| [Purpose]The main content of drug Phase ? clinical trial is to evaluate safety profiles to new drugs and its pharmacodynamic properties,and provide guidance to clinical trials of next phases.Phase ? clinical trials have a high risk because a new compound is applied to the human body in these trials for the first time.Besides,with a large number of healthy participants,a professional research team is needed to conduct trails and monitor subjects in the ward,which induces need of unique mangement.Previous researches used to focus on a certain aspect or part of quality management of Phase ? clinical trials.There were few systematic quality management research of clinical trials from macro perspectives,especially empirical researches under macro and micro perspectives.Based on the foundation of literature review as well as laws and regulation summarization,and through methods of expert consultation,cross-sectional study,case study and mathematical analysis,this research aimed to construct a quality management model for Phase ? drug clinical trials at the macro level and a quality management evaluation index system for Phase ? drug clinical trials at the micro level,and to provide suggestion for quality enhancement of Phase ? drug clinical trials,which is expected to fill gaps of research on drug clinical trial quality management and fullfil urgent needs of mordern drug research and development(such as development of Covid-19 vaccine).[Methods]Data of clinical trials was collected from Clinical Trials of the United States(Clinical Trials.gov)and clinical trial registration and information disclosure platform of China(www.chinadrugtrials.org.cn).Research period was set from March 2013 to September2018.Literature research was combined to understand and summarize the characteristics,regulations,quality management issues and countermeasures of Phase ? clinical trials.According to literature review,and based on theory of total quality management and stakeholder,structured questionnaires were produced using Likert scale(better quality with higher scale).The quality of Phase ? clinical trials was evaluated by five aspects of general quality,rights protection of subject,construction of quality assurance system,construction and management of trial wards,risk management etc.Five-scale Likert method was used to investigate the influence of five management factors,including government regulation,industrial management,medical institutions management,sponsor/CRO management and study team management,on quality of Phase ? clinical trials.Data from 604 personnel related to Phase ? clinical trials were collected using this questionnaire.Descriptive analysis,correlation anaysis as well as ordinal ploytomous Logistic regression regarding Phase ? clinical trial quality and five categories of its influential factors were conducted by SPSS 19.0.Structural Equation Modelling(SEM)for Phase ? clinical trial quality and five categories of its influential factors was constructed by Mplus7.4.The index system of quality management of Phase ? clinical trials was constructed by tworound Delphi method.An empirical study on the quality assessment of Phase ? clinical trials was conducted in 22 medical institutions.Spearman correlation analysis on comprehensive scoring,comprehensive index and TOPSIS was conducted to generate coefficients(r)and p values,and to evaluate the feasibility of index system.A case study was conducted in Peking University First Hospital,to analysis characters of Phase ? clinical quality management,and to lay foundation for policy suggestions.[Results]Current situation of Phase ? drug clinical trials: compared with EU countries,Japan,United States and global average level,the number of Phase ? clinical trials in China is less(China 1458 items,EU countries 2741 items,Japan 344 items,and United States 6388 items).Percetage of blind method usage is relatively low(China 28%,EU countries 37%,Japan 42%,United States 36%,and global average level 38%).Percentage of trials adopted radomized protocol is relatively high(China 62%,EU countries 45%,Japan 42%,United States 42%,and global average level 43%).Percentage of trials recruiting health volunteers is relatively high(China 56%,EU countries 47%,Japan 33%,United States 32%,and global average level 37%).And nealy all sponsors of Phase ? clinical trials in China are enterprises(China96%,EU countries 60%,Japan 59%,United States 57%,and global average level 42%).Framework of quality management model of Phase ? clinical trials.By summarizing current situation of Phase ? drug clinical trials,and related laws and regulations as well as law enforcements,we preliminarily obtained element lists of Phase ? drug clinical trial quality management:(1)at macro level,stakeholders of Phase ? drug clinical trial quality management should include government regulation,industrial management,medical institutions management,sponsor/CRO management and study team management.(2)at micro level,main content of Phase ? drug clinical trial quality management should include construction and management of Phase ? clinical laboratory,quality assurance system of sponsors and investigators,trial design and risk management in the process of the trial,drafting and implementation of codes and SOPs.Based on expert consultation,a framework of Phase ? drug clinical trials quality management model was constructed including elements mentioned above.Quality management model of Phase ? clinical trials.Through questionnaire investigation,the overall quality score of Phase ? clinical trials was 3.81 out of 5,which was between good and fine.The score of the risk management of trial implementation was relatively low,and the score of the protection of subjects' rights and interests was the highest.Based on descrptive analysis,single and multiple regression analysis,through exploratory factor analysis,conformatory factor analysis and structural equation modeling,a management model for Phase ? clinical quality was established.The adaptation index of structural equation modeling was good: RMSEA=0.057,TLI=0.971,CFI=0.974.Except study team management(?=0.055,P=0.468),government regulation(?=0.249,P<0.001),industry management(?=0.344,P<0.001),medical institutions management(?=0.203,P=0.023)and sponsor/CRO management(?=-0.253,P=0.005)significantly affect the quality of phase I clinical trials,which is in line with results of ordinal ploytomous Logistic regression.Besides,the structural equation modeling revealed that influencing factors that affected Phase ? clinical trial quality also interacted with each other: government regulation interacted with industrial management,medical institute management,study team management and sponsor/CRO management(?=0.664,0.661,0.569,0.560,p<0.001);medical institute management interacted with industrial management,study team management and sponsor/CRO management(?=0.729,0.766,0.790,p<0.001);industrial management interacted with study team management and sponsor/CRO management(?=0.644,0.663,p<0.001);study team management interacted with sponsor/CRO management(?=0.777,p<0.001).Index system of Phase ? drug clinical trials.An index system was obtianed through 2rounds Delphi method,which includes 4 primary measures: construction and management of Phase ? clinical laboratory,quality assurance system,trial design and risk management,trial process management,15 secondary measures and 73 tertiary measures.Recovery rate of two rounds of questionnaire were both 100%.Authority coefficient were above 0.7 for primary and secondary measures.Coordination coefficient was 0.387(P<0.05).An empirical study including 22 hospitals was conducted using the index system.19 hospitals obtained good scores(above 4 out of 5).The rest 3 hospital's scores were close to good(3.88-3.99 out of 5).The scores of sponsor/CRO quality assurance and risk management were relatively low(lower then 4 out of 5).The evaluation results were analyzed by comprehensive scoring,comprehensive index and TOPSIS.Correlation coefficients between comprehensive scoring and comprehensive index,comprehensive scoring and TOPSIS were 0.954 and 0.994 respectively,which revealed decent consistency.Case study on improving quality management of Phase ? drug clinical trials: the results revealed that positive effects of flat organizational structure,outstanding and interdisciplinary research team,rigorous and efficient ethical evaluation as well as effective risk control on quality management of Phase ? drug clinical trials.[Conclusions]1.For the first time,this study constructed a Phase ? clinical trials quality management model characterized by multi-stakeholder participation and cooperation or multi-party integrated management.Factors of government regulation,industry management and medical institution management positively affect the quality of Phase ? drug clinical trials.The impact of study team management was not statistically significant,which indicated study team may not exert enough influence during the trial.The impact of sponsor/CRO negatively affect the quality of Phase ? drug clinical trials,which indicated the lack of responsibility of sponsor/CRO.These results can provide a basis for the macro management of the quality of Phase ? clinical trials.2.A index system for Phase ? drug clinical trial quality management,which cover key content of Phase ? clinical trial,with good reliability and validity,was established to serve as an evaluation tool for Phase ? drug clinical trial quality management.It was revealed in this study that sponsor/CRO quality assurance and risk management need to be improved in Phase ? clinical trials.3.Suggestions for enhance the quality management of Phase ? clinical trials: Frist,further measures should be taken to strengthen the government's leading role in the construction of clinical research quality supervision system.It is recommended to set up a special working group to establish an effective coordination mechanism and jointly promote the high-quality and high-level development of domestic Phase ? clinical trials.Regulations and guidance should be revised as soon as possible in accordance with the newly promulgated Drug Administration Law.Meanwhile,it is recommended to explore the establishment of an efficient inspection mode,incorporate the sponsor/CRO into regulation system of drug clinical trials.Second,it is necessary to encourage and promote industry organizations to actively participate in the construction of Phase ? clinical trials quality system.They can assist the government in developing technical guidelines of relevant clinical trials,constructing subject's recruitment databases,offering trainings and qualifications for various technical personnel,and establishing regional ethics centers.Besides,it is also acceptable to be entrusted as the third party to undertake the audit and inspection of the Phase ? clinical trials.Third,medical institutions should correctly handle the development direction of Phase ? clinical trials,focus on construction of Phase ? clinical trial quality system,and pay higher attention to trials' quality demand.[Innovation and Deficiency]We conducted a comprehensive analysis regarding current situation of Phase ? clinical trials.Combing with analysis of related regulation rules and actions,management elements of Phase ? clinical trials were summarized.This is the first study which built the quality management tools and models of Phase ? clinical trials,providing micro and macro evidence basis for total quality management and continuously quality improvement of Phase ? clinical trials.There might be limitations in the promotion of results in this research to other countries or regions since the respondents were only from Chinese clinical trial institutions. |
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