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

Sponsor

TaiwanRegulatory Authority

The Relevant IRB

Apply to all Local or Global Clinical Trials

PI

死亡 或 危及生命之 SUSAR < 7 days死亡 . 危及生命以外之 SUSAR<15 days

SAE

SUSAR

獲知時立即

SUSAR

獲知時立即

其它委託機構或

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 ScaleCERTAIN 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 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

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)

Death

Life-threatening

Hospitalisation

Planned hospitalization

X

Disability/incapacity

Congenital abnormality/birth defect

Important medical event/medical intervention

使用藥物時發生以下狀況：

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

•Suspected• Unrelated

• Serious• Non-serious

• Expected• Unexpected

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?

Thank you for your attention