【正文】 非臨床實驗室常見錯誤 Study director (cont’d) ? Final Report Commonly see failures to address issues that occurred during study that could affect outes 非臨床實驗室常見錯誤 Study director (cont’d) ? Failure to record all data and verify Formulation Dosing 非臨床實驗室常見錯誤 Study director (cont’d) ? 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 afterthefact 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 ? 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 protocol and report or raw data and report. 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 Transfer of data, specimens, records to archives ? At pletion of study ? Not all records transferred 非臨床實驗室常見錯誤 ? 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/nonGLP, 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 GLP…When is FDA “more likely” to accept non GLP (US domestic only)? ? Oncology (safety data is from published literature) ? Biologics (small panies, 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 pliant 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 nontraditional sources, non ICH countries, request inspection ? MOU, memorandum of understanding with different countries ? Request permission to do inspection from the entity doing the study ? Countries accept inspection by DSI or might not ? Acceptance of these studies is up to the reviewer/Division in CDER 案例分析 (1) RCC： Findings in a rat repro tox study audited: ? Only one abnormality/variation/developmental delay, etc. in thoracic and abdominal viscera of fetuses from control or treated animals in three studies ? Possibly fewer than expected a/v/dd in skeletons ? Almost no visceral a/v/dd in historical controls, but skeletal rates reasonable Question: Were observation thresholds sufficiently sensitive? Inspectional findings The Study Director and head of the reprotox department had only a high school diploma and a few months of on thejob training, mostly for skeletal evaluations. ? The lead technician had less than elementary school education. Before ing to RCC, his butcher business had failed. Technician had onthejob training at RCC. ? SOPs were OK for cranial/skeletal, weak for visceral. ? Recorded cranial/skeletal data fairly represented the specimens. ? External findings were reasonable, parable to literature. No satisfactory explanation for the low rates IN SOFT TISSUES 案例分析 (1) 案例分析 (1) Q: ? what is the deficiency of this GLP repro tox study audited vs regulations? ? Is data acceptable for supporting safety evaluation? 案例分析 (1) A: ? what is the deficiency of this GLP repro tox study audited vs regulations? ? 人員資質(zhì) ? 培訓(xùn) ? Is data acceptable for supporting safety evaluation? ? NO！！ 案例分析 (2) Inspection at ABC Company Findings: ? The final study report did not include the signed and dated reports of the individual scientists or other professionals involved in the study: – study director did not receive contributing scientists39。 what is in a protocol frequently changes during the course of a study ? Note important dates (e