【正文】 xperimental design landmarks) – experimental or dosing start date (REPORT) – study initiation date (REPORT) – protocol amendment date(s) (AMENDMENTS) – experimental pletion date/necropsy date (REPORT) 現(xiàn)場核查要點 Step 3: The experimental design 試驗設計 ? Note how experimental design/methods changed – look at protocol amendments and deviations – consider if the changes invalidated the study’s 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 現(xiàn)場核查要點 Step 4: Compare documents for consistency 一致性 ? Do reports ply with GLP requirements on reporting for – test article characteristics – testing of dosing formulations for ? purity ? stability ? uniformity 現(xiàn)場核查要點 Step 4: Compare documents for consistency Make sure that data and their associated documents are consistent with one another. Compa re th is…. …to thi s prot ocol GLPs prot ocol st at ed gu i delin e/meth od prot ocol re po rt’s metho ds sec tio n prot ocol amendmen ts re po rt’s metho ds sec tio n prot ocol devia tio ns re po rt’s metho ds sec tio n re po rt tex t re po rt su mmary ta bles prot ocol , proto col a mendme nt s an d devi at io ns re po rt ov er al l re po rt su mmary ta bles re po rt ind iv idu al tables re po rt GLPs re po rt re st of s ub miss io n 現(xiàn)場核查要點 Step 4: Compare documents for consistency ? Are protocolspecified evaluations of data applied? – statistical tests – criteria for acceptable study, positive finding (., genotoxicity tests) – Does selection of highest dose ply with protocol? With referenced guideline? 現(xiàn)場核查要點 Step 4: Compare documents for consistency ? Are findings for all protocolspecified evaluations reported – body weight – clinical chemistry – histopathology for all protocolspecified dose groups – toxicokiics 現(xiàn)場核查要點 Step 5: Do data seem credible? Report Raw data/Reality 現(xiàn)場核查要點 Step 6: Evaluation of significance of lapses 失誤的評估 The big questions – – Did problems in study documents result in your inability to draw meaningful conclusions from the study (with respect to study’s 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? 現(xiàn)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 errors widespread? Limited? ? Do errors occur in reporting of endpoints that are critical to scientific interpretation? ? Do errors speak for a reportspecific problem or something that is a systemic problem ? 現(xiàn)場核查要點：職責 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) 現(xiàn)場核查要點：職責 TESTING FACILITY MANAGEMENT: (cont’d) ? 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(xiàn)場核查要點：職責 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 現(xiàn)場核查要點：職責 STUDY DIRECTOR: (cont’d) Protocol preparation 現(xiàn)場核查要點：職責 STUDY DIRECTOR: (cont’d) Contributors ? Ophthalmology ? Cardiology ? Immunology ? Analytical – Formulation analysis – Bioanalytical Statistical analysis ? Specialists/Consultants Antibodies Bone marrow differential counts Specialized clinical pathology Sperm Analysis 現(xiàn)場核查要點：職責 STUDY DIRECTOR: (cont’d) 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(xiàn)場核查要點：職責 STUDY DIRECTOR: (cont’d) MultiSite Studies* ? Work (. phase of a GLP study) performed at a geographically distinct site (Not a FDA GLP term) ? Assign a PI to ensure pliance with GLPs – Will sign an Acceptance of Responsibilities form – Will sign a statement to this fact upon pletion 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 現(xiàn)場核查要點：職責 STUDY DIRECTOR: (cont’d) Study Scheduling Considerations ? Test article availability ? Animal availability/ordering ? Housing ? Trained staff ? Analytical chemistry ? Clinical pathology ? Necropsy ? Reports 現(xiàn)場核查要點：職責 STUDY DIRECTOR: (cont’d) Test Article ? Calculations How much will you need? ? When is it available? ? Final doses? ? Analytical Confirmation ? Storage/handling conditio