Step 3: Comments are collected and incorpo-
rated and drafts referred to the ICH steering
committee.
Step 4: Final draft is discussed within the ICH
steering committee and adopted by the three
regulatory parties.
Step 5:The full recommendations are incorpo-
rated into domestic regulations.
ICH E2 (1994) described clinical safety data man-
agement. The now familiar definitions and stan-
dards for expedited reporting of individual adverse
events when serious, unexpected and treatment
associated are the result of ICH E2 (and the reg-
ulatory transcriptions, e.g. 21CFR312.32).
ICHE2definedanadverse event(oradverse
experience) as ‘any untoward medical occurrence
in a patient or clinical investigation subject admi-
nistered a pharmaceutical product which does not
necessarily have a causal relationship with this
treatment’. An ADR reported in the marketplace,
that is post-NDA/PLA approval was defined as ‘a
response to a drug which is noxious and unin-
tended and which occurs at doses normally
used in man for prophylaxis, diagnosis or therapy
of disease, or for modification of physiological
function’.
Minimum reporting criteria defined by ICH for
initial reports of adverse events are when:
a specific individual patient is reported;
a specific suspected medicinal product;
an identifiable reporting source, and
an event or outcome that is serious, unexpected
and reasonably treatment associated.
An SAE (or experience, or reaction) is defined as
any untoward medical occurrence that at any dose
results in death, is life threatening, requires inpa-
tient hospitalization or prolongation of existing
hospitalization, results in persistent or significant
disability/incapacity, or is a congenital anomaly/
birth defect.
An adverse event isunexpectedwhen its nature
or severity is not consistent with information in the
relevant source document(s)’. Relevant source
documents include the investigator’s brochure for
investigational drugs, and the master data sheet or
core safety data sheet, or local product labeling for
marketed products. The determination of whether
an adverse event is unexpected usually resides with
the company that sponsors the clinical trial or
markets the product.
The causalityortreatment relatednessof clin-
ical investigation cases is determined by the report-
ing healthcare professional or the sponsor, and is
based on a ‘reasonable suspected’ causal relation-
ship between patient exposure to the suspect
drug and the occurrence of the adverse event.
Spontaneous reports about marketed products are
always taken to imply that the reporter has assessed
an adverse event with causality by the reported
product (and are thus also always adverse events
per se).
ICH recommended that fatal or life-threatening
unexpected ADRs should be expedited to regula-
tory agencies as soon as possible, but no later than
seven calendar days after first being known to the
Sponsor. As complete a report as possible is recom-
mended within eight additional calendar days. All
other serious unexpected ADRs should be reported
within 15 calendar days.39.4 Spontaneous case reports
These are unsolicited adverse events that are
reported to the company after the drug is on the
market. Their sources include consumers, their
relatives, clinicians (whether nurses, pharmacists
or prescribers) and, occasionally, lawyers or sales
representatives (the last even being from other
companies).
Although of limited value in isolation, these
reports can be important in aggregate. By defini-
tion, spontaneously reported adverse events are
deemed possibly treatment related by the reporter,
even when the motivation is to inquire into the
possibility that the subject drug could be associated
with the adverse event type that has been observed39.4 SPONTANEOUS CASE REPORTS 539