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AE (Adverse events) Definition

AE
An AE is a unique representation of a specific event used for medical
documentation and scientific analyses.

Each AE term is mapped to a MedDRA v 6.0 term and code.

Same term and code used in Japan and the EU.

Adverse Event can be Physical signs and 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 If there is any doubt whether an event constitutes an AE, it should be treated as such
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There are multiple causes of AEs:

Pre-existing conditions Hypertension Diabetes Concomitant medications Anticoagulants Steroids Other causes Transfusion reactions Accidental injuries

Reporting and grading an AE simply reports that an event occurred and the seriousness of the event. The clinician must assign attribution of the event, either to the intervention or something else.
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Sources of AEs
All directly observed events Events discovered after questioning the subject Events spontaneously volunteered by the subject Laboratory, EKG or other test results

Definition : unexpected adverse event

Any ADR, the specificity or severity of which is not consistent with the current

investigator brochure.
Unexpected as used in this definition, refers to an adverse experience that has

not been previously observed( included in the investigator brochure) rather than
perspective of such experience not being anticipated from the pharmacological

properties of the pharmaceutical product.

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What is Safety Surveillance?

The Detection, medical management and reporting of adverse events associated with an investigational product in accordance with the protocol, and in compliance with GCP and applicable regulatory requirements It plays a key role in Clinical Trials

AE are Collected During Trials to:

Protect safety of patients in the clinical trials, through appropriate modification of study protocols, improvement in study design and procedures and if necessary, termination of subjects involvement or even termination of the trial Improve understanding of the overall safety profile of the product

Evaluate the benefits and risks of a drug

Provide information for the package insert if a drug is marketed Comply with regulatory requirements
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Definition: Serious Adverse Event

An AE becomes serious when it: Results in Deaths Is life threatening i.e. subject at immediate risk of death from the reaction as it occurred e.g. anaphylactic shock (not allergic reaction)

Results in in-patient hospitalization or prolongation of existing hospitalization

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 Results in a persistent or significant disability or incapacity i.e. disruption of the

subjects ability to carry out normal life functions e.g. amputation of leg
Is a congenital anomaly or birth defect Is any other important medical events, based upon appropriate medical judgment, that may jeopardize the subject or may require medical or surgical intervention to prevent or avert one of the outcomes listed above
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Serious vs. Severe

Seriousness
Serves as a guide for defining regulatory reporting obligations; based upon event outcome

Severity
Describes the intensity of the event e.g. mild, moderate, severe E.g. A severe headache may not be serious, a mild stroke resulting in disability is serious.
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AE Evaluation and Reporting

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AE Evaluation and Reporting

Reporting All AEs in all treatment groups must be graded for severity and

assessed for relationship to study product

All AEs in all treatment groups must be reported on AE case report forms AE term Onset date Severity

Relationship to study product

Study product administration Status/outcome and date
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Grades
Grade refers to the severity of the AE. The CTCAE (Common Terminology Criteria for Adverse Events) v3.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 : Mild AE

Grade 2 : Moderate AE
Grade 3 : Severe AE Grade 4 : Life-threatening or disabling AE Grade 5 : Death related to AE
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Physician Responsibility Regarding Attribution

Physicians are to document the relationship (ATTRIBUTION) of the protocol

intervention to each event.

Designating an event as treatment related (or not) is done two ways: 1.By the treating CLINICIAN: Formal assignment per adverse event reporting form (unlikely, possibly, etc.,) at the time of clinical evaluation.

2. By Investigators:
Later in aggregate data review and reporting by the Investigators.
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Attribution Standards 1.Unrelated: The Adverse Event is clearly not related to the investigational agent(s) 2.Unlikely: The Adverse Event is doubtfully related to the investigational agent(s) 3.Possible: The Adverse Event may be related to the investigational agent(s) 4.Probable: The Adverse Event is likely related to the investigational agent(s) 5.Definite: The Adverse Event is clearly related to the investigational agent(s)
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Sponsors Responsibilities

Expedited the reporting of all serious, unexpected ADR to all concerned Investigators, Regulatory Authority and Ethics Committee

Periodic submission of all safety updates to regulatory authority

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Guidelines for submitting serious adverse events

For pre-market drug
Investigator to IRB unanticipated problems involving risks to subjects or otherspromptly Unanticipated adverse device effects ---no later than 10 working days All adverse drug reactions that are serious and unexpected within 15 calendar days of the investigator learning the event. Investigator to sponsor Any adverse event that may reasonably be regarded as caused by or probably caused by the drug immediately Unanticipated adverse device effects ---no later than 10 working days Serious adverse events --immediately
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For Pre-market drug Sponsor to FDA

Any adverse experience associated with the use of the drug and is serious and
unexpected within 15 days of the sponsors initial receipt of the information Any unexpected fatal or life threatening within 7 calendar days Unanticipated adverse device effects ---within 10 working days For post-market drug

Fatal/ life-threatening within 7 calendar days

Serious, unexpected within 15 calendar days
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Post marketing reporting

Voluntary system of reporting by health professionals or consumers

Can report by phone , by fax (FDA 3500A form) or online

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Key Points to Remember

Subject safety is paramount in clinical trials

Differences between clinical practice and clinical trials when reporting adverse
events

Definitions used in adverse event reporting are regulatory definitions, not

clinical definitions Adverse events that are serious and related require expedited reporting the FDA
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All investigators working within investigational drug must be informed of any event with the drug that is serious, related and unexpected Investigator must inform the IRB of any IND safety reports Protocols should contain explicit directions for collecting, assessing and reporting

adverse events

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