品研究实验原始记录审核技术要求.ppt

,药品研究中GLP实验室 实验原始记录审核技术要求 龚兆龙博士 资深副总裁兼首席技术官 昭衍新药研究中心,1,新药研发过程,2,新药研发过程质量规范,GLP 历史沿革 遵从 GLP 的意义 GLP 规范基本要求 原始数据核查要点 非临床实验室常见错误 法规对 GLP 或非 GLP的要求 案例分析,内容提要,4,GLP 历史 美国,What prompted US FDA to issue GLP regulations? In the 1960s and 1970s, in addition to the “Thalidomide” story, FDA found: Selectively submitted findings Fabricated data Falsified data Discrepancies in reporting (e.g., between individual and summary data) Poor laboratory recordkeeping (resulting in inability to reconstruct study performance),GLP 历史 美国,In the 1960s and 1970s, FDA also found: No protocols, protocols written after study performance, study not performed according to protocol No one in charge of studies Sloppy laboratory practices,US FDA GLP 法规,1976 Congressional hearings GLPs proposed 1978 GLPs finalized 1979 GLPs become effective,US FDA GLP 法规,21 CFR: Code of Federal Regulations, Food Electronic Signatures,US FDA GLP Part 58 要求,Describes requirements for conducting and reporting nonclinical laboratory studies Intent: provides a framework for conducting well-controlled studies assures quality and integrity of the data facilitates study reconstruction provides overall accountability Nonclinical studies that evaluate safety must be GLP compliant,US FDA GLP 检查,FDA GLP检查过的美国国内实验室 200余家, CRO, 药厂,US FDA GLP 检查,FDA GLP检查过的美国境外实验室 40余家, CRO, 药厂,US FDA GLP 检查：MOU,8 个国家 日本 法国 德国 加拿大 意大利 瑞典 瑞士 荷兰,US FDA GLP 检查：中国GLP实验室,2009 年7月检查了三家GLP实验室 国家安评中心 (NCSED) 昭衍（JOINN) Bridge (康龙化成) 昭衍提交的试验报告获得美国FDA 认可, 用于支持美国的临床试验。,OECD GLP 规范,Developed in 1978 USFDA GLP provided the basis for OECD Revised OECD principles adopted in 1997 Primary objective similar to USFDA To ensure the generation of high quality and reliable test data related to the safety of industrial chemical substances and preparations in the framework of harmonising testing procedures for the mutual acceptance of data (MAD),OECD MAD （数据互认）,Data generated in the testing of chemicals in an OECD member country in accordance with OECD Test Guidelines and OECD Principles of GLP shall be accepted in other Member countries for purposes of assessment and other uses relating to the protection of man and the environment OECD Member Countries Australia, Austria, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Japan, Korea, Luxembourg, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Slovak Republic, Spain, Sweden, Switzerland, Turkey, United Kingdom, United States,中国GLP发展历史,1993年12月，国家科委发布了GLP（试行） 1999年10月，SDA发布GLP（试行） 2001年中国修订中华人民共和国药品管理法、 药品法实施条例，将GLP明确为法定要求 2003年9月,SFDA颁布实施GLP（二号令）280 条, 开展GLP认证检查 2007年1月 法规毒理实验强制要求GLP 2009年7月 3家在中国的GLP 实验室接受美国 FDA检查,中国GLP管理规范,药物非临床研究质量管理规范（局令第2号） 2003年9自2003年9月1日起施行 共九章45条 非临床研究质量管理规范认证标准 280条 药品注册现场核查管理规定 7章、59条、5个附件,遵从 GLP 的意义,Assures quality data and data integrity Protects the well-being of subjects in clinical trials many of whom are healthy volunteers (human safety) Ensures that a study can be completely reconstructed from archived records 对中国CRO来说，研究报告可以得到国际认可。,GLP 规范要素,What is a nonclinical laboratory? In the SFDA or USFDA regulatory world, a laboratories that conduct nonclinical studies involving test articles to develop data that will be submitted to the agency in support of an application and marketing approval,GLP 规范要素,Test Articles the SFDA-/USFDA-regulated product being tested,GLP 规范要素,Test Systems Mouse/Rat, Guinea Pig, Rabbit, Dog (Beagle), Pig, Monkey, Primate, (Chimpanzee),The ABC of GLP Regulations Definitions,Person,Individual,Partnership,Government agency,Organizational unit,Corporation,Scientific or academic establishment,GLP 规范要素 Raw Data,Laboratory worksheets Records & document Memoranda Notes Computer print-outs All communications (internal/external/sponsors),GLP 规范要素 Organization and Personnel,Education Training Experience Job description,Personnel Record,Personnel,Management,Study Director,QAU,Follow protocol Document deviations Archive,GLP 规范要素 Organization and Personnel,Review,QAU,Personnel,Study Director,Master schedule sheet Protocols Inspection records SOPs,Management,Status report,Final study report,GLP 规范要素 Facilities,Nonclinical laboratory,Receipt and storage Mixing,GLP现场核查,Process-oriented quality data as a result of proper utilization of and control over facilities, personnel and procedures Allows flexibility in laboratory operation and use of scientific judgment study directors must exert this judgment overall responsibility for technical conduct, interpretation and reporting,现场核查要点,Step 1: Inventory Documents 文件清单 Make sure necessary documents were included in the study report Protocol Protocol amendments 方案修改 Protocol deviations 方案偏离 (with explanations on possible impact to study interpretation and validity) Report (with sufficiently detailed summary and individual animal data),现场核查要点,Step 2: Identify test article 供试品 test article code or name salt form formulation purity Uniformity 均一性 Stability 稳定性 lot or batch#,现场核查要点,Step 3: The experimental design 试验设计 Studies are fluid; what is in a protocol frequently changes during the course of a study Note important dates (experimental design landmarks) experimental or dosing start date (REPORT) study initiation date (REPORT) protocol amendment date(s) (AMENDMENTS) experimental completion date/necropsy date (REPORT),现场核查要点,Step 3: The experimental design 试验设计 Note how experimental design/methods changed look at protocol amendments and deviations consider if the changes invalidated the studys objectives consider if the changes caused study to be inconsistent with stated guidelines/methods (and evaluate significance) Make sure you understand experimental design (as performed) and chronology per amendments and documented deviations,现场核查要点,Step 4: Compare documents for consistency 一致性 Do reports comply with GLP requirements on reporting for test article characteristics testing of dosing formulations for purity stability uniformity,现场核查要点,Step 4: Compare documents for consistency Make sure that data and their associated documents are consistent with one another.,现场核查要点,Step 4: Compare documents for consistency Are protocol-specified evaluations of data applied? statistical tests criteria for acceptable study, positive finding (e.g., genotoxicity tests) Does selection of highest dose comply with protocol? With referenced guideline?,现场核查要点,Step 4: Compare documents for consistency Are findings for all protocol-specified evaluations reported body weight clinical chemistry histopathology for all protocol-specified dose groups toxicokinetics,现场核查要点 Step 5: Do data seem credible? Report Raw data/Reality,现场核查要点,Step 6: Evaluation of significance of lapses 失误的评估 The big questions Did problems in study documents result in your inability to draw meaningful conclusions from the study (with respect to studys stated objective)? Did inconsistencies in this part of the submission, relative to other parts of the submission, make you have less faith in the integrity of other portions of the submission? In the conclusions of other studies?,现场核查要点,Not all lapses preclude drawing conclusions from a study mistakes can happen in performing a study in describing fact sometimes fact is not convenient The evaluation of mistakes requires an evalution of their magnitude and nature. Are errors widespread? Limited? Do errors occur in reporting of endpoints that are critical to scientific interpretation? Do errors speak for a report-specific problem or something that is a systemic problem ?,现场核查要点：职责,TESTING FACILITY MANAGEMENT: Overall laboratory management and administrative functions designates study director before study is initiated replaces study director (promptly), if necessary assures there is a quality assurance unit (QAU) assures test and control articles have been appropriately evaluated for identity, strength, purity, stability and uniformity (as applicable),现场核查要点：职责,TESTING FACILITY MANAGEMENT: (contd) assures appropriate staffing, facilities, equipment and materials are available for scheduled tests assures that staff understands the functions they are to perform assures deviations reported by QAU are promptly reported to study director,现场核查要点：职责,STUDY DIRECTOR Single point of study control has overall responsibility for: Protocol preparation technical conduct of study interpretation of results analysis of results documentation of results reporting of results Archiving,现场核查要点：职责,STUDY DIRECTOR: (contd) Protocol preparation,现场核查要点：职责,STUDY DIRECTOR: (contd) Contributors Ophthalmology Cardiology Immunology Analytical Formulation analysis Bioanalytical Statistical analysis,Specialists/Consultants Antibodies Bone marrow differential counts Specialized clinical pathology Sperm Analysis,现场核查要点：职责,STUDY DIRECTOR: (contd) Special Procedures Considerations Are there SOPs in place? Are the staff appropriately trained? Is this training documented? Are literature searches necessary? IACUC implications? Do you need to use a consultant/PI for the work?,现场核查要点：职责,STUDY DIRECTOR: (contd) Multi-Site Studies* Work (i.e. phase of a GLP study) performed at a geographically distinct site (Not a FDA GLP term) Assign a PI to ensure compliance with GLPs Will sign an “Acceptance of Responsibilities“ form Will sign a statement to this fact upon completion of the work Study director remains the single point of control and maintains responsibility for overall conduct Quality assurance of the test site *OECD requirement,现场核查要点：职责,STUDY DIRECTOR: (contd) Study Scheduling Considerations Test article availability Animal availability/ordering Housing Trained staff Analytical chemistry Clinical pathology Necropsy Reports,现场核查要点：职责,STUDY DIRECTOR: (contd) Test Article Calculations - How much will you need? When is it available? Final doses? Analytical Confirmation Storage/handling conditions Certificate of Analysis (COA), MSDS, purity, stability Is there a dose formulation?,现场核查要点：职责,STUDY DIRECTOR: (contd) Protocol Review & Approval Management SD Sponsor (if done by CRO) Scientific contributors and laboratory staff Report preparation staff QAU IACUC,现场核查要点：职责,STUDY DIRECTOR: (contd) Ovetsight of Study Conduct Observe animals and procedures Review data Communicate with scientific contributors and technical staff QA audits internal and external Interactions with contributors/ PIs Submission of samples Receipt/review of report Respond to unexpected events,现场核查要点：职责,STUDY DIRECTOR: (contd) Oversight of Study Conduct Protocol amendments - a planned change Protocol deviations not planned; impact on study must be determined SOP deviations,现场核查要点：职责,STUDY DIRECTOR: (contd) Example of Documentation Protocol/protocol amendment Protocol/SOP deviations Animal order Test article receipt/information Test article preparation procedure Dose accountability (out of range?) Study file notes Veterinary requests/approval of treatment Environmental deviations (e.g. light/dark cycle and humidity) observations of animals/procedures Data review Correspondence email, fax, letter, telephone calls Reports,现场核查要点：职责,STUDY DIRECTOR: (contd) Report Preparation,现场核查要点：职责,STUDY DIRECTOR: (contd) Archiving Protocol/amendments Raw data Documentation Specimens Final report,现场核查要点：职责,STUDY DIRECTOR: (contd) SD Responsibilities for a Final Report Data interpretation Preliminary draft audited? unaudited? Integration of toxicology, pathology, TK and other supportive data Contributing Scientist/PI reports Stopped/suspended programs GLP compliance Deviations and impact on data,现场核查要点：职责,STUDY DIRECTOR: (contd) assures that: protocol, including any changes, is approved as specified in GLPs, and is followed all experimental data, including observations of unanticipated responses of the test system, are accurately recorded and verified unforeseen circumstances, that may affect the quality and integrity of the study, are noted when they occur, and that corrective action is taken and documented,现场核查要点：职责,QUALITY ASSURANCE UNIT (QAU): Oversees GLP Compliance in laboratory responsible for monitoring each study for GLP compliance organizationally, QAU reports to test facility management independent of the personnel engaged in the direction and conduct of individual studies assures that facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the GLPs,现场核查要点：职责,QUALITY ASSURANCE UNIT (QAU): (contd) Oversees GLP compliance in laboratory keeps up-to-date records of all studies scheduled/performed with master schedule at lab maintains copies of all study protocols,现场核查要点：职责,QUALITY ASSURANCE UNIT (QAU): (contd) Inspects studies at intervals adequate to assure the integrity of the study maintains written and properly signed records at each inspection identifying date of inspection the study inspected phase or segment of study inspected person performing inspection,现场核查要点：职责,QUALITY ASSURANCE UNIT (QAU): (contd) maintains written and properly signed records at each inspection identifying findings and problems observed during inspection scheduled date for reinspection, if applicable problems must immediately be brought to attention of study director and management,现场核查要点：职责,QUALITY ASSURANCE UNIT (QAU): (contd) submits periodic status reports on each study to management and study director notes problems notes corrective actions taken determines that no deviation from approved protocols or standards operating procedures were made without proper authorization and documentation,现场核查要点：职责,QUALITY ASSURANCE UNIT (QAU): (contd) Reviews final study report to assure that: report accurately describes methods and standard operating procedures reported results accurately reflect the studys raw data Prepares and signs statements to be included with the final report specifying details on inspections,现场核查要点：职责,Facility Operations Standard operating procedures (SOP) Complete and comprehensive Up to date Sound science and practical Reagents and solutions Identity, titer/concentration, storage requirements, and expiration date Animal care and IACUC,Major issues of data audit What do we look for while auditing a GLP lab,Study Director,Facility Management,Quality Assurance,Chemistry,Pathology (Clinical and anatomical),Technical Staff,Report writing,Sponsor,Accounting,Subcontractors,非临床实验室常见错误,Study director Failure to follow protocol Most common because everything is driven by protocol. Examples: TA Stability determination Environmental conditions Exposure to test article (dosing),非临床实验室常见错误,Study director (contd) Final Report Commonly see failures to address issues that occurred during study that could affect outcomes,非临床实验室常见错误,Study director (contd) Failure to record all data and verify Formulation Dosing,非临床实验室常见错误,Study director (contd) Documentation issues Best way, protocol amendment. Must be done before action (signed by SD and also QA, management and sponsor). Second best, deviation report (deviation from protocol or SOP). Completed after-the-fact by person making the observation (signed by SD and also QA and management). Deviation is noted in study report along with description of the impact the deviation has on study integrity.,非临床实验室常见错误,Inconsistencies within a protocol or between protocol and SOP Omission of necessary information from protocol Late entries in study books Non GLP corrections Failure to sign and date entries Expired reagents,非临床实验室常见错误,Failure to issue timely protocol amendments and deviation reports Paperwork missing from study book Inconsistencies between protocol and report or raw data and report.,非临床实验室常见错误,QAU fails to authorize deviation Deviations not detected by the QAU, but should have been,非临床实验室常见错误,Transfer of data, specimens, records to archives At completion of study Not all records transferred,非临床实验室常见错误,Did not follow SOPs for required auditing Inappropriate training record keeping Equipment calibration issues Sanitation cage/room disinfectants Water system attached to cage rack,GLP or not GLP,Safety Pharmacology studies, Core/GLP, follow up studies depending on the design/non GLP Primary Pharmacodynamic/non-GLP, Secondary PD/non GLP unless contribute to the safety evaluation Bridging studies, GLP QT studies, Guidance/GLP, data not required for regulatory submission/ non GLP In Vitro, if pivotal, genotox/GLP, efficacy, MOA, metabolism/non GLP,GLP or not GLP,Studies that are not within the scope of GLP regulations Include (US domestic only): Efficacy Chemical assays for quality control Stability tests Conformance pharmacopeia standards Pharmacology and effectiveness New methodology for toxicology experimentation Exploratory studies on viruses and cell biology Mode of action, synthesis, analysis Studies covered by GMPs,GLP or not GLP,Disease Model Biologic Systems, Pharmacology, Transgenic animals, efficacy/non GLP, Carc/GLP Animal Rule, Efficacy/GLP Immunotoxicity studies, Guidance does not mention GLP, not pivotal for safety and most tests routinely not conducted according to GLP Excipients, GLP,GLP or not GLP,The Standard is GLPWhen is FDA “more likely” to accept non GLP (US domestic only)? Oncology (safety data is from published literature) Biologics (small companies, university, NIH, NCI) tissue cross reactivity studies AIDS Drugs (early days, studies done by Academicians) Botanical submissions Known class of drugs Old drugs, change of route of administration to a less hazardous exposure (bridging studies) Drugs marketed overseas, tox studies performed in US but not GLPs (anti malarial, parasitic drugs),GLP or not GLP,However, for studies submitted from overseas in support of safety assessment, the FDA most likely accept only GLP compliant data: Should be GLP, OECD guidelines accepted Japanese GLP Or countries with OECD Mutual Acceptance of Data (MAD),GLP or not GLP,If from overseas and not GLP Usually more strict Studies from non-traditional sources, non ICH countries, request inspect