Transcript Adverse Events

臨床試驗
Adverse Events:
不良反應及不良事件
簡國龍老師
2015-04-22
1
Outline




Definition
Reasons for collecting adverse event data
Responsibility of investigators & sponsors
Practical issues & statistical considerations
2
Definition of AE




Unfavorable change in a patient that may occur during or
after drug or device
This change does not have to be caused by the treatment
be called an AE
Adverse experience
Adverse drug reaction, adverse device effect: When a
causal relationship has been established between a
product and AE
3
Adverse drug reaction, ADR


A response to an investigational drug that occurs at any dose and
is noxious and unintended
A response to a marketed drug that is noxious, unintended, and
that occurs at doses normally used for prophylaxis, diagnosis,
therapy, or for modification of physiological function
4
Adverse drug reactions (ADR) to an
investigational product

All noxious and unintended responses to a medicinal product
related to any dose should be considered adverse drug reactions.
A causal relationship is at least a reasonable possibility.
5
Adverse event (AE)

Any unfavorable and unintended sign, symptom, or disease
temporally associated with the use of a medicinal (investigational)
product, whether or not related to the medicinal (investigational)
product.
6
AE






Physical signs or symptoms
Abnormal laboratory values
Changes in vital signs, physical examination, or on an
electrocardiogram
An increase in the frequency or intensity (worsening) of a
condition or illness that was present before study enrollment
Complications from a surgery or procedure
Not included:


Procedures or surgeries (the medical condition that caused the need for
the procedure or surgery is the adverse effect)
Pre-existing events or illness that do not worsen during the study
procedure
7
Subsets of AE

Expected versus unexpected adverse effects


Expected for the drug based on previous experience
Unexpected for the drug, not reported in brochure or package insert,
greater severity or frequency than previously reported
8
Serious versus Non-serious adverse
effects

SAE: Any experience occurring at any dose (regardless of
relationship to study agent) meets the conditions:
 Results
in death
 Is life-threatening
 Results in persistent or significant disability/incapacity
 Requires or prolongs inpatient hospitalization
 Is a congenital anomaly/birth defect
 Important medical event
9
Why collect adverse effect data?


Investigator’s responsibility
Accurate, timely, and complete reporting of adverse effects



Determine the safety profile of a drug
Evaluate the benefits and risks of a drug
Provide information for the package insert if a drug is marketed
10
Safety profile


Monitored to determine if significant concerns that would prevent
it from being used in the target population
Investigator’s brochure


All adverse events reported in trials of the drug to date
Number of times specific events reported
11
Benefits and risk evaluation

A medical risk-benefit judgment
 Whether
the benefits of the drug outweigh its known and potential
risks

Package insert
 Adverse
event information
 Scientific facts from clinical trials
 Source document by additional adverse events reported after
marketing
12
Investigator responsibilities

Collecting adverse event data


Objectively and thoroughly observation on potential adverse effects
Systematic but non-specific way



Health problems, any changes vs. headache
Reporting adverse event data
Expedited reporting of adverse events
13
Reporting adverse event data

Different mindset from clinical practice in reference to reporting
adverse events



Report all events to the sponsor, even when opinions the event is not
related to the agent
Complete reporting is necessary
Different mechanisms to report

Depend on type of AE, seriousness and process outlined for specific
study
14
Case report forms

Event: medical terminology


Diagnosis or sign/symptom
Relationship to study drug (causality)

Evaluate whether the AE was related to, or caused by, the study drug



1. reasonable possibility
2. non a reasonable possibility
Categories:





1. unrelated
2. remotely related
3. possible related (uncertain as to relationship)
4. probably (likely) related
5. definitely related
15
(Continued)

Severity/intensity




Seriousness



Mild: patient was aware of the event but it was easily tolerated
Moderate: discomfort sufficient to interfere with normal activities
Severe: patient was incapacitated with an inability to perform normal
activities
One or more criteria in definition of SAE
Outcome as a treat to life or function
Distinction between severity versus seriousness of an event

Examples: severe vomiting, mild stroke
16
Others in reporting AE

Record data about



The onset and resolution of the event
Treatment provided in response to the event
Action taken with regard to study treatment
17
Expedited reporting of adverse events



Identify specific adverse events in an expedited manner
Outline a process for expedited reports
Separate SAE report form




Very specific information about the event
A narrative description of the event, relevant medical history, laboratory
results, diagnostic tests, concomitant medications, treatment, and
outcome of the event
Within 24 hours learning of the event
Also in the case report form or other data forms, same
terminology and supporting data
18
Sponsor responsibilities


Expedited and routine reporting of AE to FDA, even after the drug
has been approved for marketing
Expedited reporting





Serious
Unexpected (not in investigator’s brochure)
Study treatment-related
Within 15 calendar days of first knowledge of the event
Fatal or life-threatening: within 7 calendar days by telephone or fax,
followed by a written report within 8 additional calendar days
19
IND safety reports by sponsor





A summary of the event
The treatment arm the patient received (open-label trials)
Analysis of similar events that have occurred in the trial and/or in
past or present trials
Comments on the occurrence of the same adverse event with
similar therapeutic agents in the same patient population
The site report form


Investigator alert letter, safety letter, alert report
Site’s IRB
20
Routine reporting by sponsor

Semi-annual report




Discontinuations due to adverse effects
All deaths
All serious adverse events
After NDA approved

Post-marketing adverse event data reports on a quarterly basis for first 3
years after approval, then on an annual basis
21
Issues in assessing safety




Rates or relative risks of AE and laboratory data
Extent of exposure
More common adverse events and laboratory test changes
Serious adverse events and other significant AE
22
Practical issues

Coding system for AE
 COSTART:
FDA
 WHOART: WHO
 MEDDRA: ICH



AE data listing
Summary tables of AE
Graphical presentation
 scatterplot
23
Statistical analyses



Contingency tables for AE
Cochran-Mantel-Haenszel test
Integrated summary: subgroup analysis


Pooling the data
Meta-analysis
24
Table 12.4.1 Information to be Included in the List of Adverse Events
Patient identifier
Age, race, sex, weight
Location of case report forms if provided
Adverse event
Duration of the adverse event
Severity
Seriousness
Action taken
Outcome
Causality assessment
Date of onset or date of clinic visit at which the event was discovered
Timing of onset of the adverse event in relation to the last dose of the
last drug
Study treatment at the time of event or the most recent study taken
Test drug/investigational product dose in absolute amount, mg/kg or
mg/m2, at time of event
Drug concentration (if known)
Duration of test drug/investigational product treatment
Concomitant treatment during study
25
Figure 12.4.1 Scatter plot of adverse events versus incidence rates
26
Laboratory data


Least biased and most precise data for system toxicity, efficacy
and safety
Routine tests



Reference ranges
Clinically significant changes
Shift analysis

Below, within and above the normal range
27
Table 12.5.1 An Example of Categories for Assessing the Degree of Concern
Category
I
Definition
All results normal
11. No two successive abnormalities 2. Last result normal
II
11. Two or more successive abnormalities 2. Last result normal
III
11. No two successive abnormalities 2. Last result abnormal
IV
V
11. Two or more successive abnormalities 2. Last result
abnormal
28
Conclusions

Safety hypotheses cannot be specified a priori



Not designed to detect difference in safety outcomes
Not prepared to test hypotheses regarding rare safety events
Failure to achieve statistical significance does not mean that a safety
finding can be ignored
29
FDA guidelines





Frequency of treatment-emergent events
Relevant Body System categories
Severity categories
Relationship/causality
Original terms used by the investigator and group related
reactions
30
Websites:



http://adr.doh.gov.tw/main01.htm
藥物不良反應通報表
行政院衛生署






電話：(02) 2396-0100
傳真︰(02) 2358-4100
台北郵政 84-664 號信箱
網址：http://adr.doh.gov.tw
電子信箱：[email protected]
Suggested reading:

Merck feared 'unfavorable message' from Vioxx study By Alex Berenson,
Gardiner Harris, Barry Meier and Andrew Pollack The New York Times
(International Herald Tribune) Monday, November 15, 2004
31
版權聲明
頁碼
1-32
作品
版權圖示
來源/作者
本作品轉載自Microsoft Office 2010 PowerPoint 設計主題範本-Pixel，依據
Microsoft 服務合約及著作權法第46、52、65條合理使用。
25
《Design and analysis of clinical trials: concepts and methodologies》， 作
者:Chow, SC, Liu, JP ，出版社: Wiley(third edition )，p.596。本作品依據著作權
法第 46、52、65 條合理使用。
http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html
26
《Design and analysis of clinical trials: concepts and methodologies》， 作
者:Chow, SC, Liu, JP ，出版社: Wiley(third edition )，p.598。本作品依據著作權
法第 46、52、65 條合理使用。
http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html
28
《Design and analysis of clinical trials: concepts and methodologies》， 作
者:Chow, SC, Liu, JP ，出版社: Wiley(third edition )，p.605。本作品依據著作權
法第 46、52、65 條合理使用。
http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html
32