SUSAR for Expedited Reporting

1. SUSAR for Expedited Reporting 徐麗娟組長 臨床組 醫藥品查驗中心 100-5-28

2. Disclaimer • This presentation was not officially cleared, and the views offered here do not necessarily reflect official positions of DOH ,including TFDA.

3. 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。

4. Expedited Reporting:台灣通報規定 99.07.19 Apply to all Local or Global Clinical Trials SUSAR 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 SAE SUSAR PI 獲知時立即 TaiwanRegulatory Authority Sponsor The Relevant IRB

5. The crucial elements of SUSAR Causality Seriousness Expectedness

6. 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 Definition of Causality

7. 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

8. WHO Probability Scale

9. 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

10. 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

11. Suspected adverse reaction-examples • A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure • angioedema, hepatic injury, Stevens-Johnson syndrome, blood dyscrasias, rhabdomyolysis • 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 • 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

12. 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

13. Hospitalisation Death Life-threatening X Planned hospitalization Important medical event/medical intervention Definition of Seriousness (≠Severe) 使用藥物時發生以下狀況： Congenital abnormality/ birth defect Disability/incapacity

14. 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

15. 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

16. 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)

17. 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

18. Expected • Unexpected • Serious • Non-serious • Suspected • Unrelated The Crucial Factors of Assessment

19. What Should be Reported ? • Single cases of serious, unexpectedADRs Related + Serious + unexpected →Suspected Unexpected Serious AdverseReaction • 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

20. 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

21. 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)

22. 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

23. 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?

24. Thank you for your attention