Table 3 Definition of safety assessments

1.

Adverse event (AE)

An adverse event is defined in the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice as “any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment.” (ICH E6:1.2). The investigator is responsible for reviewing laboratory test results and determining whether an abnormal value in an individual study subject represents a change from values before the study. In general, abnormal laboratory findings without clinical significance (based on the investigator’s judgment) should not be recorded as adverse events; however, laboratory value changes requiring therapy or adjustment in prior therapy are considered adverse events.

2.

Serious adverse event (SAE)

A serious adverse event (SAE) is defined as an adverse event that meets at least 1 of the following criteria: a) fatal, b) life threatening (places the subject at immediate risk of death), c) requires in-patient hospitalization or prolongation of existing hospitalization, d) results in persistent or significant disability/incapacity or congenital anomaly/birth defect e) other significant medical hazard. A hospitalization meeting the regulatory definition for “serious” is any inpatient hospital admission that includes a minimum of an overnight stay in a health care facility. Any adverse event that does not meet one of the definitions of serious (e.g., emergency room visit, outpatient surgery, or requires urgent investigation) may be considered by the investigator to meet the “other significant medical hazard” criterion for classification as a serious adverse event. Examples include allergic bronchospasm, convulsions, and blood dyscrasias.

3.

Adverse drug reaction (ADR)

All untoward and unintended responses to a medicinal product related to any dose administered. The phrase “responses to a medicinal product” means that a causal relationship between the medicinal product and the adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out.

4.

Serious adverse drug reaction (SADR)

A serious ADR (SADR) is an ADR that meets the definition of SAE

5.

AE attributes

The investigator will assign the following adverse event attributes:

Adverse event diagnosis or syndrome (s), if known (if not known, signs or symptoms)

Dates of onset and resolution

Severity

Assessment of relatedness to IP

Action taken.

6

AE grading

The following adverse events severity grading scale used in the trial.

MILD: Aware of sign or symptom, but easily tolerated

MODERATE: Discomfort enough to cause interference with usual activity

SEVERE: Incapacitating with inability to work or do usual activity

LIFE-THREATENING: Refers to an event in which the patient was, in the view of the investigator, at risk of death at the time of event.

FATAL