1、1新藥研發過程新藥研發過程2新藥研發過程質量規范新藥研發過程質量規范GLP 歷史沿革歷史沿革 遵從遵從 GLP 的意義的意義GLP 規范基本要求規范基本要求原始數據核查要點原始數據核查要點 非臨床實驗室常見錯誤非臨床實驗室常見錯誤法規對法規對 GLP 或非或非 GLP的要求的要求案例分析案例分析內容提要內容提要4GLP 歷史歷史 美國美國What prompted US FDA to issue GLP regulations?In the 1960s and 1970s, in addition to the “Thalidomide” story, FDA found: Selective

2、ly 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 歷史歷史 美國美國In the 1960s and 1970s, FDA also found: No protocols, protocols written afte

3、r study performance, study not performed according to protocol No one in charge of studies Sloppy laboratory practicesUS FDA GLP 法規法規1976Congressional hearings GLPs proposed1978 GLPs finalized1979 GLPs become effectiveUS FDA GLP 法規法規 21 CFR: Code of Federal Regulations, Food & Drug Administratio

4、n. 21 CFR Part 58: Good Laboratory Practices for Nonclinical Laboratory Studies 21 CFR Part 11: Electronic Records; Electronic SignaturesUS FDA GLP Part 58 要求要求 Describes requirements for conducting and reporting nonclinical laboratory studies Intent: provides a framework for conducting well-control

5、led studies assures quality and integrity of the data facilitates study reconstruction provides overall accountability Nonclinical studies that evaluate safety must be GLP compliantUS FDA GLP 檢查檢查FDA GLP檢查過的美國國內實驗室檢查過的美國國內實驗室200余家余家, CRO, 藥廠藥廠US FDA GLP 檢查檢查FDA GLP檢查過的美國境外實驗室檢查過的美國境外實驗室40余家余家, CRO,

6、藥廠藥廠US FDA GLP 檢查：檢查：MOU8 個國家個國家日本日本法國法國德國德國加拿大加拿大意大利意大利瑞典瑞典瑞士瑞士荷蘭荷蘭US FDA GLP 檢查：中國檢查：中國GLP實驗室實驗室 2009 年年7月檢查了三家月檢查了三家GLP實驗室實驗室 國家安評中心國家安評中心 (NCSED) 昭衍（昭衍（JOINN) Bridge (康龍化成康龍化成) 昭衍提交的試驗報告獲得美國昭衍提交的試驗報告獲得美國FDA認可認可, 用于支持美國的臨床試驗。用于支持美國的臨床試驗。OECD GLP 規范規范 Developed in 1978 USFDA GLP provided the basis

7、 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 o

8、f data (MAD)OECD MAD （數據互認）（數據互認） 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 en

9、vironment 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,

10、 United Kingdom, United States中國中國GLP發展歷史發展歷史 1993年年12月，國家科委發布了月，國家科委發布了GLP（試行）（試行） 1999年年10月，月，SDA發布發布GLP（試行）（試行） 2001年中國修訂年中國修訂中華人民共和國藥品管理法中華人民共和國藥品管理法、 藥品法實施條例藥品法實施條例，將，將GLP明確為法定要求明確為法定要求 2003年年9月月,SFDA頒布實施頒布實施GLP（二號令）（二號令）280 條條, 開展開展GLP認證檢查認證檢查 2007年年1月月 法規毒理實驗強制要求法規毒理實驗強制要求GLP 2009年年7月月 3家在中國的

11、家在中國的GLP 實驗室接受美國實驗室接受美國FDA檢查檢查中國中國GLP管理規范管理規范藥物非臨床研究質量管理規范（局令第藥物非臨床研究質量管理規范（局令第2號）號）2003年年9自自2003年年9月月1日起施行日起施行 共九章共九章45條條 非臨床研究質量管理規范認證標準非臨床研究質量管理規范認證標準280條條 藥品注冊現場核查管理規定藥品注冊現場核查管理規定7章、章、59條、條、5個附件個附件遵從遵從 GLP 的意義的意義 Assures quality data and data integrity Protects the well-being of subjects in clin

12、ical trials many of whom are healthy volunteers (human safety) Ensures that a study can be completely reconstructed from archived records 對中國對中國CRO來說，研究報告可以得到國際來說，研究報告可以得到國際認可。認可。GLP 規范要素規范要素What is a nonclinical laboratory? In the SFDA or USFDA regulatory world, a laboratories that conduct nonclini

13、cal studies involving test articles to develop data that will be submitted to the agency in support of an application and marketing approvalGLP 規范要素規范要素Test Articles the SFDA-/USFDA-regulated product being testedGLP 規范要素規范要素 Test Systems Mouse/Rat, Guinea Pig, Rabbit, Dog (Beagle), Pig, Monkey, Prim

14、ate, (Chimpanzee)The ABC of GLP Regulations DefinitionsPersonIndividualPartnershipGovernment agencyOrganizational unitCorporationScientific or academic establishmentGLP 規范要素規范要素Raw Data Laboratory worksheets Records & document Memoranda Notes Computer print-outs All communications (internal/exte

15、rnal/sponsors)GLP 規范要素規范要素Organization and PersonnelEducationTrainingExperienceJob descriptionPersonnel RecordPersonnelManagementStudy DirectorQAUFollow protocolDocument deviationsArchiveGLP 規范要素規范要素Organization and PersonnelReviewQAUPersonnelStudy DirectorMaster schedule sheetProtocolsInspection re

16、cordsSOPsManagementStatus reportFinal study reportGLP 規范要素規范要素FacilitiesNonclinical laboratoryReceipt and storageMixingGLP現場核查現場核查Process-oriented quality data as a result of proper utilization of and control over facilities, personnel and proceduresAllows flexibility in laboratory operation and use

17、 of scientific judgment study directors must exert this judgment overall responsibility for technical conduct, interpretation and reporting現場核查要點現場核查要點Step 1: Inventory Documents 文件清單文件清單 Make sure necessary documents were included in the study report Protocol Protocol amendments 方案修改方案修改 Protocol d

18、eviations 方案偏離方案偏離(with explanations on possible impact to study interpretation and validity) Report (with sufficiently detailed summary and individual animal data)現場核查要點現場核查要點Step 2: Identify test article 供試品供試品 test article code or name salt form formulation purity Uniformity 均一性均一性 Stability 穩定性穩

19、定性 lot or batch#現場核查要點現場核查要點Step 3: The experimental design 試驗設計試驗設計 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 amendm

20、ent date(s) (AMENDMENTS) experimental completion date/necropsy date (REPORT)現場核查要點現場核查要點Step 3: The experimental design 試驗設計試驗設計 Note how experimental design/methods changed look at protocol amendments and deviations consider if the changes invalidated the studys objectives consider if the changes c

21、aused 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現場核查要點現場核查要點Step 4: Compare documents for consistency 一致性一致性 Do reports comply with GLP require

22、ments on reporting for test article characteristics testing of dosing formulations for purity stability uniformity現場核查要點現場核查要點Step 4: Compare documents for consistency Make sure that data and their associated documents are consistent with one another. 現場核查要點現場核查要點Step 4: Compare documents for consis

23、tency 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?現場核查要點現場核查要點Step 4: Compare documents for consistency Are findings for

24、 all protocol-specified evaluations reported body weight clinical chemistry histopathology for all protocol-specified dose groups toxicokinetics現場核查要點現場核查要點Step 5: Do data seem credible?Report Raw data/Reality現場核查要點現場核查要點Step 6: Evaluation of significance of lapses 失誤的評估失誤的評估The big questions Did pr

25、oblems 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 th

26、e submission? In the conclusions of other studies?現場核查要點現場核查要點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 err

27、ors 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 ?現場核查要點：職責現場核查要點：職責 TESTING FACILITY MANAGEMENT: Overall laboratory management and administrative f

28、unctions 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)現場

29、核查要點：職責現場核查要點：職責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現場核查要點：職

30、責現場核查要點：職責STUDY DIRECTOR Single point of study controlhas overall responsibility for: Protocol preparation technical conduct of study interpretation of results analysis of results documentation of results reporting of results Archiving現場核查要點：職責現場核查要點：職責STUDY DIRECTOR: (contd)Protocol preparation現場核查

31、要點：職責現場核查要點：職責 STUDY DIRECTOR: (contd)Contributors Ophthalmology Cardiology Immunology Analytical Formulation analysis BioanalyticalStatistical analysis Specialists/Consultants AntibodiesBone marrow differential countsSpecialized clinical pathologySperm Analysis 現場核查要點：職責現場核查要點：職責 STUDY DIRECTOR: (c

32、ontd)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? 現場核查要點：職責現場核查要點：職責 STUDY DIRECTOR: (contd)Multi-Site Studies* Work

33、(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 a

34、nd maintains responsibility for overall conduct Quality assurance of the test site*OECD requirement 現場核查要點：職責現場核查要點：職責 STUDY DIRECTOR: (contd)Study Scheduling Considerations Test article availability Animal availability/ordering Housing Trained staff Analytical chemistry Clinical pathology Necropsy

35、Reports 現場核查要點：職責現場核查要點：職責 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? 現場核查要點：職責現場核查要點：職責 STUDY DI

36、RECTOR: (contd)Protocol Review & Approval Management SD Sponsor (if done by CRO) Scientific contributors and laboratory staff Report preparation staff QAU IACUC 現場核查要點：職責現場核查要點：職責STUDY DIRECTOR: (contd)Ovetsight of Study Conduct Observe animals and procedures Review data Communicate with scienti

37、fic contributors and technical staff QA audits internal and external Interactions with contributors/ PIs Submission of samples Receipt/review of report Respond to unexpected events現場核查要點：職責現場核查要點：職責STUDY DIRECTOR: (contd)Oversight of Study Conduct Protocol amendments - a planned change Protocol devi

38、ations not planned; impact on study must be determined SOP deviations 現場核查要點：職責現場核查要點：職責STUDY DIRECTOR: (contd)Example of DocumentationProtocol/protocol amendment Protocol/SOP deviationsAnimal order Test article receipt/information Test article preparation procedureDose accountability (out of range?

39、)Study file notesVeterinary requests/approval of treatmentEnvironmental deviations (e.g. light/dark cycle and humidity) observations of animals/procedures Data reviewCorrespondence email, fax, letter, telephone callsReports 現場核查要點：職責現場核查要點：職責STUDY DIRECTOR: (contd)Report Preparation現場核查要點：職責現場核查要點：職

40、責STUDY DIRECTOR: (contd)Archiving Protocol/amendments Raw data Documentation Specimens Final report 現場核查要點：職責現場核查要點：職責STUDY DIRECTOR: (contd)SD Responsibilities for a Final Report Data interpretation Preliminary draft audited? unaudited? Integration of toxicology, pathology, TK and other supportive

41、data Contributing Scientist/PI reports Stopped/suspended programs GLP compliance Deviations and impact on data 現場核查要點：職責現場核查要點：職責STUDY DIRECTOR: (contd) assures that: protocol, including any changes, is approved as specified in GLPs, and is followed all experimental data, including observations of u

42、nanticipated 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現場核查要點：職責現場核查要點：職責QUALITY ASSURANCE UNIT (QAU):Oversees GLP C

43、ompliance 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, record

44、s, and controls are in conformance with the GLPs現場核查要點：職責現場核查要點：職責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現場核查要點：職責現場核查要點：職責QUALITY ASSURA

45、NCE 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現場核查要點：職責現場核查要點：職責QU

46、ALITY 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現場核查要點：職責

47、現場核查要點：職責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 an

48、d documentation現場核查要點：職責現場核查要點：職責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

49、report specifying details on inspections現場核查要點：職責現場核查要點：職責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 IACUCMaj

50、or issues of data auditWhat do we look for while auditing a GLP labStudy DirectorFacility ManagementQuality AssuranceChemistryPathology(Clinical and anatomical)Technical StaffReport writingSponsorAccountingSubcontractors非臨床實驗室常見錯誤非臨床實驗室常見錯誤Study director Failure to follow protocolMost common because

51、 everything is driven by protocol. Examples: TA Stability determination Environmental conditions Exposure to test article (dosing)非臨床實驗室常見錯誤非臨床實驗室常見錯誤Study director (contd) Final ReportCommonly see failures to address issues that occurred during study that could affect outcomes非臨床實驗室常見錯誤非臨床實驗室常見錯誤St

52、udy director (contd) Failure to record all data and verifyFormulationDosing非臨床實驗室常見錯誤非臨床實驗室常見錯誤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 protoc

53、ol 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.非臨床實驗室常見錯誤非臨床實驗室常見錯誤 Inconsistencies within a protocol or between protocol and

54、 SOP Omission of necessary information from protocol Late entries in study books Non GLP corrections Failure to sign and date entries Expired reagents非臨床實驗室常見錯誤非臨床實驗室常見錯誤 Failure to issue timely protocol amendments and deviation reports Paperwork missing from study book Inconsistencies between proto

55、col and report or raw data and report.非臨床實驗室常見錯誤非臨床實驗室常見錯誤 QAU fails to authorize deviation Deviations not detected by the QAU, but should have been非臨床實驗室常見錯誤非臨床實驗室常見錯誤Transfer of data, specimens, records to archives At completion of study Not all records transferred非臨床實驗室常見錯誤非臨床實驗室常見錯誤 Did not foll

56、ow SOPs for required auditing Inappropriate training record keeping Equipment calibration issues Sanitation cage/room disinfectants Water system attached to cage rackGLP or not GLP Safety Pharmacology studies, Core/GLP, follow up studies depending on the design/non GLP Primary Pharmacodynamic/non-GL

57、P, 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 GLPGLP or not GLPStudies that are not within the scope of GLP regul

58、ations 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

59、 covered by GMPsGLP 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, GLPG

60、LP or not GLPThe 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 Know