【中英对照】《药物临床试验数据现场核查要点》Boss,Are U OK?
2016/1/5 经纬传奇

     CFDA issued Key Points for On-site Verification of Drug Clinical Trial Data

     015年11月10日,国家食品药品监督管理总局发布了《药物临床试验数据现场核查要点》(2015年第228号),内容如下:On November 10, 2015, CFDA issued the KeyPoints for On-site Verification of Drug Clinical Trial Data ([2015] No.228)with the following contents:

     药物临床试验数据现场核查要点Key Points for On-siteVerification of Drug Clinical Trial Data

     一、Ⅱ、Ⅲ期临床试验、人体生物等效性(BE)/人体药代动力学(PK)试验、疫苗临床试验数据现场核查要点——通用内容I. Key points for on-site verification of thedata in phase II and III clinical trials, human bioequivalence (BE)trials/human pharmacokinetics (PK) trials and vaccine clinical trials – generalcontents1. 临床试验条件与合规性(含各方在临床试验项目中职责落实)1.Conditions and compliance of clinical trials (including responsibilitiesassumed by all parties in the clinical trial project)

     1.1* 临床试验单位承担药物临床试验的条件与合规性: 1.1* Conditions and compliance of clinicaltrials conducted by the clinical trial institutions:1.1.1 临床试验须在具有药物临床试验机构资格的医院内进行(含具有一次性临床试验机构资格认定的批件),落实临床试验条件是否支持试验项目实际的实施过程。1.1.1 Clinical trials must be conducted inthe hospitals with the qualification of drug clinical trials (including theapproval documents for one-time qualification of clinical trial institutions)and after confirming whether the clinical test conditions support the actualimplementation processes of the trial project.1.1.2 具有合法的《药物临床试验批件》。1.1.2 The clinical trial institution hasobtained the legitimate Approval Letter for Drug Clinical Trial.1.1.3 核对项目开始实施时间与国家食品药品监督管理总局《药物临床试验批件》时间相符性。1.1.3 The clinical trial institution checkswhether the project initiation time is consistent with the time of ApprovalLetter for Drug Clinical Trial issued by the CFDA.

     1.2 伦理审查批件及记录的原始性及完整性: 1.2 Originality and integrity of approvalletter for ethical review and records:1.2.1 有出席伦理审查会议的签到表和委员讨论的原始记录。1.2.1 Sign-in table of attending theethical review meeting and original record of member discussion1.2.2 委员表决票及审查结论保存完整且与伦理审批件一致。1.2.2 Members’votes and review conclusionshould be kept intact and consistent with the approval letter for ethicalreview.

     1.3 临床试验合同经费必须覆盖临床试验所有开支(含检测、受试者营养/交通费补贴、研究者观察费等)。 1.3 Clinical trial contract funds mustcover all the clinical trial expenses (including examination cost,nutrition/transportation subsidies of the subject, observation cost of theinvestigator, etc.).

     1.4 申办者/合同研究组织(CRO)按照药物临床试验管理规范(GCP)原则、 方案及合同承担相应职责的文件和记录(如合同或方案中规定的项目质量管理责任及监查、稽查相关记录等)。 1.4 Documents and records of the sponsor/contract research organization (CRO) who assumes corresponding responsibilityin accordance with the Good Clinical Practice (GCP) principles, protocol andcontract (such as records related to project quality management responsibility,monitoring and audit stipulated in the contract or protocol)

     2. 临床试验部分(以研究数据的真实完整性为关注点)2. Clinical trials (with the authenticity andintegrity of the research data as the focus)

     2.1 受试者的筛选/入组相关数据链的完整性: 2.1 Integrity of the data chain related tosubject screening/inclusion2.1.1* 申报资料的总结报告中筛选、入选和完成临床试验的例数与分中心小结表及实际临床试验例数一致,若不一致须追查例数修改的环节。2.1.1* The number of cases screened,enrolled and completing the clinical trial in the summary report of theapplication dossiers should be consistent with the number of cases recorded inthe summary table of the sub-center and actually participating in the clinicaltrial. If not, the processes of modifying the number of cases should betracked.2.1.2* 方案执行的入选、排除标准符合技术规范(如实记录体检、血尿常规、血生化、心电图等详细内容),其筛选成功率为多少?(含有证据的初筛受试者例数)。2.1.2* If the inclusion and exclusioncriteria for implementing the protocol are consistent with the technicalspecifications (faithfully record the detailed contents of physicalexamination, blood routine test, urine routine test, blood biochemical test andECG), what is the success rate of screening? (The evidenced number of subjectsinitially screened is included.)2.1.3* 受试者代码鉴认表或筛选、体检等原始记录涵盖受试者身份鉴别信息(如姓名、住院号/门诊就诊号、身份证号、联系地址和联系方式等),由此核查参加临床试验受试者的真实性。2.1.3* Because the subject codeidentification table or screening record, physical examination record and otheroriginal records cover the subject identification information (such as thename, admission number/outpatient number, ID number, contact address andcontact number, etc.), the authenticity of the subject participating in theclinical trial can be verified upon these information.2.1.4 对受试者的相关医学判断和处理必须由本机构具有执业资格的医护人员执行并记录,核查医护人员执业许可证及其参与临床试验的实际情况。2.1.4 Medical judgment and treatmentrelated to the subjects must be performed and recorded by qualified medicalstaff in the institution, and the practice license of medical staff and theiractual situations of participating in the clinical trial must be verified.2.1.5 受试者在方案规定的时间内不得重复参加临床试验。2.1.5 Subjects should not participate inthe clinical trial repeatedly within the time specified in the protocol.

     2.2 知情同意书的签署与试验过程的真实完整性: 2.2 Signing the informed consent form andthe authenticity and integrity of the trial process:2.2.1 已签署的知情同意书数量与总结报告中的筛选和入选病例数一致。2.2.1The number of signed ICF should beconsistent with the number of screened and enrolled cases in the summaryreport.2.2.2 所有知情同意书签署的内容完整、规范(含研究者电话号码,签署日期等)。2.2.2 The contents of all the ICFs signedshould be intact and standardized (containing the phone number and signaturedate of the investigator).2.2.3 知情同意签署时间不得早于伦理批准时间,记录违规例数。2.2.3 The time of signing the ICF shouldnot be earlier than the time of ethical approval, and the number of casesviolating the rules should be recorded.2.2.4* 知情同意书按规定由受试者本人或其法定代理人签署(必要时,多方核实受试者参加该项试验的实际情况)。2.2.4* The ICFs should be signed uponregulations by the subjects themselves or their legal agents. (When necessary,their actual conditions of participating in the clinical trial should beverified by multiple parties.)

     2.3 临床试验过程记录及临床检查、化验等数据的溯源: 2.3 Recording of the clinical trial processand tracing the data of clinical examinations and laboratory tests:2.3.1 临床试验的原始记录,如执行方案、病例报告表(CRF)、采血记录、接种记录、观察记录、受试者日记卡等保存完整;核查任何一项不完整、不真实的数据。2.3.1 The original records of clinicaltrials, such as the implementation protocol, case report form (CRF), bloodcollection records, vaccination records, observation records and subjects’diary cards, should be kept intact, and any one of incomplete and unreal datashould be checked.2.3.2 核查CRF记录的临床试验过程(如访视点、接种时间、采血点、观察时间等)与执行方案的一致性;核查任何一项不一致、不真实的数据。2.3.2 The consistency of the clinical trialprocess recorded in the CRF (such as the visiting points, vaccination points,blood collection points, observation time points, etc.) with the implementationprotocol and any one of incomplete and unreal data should be checked.2.3.3*核查CRF中的检查数据与检验科、影像科、心电图室、内镜室(LIS、PACS等信息系统)/等检查数据一致;核实任何一项不一致/不能溯源的数据。2.3.3* The consistency of the test data inthe CRF with the test data of the clinical laboratory, imaging department, ECGroom and endoscopy room (LIS, PACS and other information systems) and any oneof inconsistent/untraceable data should be checked.2.3.4 核查CRF中的数据和信息与住院病历(HIS)中入组、知情同意、用药医嘱、访视、病情记录等关联性记录;核实完全不能关联的受试者临床试验的实际过程。2.3.4 The consistency of the data andinformation in the CRF with the relevant data of the enrollment, informedconsent, medical instructions, visiting and medical history records and theactual clinical trial process of the completely irrelevant subjects should bechecked.2.3.5 核查门诊受试者的CRF中入组、访视、病情记录等信息与门诊病历(研究病历)的关联性(必要时,可通过医院HIS系统核查门诊就诊信息)。2.3.5 The correlation of the enrollment,visiting, medical records and other information of the outpatient subjects inthe CRF with the outpatient medical records should be checked. (When necessary,the outpatient consultation information can be checked via the HIS system ofthe hospital.)2.3.6 受试者用药应有原始记录,如受试者日记卡或医嘱或原始病历(住院/门诊 /研究病历)等;核查记录的完整性(用药时间、用药量等)及其原始性。2.3.6 The subjects should have the originalrecords before medication, such as their diary cards or medical instructions ororiginal medical records (admission/ outpatient/medical records). The integrity(medication time and doses) and originality of the records should be checked.2.3.7* CRF/研究病历中的临床检查数据与总结报告一致(2.3.3款继续核查); 落实任何一项不一致数据发生的原由。2.3.7* The consistency of the clinicaltrial data in the CRF/medical records with the summary report should be checked(with Item 2.3.3 continuously), and the reasons for any one of inconsistentdata should be determined.2.3.8 核查CRF的不良事件(AE)的记录及判断与原始病历/总结报告一致,核实并记录漏填的AE例数。2.3.8 The consistency of the records andjudgments of adverse events (AEs) in the CRF with the original medical records/summary report and the number of cases with AE who missed filling in the tableshould be checked.

     2.4 CRF中违背方案和严重不良事件(SAE)例数等关键数据: 2.4 Key data such as the number of casesviolating the protocol and the number of cases with severe adverse events (SAE)in the CRF:2.4.1核查CRF中合并用药记录与门诊/住院病历记载是否一致,核实并记录漏填的合并用药例数;若一致则核实其与总结报告是否一致。2.4.1 The consistency of the records ofcombined medication in the CRF with the outpatient/admission medical records aswell as the number of cases who are missed out and receive combined medicationshould be checked and recorded. If consistent, their consistency with thesummary report should be checked.2.4.2 核查CRF中违背方案的合并禁用药的记录与门诊/住院病历记载是否一致,核实并记录漏填合并方案禁用药的例数;若一致则核实其与总结报告是否一致。2.4.2 The consistency of the records ofcombined contraindicated medication violating the protocol in the CRF with theoutpatient/admission medical records as well as the number of cases who aremissed out and receive combined contraindicated medication should be checkedand recorded. If consistent, their consistency with the summary report shouldbe checked.2.4.3 CRF中偏离和/或违背方案相关记录和处理与实际发生例数(门诊/住院病 历)及总结报告一致;核实并记录漏填的例数。2.4.3 The consistency of the relevant recordsand handling of deviating and/or violating the protocol in the CRF with theactual number of cases (outpatient/admission medical records) and summaryreport as well as the number of cases with AE who are missed out should bechecked and recorded.2.4.4* CRF中发生的SAE处理和报告记录,与原始病历(住院病历、门诊/研究病 历)、总结报告一致;核实并记录瞒填的例数。2.4.4* The consistency of SAE handling andreport records in the CRF with the original medical records(admission/outpatient/ medical records) and summary report as well as thenumber of cases with AE who are falsely reported should be checked andrecorded.

     2.5 试验用药品/疫苗的管理过程与记录: 2.5 Management processes and records ofinvestigational drugs/vaccines:2.5.1* 试验用药品/疫苗的来源和药检具有合法性(参比制剂的合法来源证明为药检报告、药品说明书等)。2.5.1*The sources and testing ofinvestigational drugs/vaccines should be legitimate. (The legitimate sources ofthe reference products should be proved by the CoA and package inserts of thedrug, etc.)2.5.2* 试验用药品/疫苗的接收、保存、发放、使用和回收有原始记录;核实原始记录各环节的完整性和原始性。2.5.2* There should be the original recordsfor the reception, storage, distribution, use and recovery of investigationaldrugs/ vaccines. The integrity and originality of all processes in the originalrecords should be checked.2.5.3* 试验用药品/疫苗接收、保存、发放、使用、回收原始记录的数量一致, 核实并记录各环节数量的误差。2.5.3* The number of investigational drugs/vaccines received, stored, distributed, used and recovered should be consistentin the original records. The errors in the number of all processes should bechecked and recorded.2.5.4试验用药品/疫苗运输和储存过程中的温度均符合要求。2.5.4 The temperatures of investigational drugs/vaccinesduring transportation and storage should meet the requirements.2.5.5 试验用药品/疫苗批号与药检报告、总结报告等资料一致。2.5.5 The batch numbers of investigationaldrugs/vaccines should be consistent with the data such as CoA and summaryreport.

     2.6 临床试验的生物样本采集、保存、运送与交接记录: 2.6 Collection, storage, delivery andreception records of biological samples in the clinical trial:2.6.1* 生物样本采集、预处理、保存、转运过程的各环节均有原始记录;追溯各环节记录的完整性和原始性。

     2.6.1* There should be the original recordsfor the collection, pretreatment, storage and transportation of biologicalsamples. The integrity and originality of all processes in the original recordsshould be tracked. 2.6.2 血样采集时间与计划时间的变化与总结报告一致。2.6.2 The blood sample collection time andchanges of planned time should be consistent with those in the summary report.2.6.3 根据化学药品性质需进行特殊处理的生物样本采集、预处理应在方案中有规定,且原始记录与方案要求一致。2.6.3 The collection and pretreatment ofbiological samples that should be specially treated according their chemicalproperties should be prescribed in the protocol, and the original recordsshould meet the requirements of the protocol.

     3. 委托研究3.Entrusted research

     3.1 其他部门或单位进行的研究、检测 等工作,是否有委托证明材料。委托证明材料反映的委托单位、时间、项目及方案 等是否与申报资料记载一致。被委托机构 出具的报告书或图谱是否为加盖其公章的 原件。对被委托机构进行现场核查,以确 证其研究条件和研究情况。 3.1 Whether other departments orinstitutions responsible for the research and testing have the entrustingcertificates, whether the entrusted institution, time, project and protocolreflected in the entrusting certificate are consistent with those recorded inthe application dossiers and whether the report or map issued by the entrustedinstitution is the original document affixed with the official seal should bechecked. The entrusted institution is inspected on site to confirm its researchconditions and research state.4. 其他Others

     4.1* 出现下列情况,视为拒绝或逃避检查: 4.1* Any one of the conditions will beconsidered as refusing or evading from inspection:4.1.1拖延、限制、拒绝检查人员进入被检查场所或者区域的,或者限制检查时间的;4.1.1 The inspectors are withheld,restricted and refused to enter the inspected places or areas, or theinspection time is limited.4.1.2 无正当理由不提供或者规定时间内未提供与检查相关的文件、记录、票据、凭证、电子数据等材料的;4.1.2 The documents, records, bills,vouchers, electronic data and other materials related to inspection are notprovided with justified reasons or within the specified period.4.1.3 以声称相关人员不在,故意停止经营等方式欺骗、误导、逃避检查的;4.1.3 Inspectors are deceived, mislead andevaded by claiming the absence of related personnel and arbitrarydiscontinuation of the operation.4.1.4 拒绝或者限制拍摄、复印、抽样 等取证工作的;4.1.4 Photographing, photocopying, samplingand other evidencing works are refused or limited.4.1.5 其他不配合检查的情形。4.1.5 Other conditions of beingincooperative with the inspectio

     二、人体生物等效性(PK)/人体药代 动力学(PK)试验数据现场核查要点—— 专有内容II.Key points for on-site verification of the data in the human bioequivalence(BE) trials/human pharmacokinetics (PK) trials – proprietary contents[编者按:药研发仅对原文进行中英文排版工作,并调整字体大小以方便各位读者微信端/PC端阅读。]5.BE、PK生物样本检测部分(检测数据的真实完整性为重点)5.Detection of BE and PK biological samples (with the authenticity and integrityof the test data as the focus)

     5.1 具备与试验项目相适应实验室检测设备与条件: 5.1 Has the laboratory test instruments andconditions suited to test items:5.1.1 分析测试的关键实验设备、仪器应有相关维护记录。5.1.1 There should be related maintenancerecords of key laboratory equipment and instrument for analysis and testing.5.1.2* 遵循《药物I期临床试验管理指导原则》(试行), 2011年12月2日以后的试验项目须开启源计算机(采集原始数据的计算机)和工作站的稽查系统。5.1.2* Guidelines for Phase I Drug ClinicalTrial Management (Interim) should be followed. For test projects initiatedafter December 2, 2011, the audit system of the source computer (computercollecting the original data) and work station must be started.

     5.2 生物样本检测实验过程记录的真实完整性: 5.2 Authenticity and integrity of therecords of biological sample detection process:5.2.1 生物样本检测实验须有完整的原始记录(包括实验单位、人员、日期、条件及实验结果等);核实记录的完整和原始性。5.2.1 There should be complete originalrecords of testing the biological samples (including the testing institution,personnel, date, conditions and results). The completeness and originality ofthe records should be checked.5.2.2* 生物样本分析方法学确证的原始数据与总结报告一致。5.2.2* The original data validated by theanalytical method of biological samples should be consistent with those in thesummary report.5.2.3* 核查血药浓度数据与对应标准曲线计算的一致性;现场重新计算用以核实试验数据的真实性。5.2.3* The consistency of blood drugconcentrations with the calculated corresponding standard curves should bechecked. The authenticity of the test data should be checked by on-siterecalculation.

     5.3 生物样本的管理轨迹可溯源: 5.3 Traceability of management trails ofbiological samples:5.3.1* 生物样本有接收、入库、存放的原始记录,且记录完整(含样本标识、数量、来源、转运方式和条件、到达日期和到达时样本状态等信息)5.3.1* There should be the original recordsof receiving, warehousing and storing biological samples and the records shouldbe intact (contain the information like the labels, number, sources,transportation mode and conditions, arrival date and status of the samples).5.3.2 贮存的生物样本有领取、存入的原始记录。5.3.2 There should be the original recordsof receiving and storing biological samples.5.3.3 在规定期限内,该项目保存的生 物样本留样及其原始记录;核查留存生物样本的实际数量及记录的原始性。5.3.3 The retention of stored biologicalsamples and their original records of the project within the specified periodas well as the actual number of reserved biological samples and the originalityof the records should be checked.

     5.4 分析测试图谱的可溯源性: 5.4 Traceability of the map for analysisand testing:5.4.1* 图谱上的文件编码/测试样本编码与受试者生物样本编码的对应关系能够追溯;核实和记录不可追溯的环节。5.4.1* The corresponding relationshipbetween document codes/test sample codes on the map and biological sample codesof the subjects can be traced back. Untraceable processes should be checked andrecorded.5.4.2 所有纸质图谱包含完整的信息(进样时间、峰高/峰面积、血药浓度等);核实和记录不完整的信息。5.4.2 All the hard-copy maps containcomplete information (injection time, peak height/area, blood drugconcentration, etc.). Incomplete information should be checked and recorded. 5.4.3*核查未知样本、方法学验证样本及随行标准曲线、QC样本的图谱,并在源计算机溯源,核对其与工作站电子图谱的一致性;记录检查数量以及不一致和不可溯源的数量。5.4.3* The maps of unknown samples, samplesfor method validation, accompanying standard curves and QC samples should bechecked and traced on the source computer. The consistency of the maps withelectronic maps of the work stations should be checked. The testing,inconsistent and untraceable number should be recorded.5.4.4* 核查未知样本、随行标曲、QC样本图谱其进样/采集时间与文件编码顺序、试验时间顺序的对应一致性;追踪和记录所有不一致的数据。5.4.4* The corresponding consistency of themaps of unknown samples, accompanying standard curves and QC samples and theirinjection/collection time with the document coding order and test time sequenceshould be checked. All the inconsistent data should be tracked and recorded.5.4.5* 纸质图谱数据与总结报告一致性,记录不一致数量。5.4.5* The hard-copy map data should beconsistent with those in the summary report. The inconsistent number should berecorded.

     5.5* 核查并记录影响Cmax、AUC等BE评价数据手动积分。 5.5* Check and record the manual integralsaffecting Cmax, AUC and other BE evaluation data.

     5.6 复测生物样本应有复测数量、复测原因、采用数据的说明。 5.6 There should be instructions forretesting number, retesting reasons and adopted data of retested biologicalsamples.

     5.7* 血药浓度/药代动力学/生物等效性的分析计算数据及结果在相应的软件上可重现,且与总结报告一致。 5.7* The data and results of analyzing andcalculating blood drug concentration/ pharmacokinetics/bioequivalence can bereproduced in the corresponding software, and are consistent with the summaryreport.

     三、Ⅱ、Ⅲ期临床试验数据和疫苗临 床试验数据现场核查要点——专有内容III.Key points for on-site verification of the data in phase II and III clinicaltrials and vaccine clinical trials – proprietary contents

     6.Ⅱ、Ⅲ期临床试验/疫苗临床试验部分(以数据库的真实性为重点)6.Phase II and III clinical trials and vaccine clinical trials (with theauthenticity of the database as the focus)

     6.1 核查原始数据、统计分析和总结报告与锁定的数据库一致性: 6.1 Check the consistency of original data,statistical analysis and summary report with locked database:6.1.1* 数据库锁定后是否有修改及修改说明;核实和记录无说明擅自修改的数据。6.1.1* Whether there are modifications andinstructions for modifications after locking the database should be checked.The nonarbitrarily modified data should be checked and recorded.6.1.2* 锁定数据库的入组、完成例数与实际发生的入组、完成例数对应一致;核实和记录不一致的例数。6.1.2* The number of cases who are enrolledand complete the study in the locked database should be corresponding to andconsistent with the actual number of cases. The inconsistent number of casesshould be checked and recorded.6.1.3* 核查锁定数据库与CRF和原始病历记录的主要疗效指标及安全性指标一致性(如有修改需进一步核查疑问表的修改记录);记录检查例数和擅自修改的数据。6.1.3* The consistency of the lockeddatabase with the primary efficacy indicator and safety indicator recorded inthe CRF and original medical records should be checked. (If modified, themodified records of the questioning table should be further checked.) The casenumber and arbitrarily modified data should be recorded.6.1.4 核对统计报告例数与锁定数据库的一致性。6.1.4 The clinical trial institution checkswhether the case number in the statistical report is consistent with that inthe locked database.6.1.5 核对总结报告例数与锁定数据库的一致性。6.1.5 The clinical trial institution checkswhether the case number in the summary report is consistent with that in thelocked database.(信息来源:药研发)

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