. Pharmacodynamic difference For drugs that may exhibit ethnicity-specific pharmacodynamic differences (e.g.,βreceptorblocking effects, angiotensin converting enzyme inhibitory effects), it is crucial to evaluatewhether the Chinese population demonstrates altered pharmacological responses comparedto other populations. Such variations could potentially result in differential safety profiles andtherapeutic efficacy. Start Phase II study in China without separate Phase I PK study Situation A foreign pharmaceutical company was interested in conducting a Phase II study in China for anoncology asset. The sponsor asked Parexel to explore a regulatory strategy to waive the Phase I PKstudy in China. Challenges All of the clinical studies (Phase I and ongoing global Phase II) were conducted outside of China,and there was no Chinese data.To minimize the prolongation of the Phase II trial and global registration timeline, the sponsorwanted to start a Phase II study in China without the safety and PK data from Chinese patients. Solution Parexel provid