关于执行“食药监安函[2004]114号文件“的反思

2004年,国家药品认证管理中心按照SFDA安全监管司的工作部署,启动了药物临床试验机构资格认定的现场检查工作。同年8月13日,安全监管司下发食药监安函【2004】114号文件(以下简称114号文件),要求在申请药物临床试验机构资格认定中的I期药物临床试验研究机构执行。管理部门做出这种决定,目的是确保I期药物临床试验研究数据真实、完整、精确。但是,由于我们向申请I期药物临床试验的医疗单位宣传力度不够,导致文件规定的执行极不通畅。1贯彻114号文件程序不明了从该文发布至今,全国已经通过资格认定现场检查的I期临床试验研究室共119家;已…     

药物临床试验数据核查临床部分常见问题的原因分析及控制措施

自国家食品药品监督管理总局发布《关于开展药物临床试验数据自查核查工作的公告》(2015年第117号)以来,药物临床试验数据核查取得了阶段性成果。本文对2015年7月至2017年6月在药物临床试验数据核查中发现的临床部分常见问题进行了原因分析并提出相关控制措施,包括临床试验过程记录及临床检验检查等数据溯源、方案执行、试验用药品管理、安全性数据记录和报告、受试者筛选/入组和知情同意书签署等。     

药物临床试验的质量问题分析

目的研究药物临床试验中存在的质量问题,以确保临床试验的伦理性和科学性。方法通过查阅机构临床试验资料,分析本机构2011年以来承担的Ⅱ~Ⅳ期药物临床试验项目中的质量问题。结果对157个药物临床试验进行问题分析后,获得研究者培训情况、监查频率执行情况、标准操作规程的更新3个因素对知情同意书亲笔签名情况、数据的可溯源性、纳入排除标准的遵守情况、不良事件/严重不良事件的记录处理和报告、研究病历和病例报告表数据的一致性等质量问题的影响的详细数据。结论药物临床试验实践过程中还存在问题,建立完善的质量保证体系,加强过程管理对解决这些问题具有重要意义。     

儿童药物临床试验项目质控中的常见问题与对策

目的:在药物临床试验中,应保障儿童受试者的合法权益和生命安全,确保试验记录和报告数据准确、完整、可信.方法:收集无锡市儿童医院药物临床试验机构、自2018年以来所有项目的质控报告,将报告中记录的问题进行分类汇总,分析问题原因,提出解决方法.结果:儿童药物临床试验在知情同意过程、试验方案执行、试验记录、原始资料收集、检查...     

2020版《药物临床试验质量管理规范》实施后药物临床试验数据现场核查的要点与浅析

目的:梳理既往接受国家药品监督管理局食品药品审核查验中心(Center for Food and Drug Inspection of NMPA,CFDI)临床试验数据的现场核查情况,分析和探讨2020版《药物临床试验质量管理规范》(Good Clinic Practice, GCP)实施后,药物临床试验数据现场核查常见问题的关注点及要求,以期为临床试验的实施和管理提供参考。方法:收集本院自2015年7月22日以来接受CFDI数据现场核查的不合格情况,共计21个项目接受临床试验核查,不合格项135条。针对既往不合格项中的常见问题,分析2020版GCP和现场核查的关注点及要求。结果:既往不合格项主要集中在过程记录及检查检验数据溯源、方案执行、安全性事件记录、试验用药品的管理与记录、生物样品流通管理、相关数据链的完整性等方面。2020版GCP与现场核查要点对于临床试验数据现场核查常见问题与既往要求有较大差异。结论:在新形势下,需改变既往观念和规则,根据2020版GCP和药物临床试验数据现场核查的关注点及要求开展药物临床试验。     

临床试验中科室工作质量管理的思考

我国临床试验机构在人员培训、标准操作规程建立、质量控制等方面工作中已经取得了一定的成效,但研究者对药物临床试验质量管理规范(GCP)的理解、对临床试验方案的执行以及受试者对临床试验过程的知情等环节仍存在不少问题。本文对我国临床试验中科室质量管理存在的问题做一概述,并提出相应的建议。     

对我国药物临床试验设立独立的伦理委员会问题的探讨

按照药物临床试验质量管理规范（Good Clinical Practice，GCP）以及《赫尔辛基宣言》的要求，临床试验机构必须建立伦理委员会以充分保障受试者的个人权益，确保临床试验的科学性和可靠性。伦理委员会的根本作用是最大限度地保护受试者的权利和尊严，避免其遭受不必要的损害。     

如何保障药物临床试验机构高效有序运行

药物临床试验机构是进行药物临床试验的主要执行单位,药物临床试验机构的规范化管理及高效有序运行对确保高质量完成新药的临床试验具有重要作用。结合湖北省中医院药物临床试验机构建设情况、药物临床试验机构资格认定的准备以及药物临床试验机构日常管理的实际情况,试述如何保障药物临床试验机构高效有序运行,以期为国内同行提供参考。     

医疗机构药物临床试验信息化操作模式的设计与实现

目的:利用计算机网络技术,实现医疗机构药物临床试验信息化管理。方法:在医院信息系统基础上研发药物临床试验专用操作模块,实施信息化的操作模式并评价其效果。结果与结论:在医院信息系统中成功嵌入免费医嘱管理、试验药物管理和机构监管模块,研究者可以在系统中进行免费检查检验、开处方以及免费药物发放的操作,机构可以通过系统实现对临床试验的过程监控。使用该管理模式后,加快了试验的开展,住院受试者的血常规报告反馈时间由1d缩短至1h,核磁共振报告反馈时间由2d缩短至1d。该模式极大地方便了机构对各临床试验项目进行药物管理、过程监管、数据溯源和数据统计等工作,提高了临床试验的安全性和数据的准确性,使临床试验质量管理更科学。     

生物样本管理系统在药物Ⅰ期临床试验样本管理中的应用

药物Ⅰ期临床试验研究的可靠性有赖于试验中的生物样本质量。本研究通过设置自定义编码规则、设计导入模板、注册样本源与样本、设计打印二维码等,对生物样本管理系统(BIMS)进行应用开发,实现了药物Ⅰ期临床试验样本系统流程化管理。通过与纸质系统以及现存数据管理系统进行比较,发现BIMS的应用能进一步提高标准化操作的效率和准确性,改善临床试验质量,并且有利于试验机构的监管。     

Comparative content evaluation of the de Haen and Drugdex drug information systems

The Missouri evaluation protocol was used for comparing the contents of the Drugdex and de Haen drug information systems. Criteria for evaluating (1) general information content and (2) content of drug-drug interactions are given in the Missouri protocol. To check the two drug information systems for content, 113 sample drugs were randomly selected to represent all pharmacologic-therapeutic categories of the American Hospital Formulary Service. A list of 215 sample drug-drug interactions was randomly selected from Hansten's Drug Interactions. Each system was then search, applying each general content criterion and drug interaction criterion to each sample drug and sample interaction, respectively. Raw data were transformed into the Missouri protocol's seven weighted variables, and aggregate scores were obtained by summing the weighted scores for the variables. All scoring measurements were done by one investigator. Both raw (unweighted) and weighted scores were analyzed. Aggregate scores showed no significant differences between Drugdex and de Haen for either general information content or content of drug-drug interactions. However, analysis of raw data contradicted these results by showing differences between systems for several variables. The de Haen system included general information on a greater percentage of the sample drugs, but Drugdex covered more information criteria per drug. Drugdex contained a greater percentage of the sample drug-drug interactions, but de Haen covered more criteria for a listed interaction. The results of this study suggest that neither Drugdex nor the de Haen system can be recommended for use in lieu of the other. The Missouri protocol has flaws that preclude its routine use for comparative evaluation of drug information systems.     

Clinical trial simulation: a tool for understanding study failures and preventing them

Execution models describe protocol deviations from a specified study design. When a clinical trial is planned, it is generally supposed that it will be executed according to a specific protocol that defines all aspects of the experimental design, from its beginning to its completion. Adherence to the protocol will allow estimation of the treatment outcome (safety and efficacy) with sufficient statistical power, or at least that is what is assumed. In reality, however, deviations from the protocol may lead to failure of the study to achieve its stated aims. In anticipation of protocol deviations that contribute to inflated residual variability and decreased study statistical power, trial designers tend to overpower studies in a rather arbitrary way. It is difficult to estimate quantitatively the consequences of one protocol deviation on statistical study power and, a fortiori, it is almost impossible to do it for a combination of protocol deviations. One way to study the consequences of model deviations is by using modelling and simulation techniques, and more specifically longitudinal stochastic models that can describe individual behaviours. Thus, execution models are powerful tools for identifying weaknesses or limitations in a proposed study design, which may be anticipated, avoided or resolved in order to increase robustness of the study design prior to implementation of the actual clinical study. As such, they are an integral component of clinical trial simulation and an essential tool in clinical trial design.     

The problem of protocol driven costs in pharmacoeconomic analysis.

The increasing number of economic evaluations of healthcare interventions and of drug therapies in particular has been well documented. Surveys of the quality of studies have demonstrated that standards of conduct of such studies have not similarly increased. Concerns over the standards have led to increased calls that economic analyses be more closely linked to randomised controlled clinical trials (RCT). Seven potential threats to the external validity of results limit the generalisability of studies based on RCTs. One such threat is the existence of protocol driven costs. There are two main types of protocol driven costs. Protocol prescribed costs arise as a result of resource use mandated by the clinical trial design. Protocol derived costs occur when increased clinical investigations mandated by trial protocols lead to atypical disease management. Methods to control for protocol driven costs within pharmacoeconomic study designs are available. Modelling studies can be based on data within clinical trials combined with observational data representing more typical resource use. The adoption of pragmatic clinical trial designs provide greater external validity though reduced internal validity. Refinements to explanatory clinical trials can also lead to reduced protocol driven costs. The extent that current studies control for such costs is unclear due to the lack of transparency in the reporting of study methods. A review of published studies found little consideration of protocol driven costs although in several studies there was evidence of their existence. Future studies conducted alongside RCTs should explicitly address how the issue of protocol driven costs was handled within the study framework.     

医院药学计算机网络系统现状与展望

医院药学计算机网络管理是医院管理信息系统（HMIS）的重要组成部分，HMIS主要采用3＋以太网和NOVELL以太网，以NOVELL网为主，体系结构以微机网络＋文件服务器系统为主。传统的小型数据库管理系统如dBase、Foxbase、FoxPro等已越来越不能适应复杂的HMIS的需要，但MsSQLServer等大型数据库是一种企业级关系型数据库，能很好地实现网络计算.将是今后网络的发展方向。     

Use of computerized systems in clinical research: A regulatory perspective

Electronic source data and documentation from clinical investigations should be attributable, legible, contemporaneous, original and accurate. 21 Code of Federal Regulations (CFR) Part 11 provides acceptance criteria for electronic records, signatures, and handwritten signatures executed to electronic records. All study protocols should identify each step at which a computerized system will be used to create, modify, maintain, archive, retrieve, or transmit source data. Standard operating procedures and controls should be established when using computerized systems to create, modify, maintain, or transmit electronic records, and when collecting source data at clinical trial sites. Access must be limited to authorized individuals. Computer generated, time-stamped electronic audits trails should be undertaken to track changes to electronic source documentation. Controls should be established to ensure that the system’s date and time are correct. Procedures and controls should be put in place to prevent the altering, browsing, querying, or reporting of data via external software applications that do not enter through the protective system software. Prompts, flags, or other help features should be incorporated in a computerized system to encourage consistent use of clinical terminology. Individuals should have training necessary to perform their assigned tasks.     

Introduction of diffusing wave spectroscopy to study self-emulsifying drug delivery systems with respect to liquid filling of capsules

The rheology of self-emulsifying drug delivery systems (SEDDS) is not thoroughly characterized these days. Since mechanical rheometers are often not well suited to study this kind of systems, there is need for novel physical methods. Several new optical techniques based on microrheology have recently made significant progress. We apply for the first time a specific microrheological technique called diffusing wave spectroscopy (DWS) to study different SEDDS. The obtained data were then correlated with the dosing precision of automated capsule filling. As a result, the dynamic viscosities obtained from microrheology were in accordance with data from capillary viscosimetry. The DWS measurements revealed that all formulations had a clearly measurable storage modulus at frequencies >200 rad/s. Thus, all samples were low-viscous, while exhibiting non-Newtonian flow behavior. Obtained values of storage and loss modulus were then successfully correlated with the weight variability of capsules that were filled on a machine. In conclusion, the DWS technique enabled rheological analysis of self-emulsifying systems in a broad frequency range. The good data correlation with a capsule quality attribute was especially promising, since microrheological techniques are typically contact-free. Thus, they have a high potential in a quality by design framework of formulation development and production.     

Pulmonary drug delivery systems for antimicrobial agents: facts and myths

Inhaled antimicrobial agents are used for the treatment of respiratory tract infections due to Gram-negative bacteria, mainly Pseudomonas aeruginosa. The effectiveness of the inhaled antimicrobial therapy is believed to correlate with the delivery system used. The objective of this review was to search for data supporting differentiation in clinical effectiveness between systems used for pulmonary delivery of antibiotics, including delivery using disposable nebulisers and oxygen flow. Published studies in peer-reviewed journals comparing the effectiveness of pulmonary drug delivery systems for antimicrobial agents were retrieved. The studies found were either in vitro or Phase I and Phase II clinical studies. Differences in in vitro parameters may affect the in vivo efficacy of the devices, and in vivo differences may imply differences in clinical effectiveness. The main difference between newer and older devices is the time needed for antibiotic delivery. Interpretation and association with clinical effectiveness is difficult. In conclusion, Phase III clinical trials comparing the clinical effectiveness of delivery systems, including delivery using a hospital's oxygen flow and disposable nebulisers, do not exist. Cost is an important parameter, which may be counterbalanced in cystic fibrosis patients by a better quality of life and a greater adherence to treatment.     

Pharmacist clinical intervention program

Our efforts have helped us demonstrate the positive impact of pharmaceutical care for patients. Our experience with the Clinical Notes section of our computer system leads us to recommend that such capabilities be sought in all pharmacy computer systems. A significant advantage to avoiding paper-based systems for documenting and collecting information relevant to clinical interventions, ADRs, DUE data, and patient outcomes has been proven in our institution. Various ways to categorize intervention data have been reported in the literature. We recommend clinical intervention categories be based on the eight categories of drug misadventuring so that data from different hospitals can be tabulated or compared. The success of our system is that it is one system rather than many systems. The importance of pharmacist documentation demands that it be simple, efficient, and painless, or it will be nonexistent.     

Intravenous thrombolysis in acute ischaemic stroke: optimising its use in routine clinical practice

Stroke is a common and important medical problem. Intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator; rtPA) is the only available direct treatment that reduces neurological injury following ischaemic stroke. Strong efficacy data from randomised, controlled trials support the use of intravenous thrombolysis to improve outcomes for patients with acute ischaemic stroke. Numerous studies have provided effectiveness data that demonstrate that intravenous thrombolytic therapy can be given safely outside clinical trial settings. However, effectiveness studies have demonstrated that intravenous thrombolytic therapy is often given despite protocol violations when it is prescribed in routine clinical practice. Protocol violations must be avoided because they are associated with adverse events including higher mortality and increased haemorrhagic complications. Although thrombolytic therapy with alteplase is currently being used in only <10% of patients with acute ischaemic stroke, recent studies demonstrate that quality management efforts can improve both the absolute rate of use as well as the proficiency with which alteplase is administered. Given the complexities inherent in prescribing thrombolysis for patients with acute ischaemic stroke, alteplase should be used by clinicians who are experienced in the diagnosis and management of stroke, working in medical centres that have systems in place to ensure that alteplase is given without protocol violations.