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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?
Thank you for your attention