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SUSAR for Expedited Reporting 徐麗娟組長 臨床組 醫藥品查驗中心 100-5-28 Disclaimer This presentation was not officially cleared, and the views offered here do not necessarily reflect official positions of DOH ,including TFDA. 藥品優良臨床試驗準則 106條 受試者發生任何嚴重不良事件(SAE)，試驗主持人應立即 通知試驗委託者(sponsor)，並儘快提供詳細書面報告。 發生未預期之嚴重藥品不良反應 (SUSAR)，試驗主持人應 立即通知人體試驗委員會(IRB) 。 (上兩點)但若試驗計畫書或其他文件明確排除者，不在此 限。 試驗委託者獲知未預期之死亡或危及生命之嚴重藥品不良 反應，應於獲知日起七日內通報主管機關或其委託機構， 並在獲知日起十五日內提供詳細書面資料。 Expedited Reporting: 台灣通報規定 99.07.19 Apply to all Local or Global Clinical Trials SUSAR Sponsor 死亡 或 危及生命之SUSAR < 7 days 死亡.危及生命以外之SUSAR<15 days 或 其它委託機構 獲 知 時 立 即 S A E PI Taiwan Regulatory Authority SUSAR 獲知時立即 The Relevant IRB The crucial elements of SUSAR Causality Seriousness Expectedness Definition of Causality Adverse Event any untoward medical occurrence associated with the use of a drug in human, whether or not considered drug related Without any judgment of causality Adverse Reaction all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reaction (ICH E6 :GCP) Any adverse event caused by a drug after a judgment Causal Relationship Karch & Lasagna scale Naranjo's scale WHO probability scale Spanish quantitative imputation scale Kramer's scale Jones scale European ABO system Bayesian system WHO Probability Scale CERTAIN A clinical event, including laboratory test abnormality, occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary. PROBABLE/LIKELY A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfil this definition.ical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfil this definition. POSSIBLE A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, but which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear. UNLIKELY A clinical event, including laboratory test abnormality, with a temporal relationship to drug administration which makes a causal relationship improbable, and in which other drugs, chemicals or underlying disease provide plausible explanations. CONDITIONAL/ UNCLASSIFIED A clinical event, including laboratory test abnormality, reported as an adverse reaction, about which more data is essential for a proper assessment or the additional data are under examination. UNASSESSIBLE/ UNCLASSIFIABLE A report suggesting an adverse reaction which cannot be judged because information is insufficient or contradictory, and which cannot be supplemented or verified. Suspected adverse reaction Any adverse event for which there is a reasonable possibility that the drug caused the adverse event For the purposes of IND safety reporting, reasonable possibility means there is evidence to suggest a causality between the drug and the adverse event A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction Suspected adverse reaction-examples Serious adverse events (e.g., mortality or major morbidity) that were likely to have been manifestations of the underlying disease Serious adverse events that commonly occurred in the study population independent of drug exposure (e.g., stroke or AMI in an elderly population Serious adverse events that were study endpoints ㄨ reasonable possibility Suspected adverse reaction-examples A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug angioedema, hepatic injury, Stevens-Johnson syndrome, blood dyscrasias, rhabdomyolysis Tendon rupture, heart valve lesions, intussusception An aggregate analysis of specific events observed in a clinical trial that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group O reasonable possibility Suspected adverse reaction-examples Reporting study endpoints A death ordinarily would not be reported as an individual case in all-cause mortality trial Death due to anaphylactic reaction in all-cause mortality trial should be reported individually Serious adverse events that are not study endpoints Disease progression High background rate of this event in study population Should not be reported individually Definition of Seriousness (≠Severe) 使用藥物時發生以下狀況： Hospitalisation Death Congenital abnormality/ birth defect X Planned hospitalization Life-threatening Disability/incapacity Important medical event/ medical intervention Definition of Seriousness If either the sponsor or investigator believes that the event is serious, the event must be considered serious and evaluated by the sponsor for expedited reporting Definition of Expectedness Unexpected Adverse Reaction: an adverse reaction, the nature or severity of which is not consistent with the applicable product information. event/reaction previously unobserved or undocumented Unexpected Nature:以前從未發生或記載 舉例：exenatide上市後的acute pancreatitis病例 Severity: 已知有發生但是嚴重度改變 舉例：A藥已知可能造成肝功能指數上升→新發現肝衰竭死亡病例 Specificity不同:如已列 cerebral vascular accident, 但發 生cerebral thromboembolism or cerebral vasculitis Class ADRs: 若其它同類藥有此ADR證據而該品並無記載其中，仍 需視unexpected Product information: 未上市藥品: 主持人手冊(IB) 已上市藥品: 仿單(label) Expectedness判讀時注意事項 不確定該AE/AR是expected or unexpected時，應視為 unexpected處理。 當雙盲試驗，test drug vs. placebo時，先都 當做用test drug來評估 當雙盲試驗，test drug vs. active comparator時，需分別評估；若不同用藥會導致 其expectedness評估結果不同時，可考慮單一解 盲 The Crucial Factors of Assessment • Expected • Unexpected •Suspected • Unrelated • Serious • Non-serious What Should be Reported ? Single cases of serious, unexpected ADRs Related + Serious + unexpected →Suspected Unexpected Serious Adverse Reaction An increased in the rate of occurrence for an expected, serious ADR 通常sponsor才知道 A significant harzard to the patient population 例如期間分析發現無療效 A major safety finding from a newly completed animal study 例如降血糖藥GLP-1 agonist 和 c-cell neoplasia and medullary thyroid carcinoma in rats Active comparator的SUSAR 仍須快速通報 在盲性試驗中如何判讀： 盡量在維持盲性的狀態下評估。 必要時(例如對治療有決定性因素時)可以單一病例解盲。 無法確定expectedness時，皆視為unexpected 舉例 某癌症病患接受一已上市化療藥物治療，發生白血球降低 至1500/mm3，住院接受反隔離和治療。→ Related Serious Expected ADR 某癌症病患參加接受雙盲化療藥物臨床試驗，發生白血球 降低至1500/mm3，住院接受反隔離和治療。→ Related Serious Expected AE (不知道是哪一組，所以不知道和 試驗藥物有沒有關係，但肯定和化療有關係) 舉例 李媽媽參加流感疫苗臨床試驗，一週後去菜市 場途中跌倒骨折，住院準備手術，術前檢查發 現血小板低下(70000/mm3)。 骨折: unrelated, serious(導致住院), unexpected 血小板低下：suspected, nonserious (CATAE Gr.2 非因此住院), expected 舉例 含新佐劑(adjuvant)的疫苗進行臨床試驗，一位受試者在 Baseline時，肝功能檢驗數值正常，接種四週後，肝功能 檢驗數值升高2.5X ULN，受試者並無症狀，無其他可疑藥 品或co-morbidities。 CTCAE Gr. 2 Suspected Unexpected Serious? 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