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170 Cobert’s Manual of Drug Safety and Pharmacovigilance
various channels. They should roughly run along these
lines as follows:
Rapid processing of the death/life-threatening clini-
cal trial cases for submission to the health authorities
within 7 calendar days from first receipt by anyone
in the company, business partners, CROs, and so
forth. This usually means completing the case within
approximately 5 calendar days. Attempts should be
made immediately to get needed follow-up informa-
tion, which would be included in a follow-up report
to the agencies.
Processing of 15-day expedited reports for clinical
trial or marketed products. These are serious cases
for which processing and submission must be com-
pleted by calendar day 15, but preferably sooner,
to allow quality review, transmission to business
partners, and transmission to the authorities. Many
companies develop workflow such that all cases
are completed by, say, calendar day 10 after initial
receipt. Completion dates tend to range from 8 to 12
calendar days in companies, though most companies
pick one time frame for all cases and stick to it. This
makes for simpler processing and tracking within the
drug safety group. CROs and companies that work
with multiple partners may (unfortunately) have to
tailor their processing procedures for each partner.
Processing of other serious cases that are not expe-
dited reports. These cases do not have to be sent to
the health agencies within 15 calendar days. Rather
they are sent in periodic reports at intervals that
vary from 3 months to several years, depending on
the status of the drug and the regulations in that
country. Thus, there is usually the potential for a
longer time frame for processing the case if needed.
Some companies will use the same processing sys-
tem for all serious cases, whether expedited or not.
Serious cases that are to be sent to subsidiaries,
business partners, and others may also require rapid
processing if contractual arrangements require this.
Many companies exchange all serious cases within
10 calendar days whether expedited or not.
Sometimes a case is not an expedited report in one
country but is an expedited case in other countries
(e.g., the local labeling or reporting regulations are
different there). This case must be transmitted to
the subsidiary or business in time to meet 15-day
reporting rules there. It is often the situation, espe-
cially in large multi-national companies, that the
sending company (e.g., drug safety in the home
office) is not able to know whether or not any par-
ticular serious case will be an expedited report in
all countries where the drug is sold. Thus, many
companies process these cases as if they were expe-
dited reports and use a completion date of about 10
calendar days (as noted above).
Non-serious cases may be processed more slowly
(e.g., 30 days) because they are not reportable at
all or are reportable only in aggregate reports; In
the EU non-serious spontaneous ICSRs are to be
reported electronically to the EMA within 90 cal.
days. It is wise to screen non-serious cases rapidly
upon receipt, especially if they come from “less than
reliable sources,” to ensure that no serious cases
are misclassified (presumably not intentionally) as
non-serious cases. Misclassification could lead to
late expedited reports.
Similarly, the “other” cases, such as literature, legal,
and cases received from health authorities, should be
processed as appropriate for the company’s needs. It
is a general rule of thumb that the process should be
kept as simple as possible and that “exceptions to the
rule” be kept limited. As few as three fundamental
procedures could serve: 7-day cases, all serious cases
(handled as if they are all expedited cases), and all
non-serious cases.
Database Entry
At this point, the case should be entered into the com-
puterized safety database if it has not already been
entered. If the case is received electronically, it should
be reviewed in a “holding area” before it is officially
uploaded into the safety database unless it comes from
a trusted source where such review is deemed unnec-
essary. Electronic edit checks can be very useful at this
point. For example, clinical trial cases uploaded from a
dedicated electronic data collection system for a com-
pany’s studies may be uploaded directly if the case is
entered in sufficient detail and there are quality checks
at the investigational site.
How an Individual Case Safety Report (ICSR) is Handled from Start to Finish 171
If the case arrives manually using a standard-
ized paper data collection form, then manual data
entry should be fairly easy to do. If not, the data may
arrive in any sort of form: case report forms, hand-
written notes, CIOMS I or MedWatch forms, hospital
records, physicians’ notes, telephone reports, and so
forth. Sometimes data entry is easy; sometimes it is
not. Some companies have an initial review by a med-
ical professional who highlights items for data entry;
other companies have the source documents sent
directly to the data entry group (nonmedical profes-
sionals) and have medical review only after that is
completed.
If a case number (also called a “control number” or
“medical reference number”) has not been assigned to
the case at the triage or logging level, it is assigned now.
MedDRA
®
coding of AEs, medical history, and other
required MedDRA fields is done either by the drug
safety group or by a dedicated coding group. Drug cod-
ing using a standardized dictionary is also done. The
case narrative is usually written at this point. The nar-
rative may be difficult and complex if the case is long
and complicated. There are standard ways that narra-
tives should be written in terms of format, content, fol-
low-up information, etc. Some companies developed
“automated narratives”: data are picked from other
recorded fields and the database generates the narra-
tive; it is then to be reviewed, potentially updated and
validated by Medics. The narrative is the key summary
of the case and should usually be a good “stand-alone”
summary of the case. Much care should be taken in its
preparation.
Quality Review
At this point, a drug safety specialist (usually a nurse
or pharmacist) reviews the data entry against the
source documents and prepares or reviews the case
narrative. Any changes or additions to the case are
made at this time. A clear methodology on the qual-
ity check should be developed so that it is done in a
systematic, standardized, and repeatable way. Those
fields, if any, that are not reviewed (e.g., height)
should be defined in the methodology up front in
addition to those fields that are. The quality review
should look at content, grammar, and format. In gen-
eral, one does not need to be a perfectionist regarding
grammar; however, sentences that are unclear or do
not convey the desired meaning should be corrected.
Short simple sentences should be used because many
of the readers may not be native English-language
speakers.
Follow-Up
Follow-up information should be requested when the
initial case is incomplete or unclear. Rarely does a case
have complete information, especially if the AE just
happened or is ongoing. Thus, it is usually required that
follow-up queries be sent to the reporter to complete
the case data. The need for follow-up is also mentioned
in 21CFR312.32(d) for IND reports and 314.80(c)(1)
(ii) for NDA reports. EU GVP module VI also notes
that follow-up is necessary: “When first received, the
information in suspected adverse reactions reports may
be incomplete. These reports should be followed-up as
necessary to obtain supplementary detailed information
significant for the scientific evaluation of the cases. This
is particularly relevant for monitored events of special
interest, prospective reports of pregnancy (see VI.B.6.1.
for guidance on the management of pregnancy reports),
cases notifying the death of a patient, or cases reporting
new risks or changes in the known risks. This is in addi-
tion to any effort to collect missing minimum criteria
for reports validation (see VI.B.2. for ICSRs validation).
Any attempt to obtain follow-up information should be
documented.”
Follow-up data should be entered into the database
using a procedure similar to the one used for initial
data. Care must be taken to ensure that the data are not
mistaken for a new case but rather are clearly identified
as follow-up to a case already received.
There is no “correct” number of follow-ups that
should be done. Follow-ups should be done to get the
needed information. Sometimes it is a single follow-up;
sometimes many. Sometimes the reporter or patient
refuses to give follow-up. At least two attempts should
be made and documented in such situations.
172 Cobert’s Manual of Drug Safety and Pharmacovigilance
Medical Review
At this point in the case, after it has been completed
and reviewed by the drug safety specialist and after it
has undergone a quality review, some or all cases should
be reviewed by the drug safety physician. Historically,
physician review was limited to serious cases, but many
companies are now having all cases undergo physician
review to ensure that no serious cases are misclassified
as non-serious. The medical review should generally
cover the medical content of the case, with particular
attention paid to the narrative, the suspect and con-
comitant drugs (including dosages), the past medical
history, and coding. It is generally not the role of the
physician to do a source document quality review
unless he or she needs to refer to the source documents
for clarification of a medical point. This varies from
company to company, however. In certain critical cases,
it is often desirable that the physician review all source
documents, even if this is not routine policy.
Case Closure
In one sense, a case is never really closed, as new infor-
mation could arrive weeks, months, or even years later,
requiring the case to be updated. But for practical pur-
poses, once the above steps are concluded and follow-up
requested, a case may be considered closed or completed
for operational purposes. If and when follow-up arrives,
the case can be reopened and processed. The distinction
between closure (or locking) of a version and closure or
completion of a case should be noted. A company may,
for practical operational reasons, “lock” each case a cer-
tain number of days after the receipt of the information
so that the case can be processed properly without new
data arriving and being entered into the case when it
is in medical review or ready to be transmitted to the
health authorities.
For example, if data are received on day 0, the case
is processed and locked on, say, calendar day 7 and sent
to the health authorities on calendar days 12–14. Note
that business partners or local country affiliates may
require shorter timelines to meet obligations. Any addi-
tional follow-up data on this case that arrive after day 7
is put into a follow-up version of the case. This prevents
the staff from scrambling to get last-minute data into
the case with the appropriate medical review, quality
control, and so forth. In such a situation, two versions
of a case may be open at the same time. Most computer
systems are able to handle these versioning issues. In
occasional situations, additional data may indeed be
added to the case at the last minute if deemed critical
(e.g., death outcome has just arrived).
Case Distribution
and Transmission
Cases are next distributed to those in the company who
need to see them (e.g., clinical research, legal) and to
other companies with whom safety exchange agree-
ments are in place. Cases are also submitted directly
to the health agencies via E2B or other direct means
(e.g., certified mail, courier) or distributed to others
in the company, such as the regulatory department, for
submission to the health authorities. Cases may also be
sent to subsidiaries or affiliates worldwide for their sub-
mission to local agencies — often with a cover letter in
the local language and, in some instances, with a trans-
lation of the case itself into the local language if English
is not accepted. In the EU, cases from clinical trials are
submitted to the national authority. Post-marketing
cases are submitted directly to EudraVigilance in E2B
format. Some jurisdictions require non-coded portions
of the case to be reported in the local language. When
using the E2B(R3) message format, the case narrative,
for example, is a repeating field, so that a translation
of the narrative may be provided in the local language
at the same time as the “official” English language
narrative.
Tracking
It is critical to have markers in the database to track
cases through the processing system. Each drug safety
specialist and manager should be aware of all pend-
ing cases, their status in the trip toward completion/
closure, and, in particular, the deadlines for each case.
How an Individual Case Safety Report (ICSR) is Handled from Start to Finish 173
It is critical that all 7- and 15-day reports be tracked so
that none is submitted late to the health authorities, sub-
sidiaries, or business partners. The manager can reallo-
cate cases or other work to ensure that the time-critical
cases are handled appropriately in case of absence, vaca-
tion, staff overload, or maldistribution of caseloads.
Similarly, non-expedited cases that need to be com-
pleted for aggregate reports should be tracked so that
they are completed before the data lock. This can be as
frequent as every 3 months for NDA periodic reports.
In the EU, non-expedited cases must be submitted to
EudraVigilance within 90 days from first awareness; the
data lock for PSURs/PBRERs, of course, is driven by the
timetable determined on a product-by-product basis by
the PRAC. The dates of the periodic reports are known
in advance, so there is no excuse for a case missing the
report. Follow-up information may be provided in the
next aggregate report.
In general, tracking should be done electronically
and generated automatically from the drug safety data-
base unless there are so few cases that manual tracking
is practical. Most modern drug safety databases have a
tracking function with customizable reports. Manual
tracking on spreadsheets is time consuming and usu-
ally not practical once AE volume grows and the staff
becomes large.
The question often arises in a small company about
whether it should have a safety department and/or a
database. In regard to a safety department, whether a
drug is in clinical trials or marketed, the answer is yes.
That department may be one person supervising the
outsourced CRO or a partner handling the safety. Such
a situation may be satisfactory for small companies with
few AE cases. Once the volume and complexity grow
(e.g., marketing in multiple countries), the need for an
in-house safety function and database becomes more
compelling. Although it is explicitly stated by some
regulatory authorities that an electronic safety data-
base is not necessarily obligatory, all the appropriate
(templated) reporting (e.g., PSURs/PBRERs) must still
be done and, without a database, this may not be fea-
sible or practical. The question then becomes whether
it is practical to rely on a CRO or partner for all safety
functions with the subsequent benefits and costs (both
monetary and not) to the business as well as safety. For
some companies, this may be worthwhile, but not so
for others.
In addition to tracking the AEs that arrive and are
processed, the following key performance indicators
should be tracked at a minimum:
Total number of AEs;
Serious AEs;
Non-serious AEs
Clinical trial AEs (i.e. SAEs, SUSARs);
Spontaneous AEs (serious and non-serious);
Overall data and data stratified by type of report;
Those submitted on time;
Those submitted late, by how much, why, and
corrective actions taken;
Cases submitted to business partners and others;
Time to process cases, depending on case type
(expedited, serious non-expedited, non-serious,
etc.);
Time to submission to each major health agency
(FDA, EMA, etc.);
Tracking by drug or class of products or drug
safety teams, depending on how the drug safety
group and the company are organized;
Timeliness of aggregate reports, e.g., DSURs,
PSURs/PBRERs, IND and NDA periodic reports.
It is useful periodically to graph and publish these
metrics (“key performance indicators”, or “KPIs”) for
the entire drug safety staff. Such data can also be used
for resource allocation, budgeting, projection of future
work (e.g., AEs for allergy drugs peak twice a year
and more staff may be needed then), and justification
for more resources. The metrics may aid in identify-
ing problems, or “rough spots,” and help to institute
changes to prevent recurrence of such problems. Pub-
licly posted data should not identify individuals or point
out “non-producers” to shame them into speeding up.
Praise should always be done publicly, but chastisement
should be done privately.
The timing, sequence, and duration of each step in
processing an AE should be clearly spelled out in mea-
surable and auditable SOPs or working documents. If
the company determines that, say, all SAEs will be com-
pleted within 10 calendar days and all non-serious cases
within 30 calendar days, this timing should be built into
174 Cobert’s Manual of Drug Safety and Pharmacovigilance
each case. This should be done automatically in the
database workflow system with a tickler, e-mail, or sim-
ilar reminders to the concerned individual, telling him
or her of the timing and due date for each case. The due
dates would be updated as needed (e.g., it is determined
to be or not to be a 15-day expedited report, or a case is
upgraded from non-serious to serious). Attention must
be paid to weekends and holidays in calculating due
dates. Note that bank holidays in the UK may be work-
ing days elsewhere and the Chinese New Year may be
celebrated outside China.
Each person in the workflow must know when his
or her task is due, and the manager must be able to
track the case through each step to ensure its comple-
tion. Other companies have “pools” of people handling
each step rather than having one drug safety specialist
“own” the case. In the pool situation, the first available
“pool” member handling that step processes the case.
Investigator Notification
The concept of investigator notification of expedited
clinical trial reports used to be simple but has now
become somewhat more complicated.
The ICH proposals in the E6(R2) guideline “Inte-
grated Addendum to ICH E6(R1): Guideline for Good
Clinical Practice E6(R2)” are somewhat ambiguous:
“The sponsor should promptly notify all concerned
investigator(s)/institution(s) and the regulatory
authority(ies) of findings that could affect adversely
the safety of subjects, impact the conduct of the
trial, or alter the IRB/IEC’s approval/favorable opin-
ion to continue the trial.” (5.16.2)
“The sponsor should expedite the reporting to all
concerned investigator(s)/institutions(s), to the
IRB(s)/IEC(s), where required, and to the regulatory
authority(ies) of all adverse drug reactions (ADRs)
that are both serious and unexpected.” (5.17.1)
The EU is more explicit:
The sponsor shall inform all investigators con-
cerned of findings that could adversely affect the
safety of study subjects.
The information can be aggregated in a line listing
of SUSARs accompanied by a summary of the evolv-
ing safety profile of the product;
In the case of blinded trials, the line listing should
present data on all SUSARs, regardless of the medica-
tion administered (e.g., active/placebo/comparator),
maintaining the blind.
If a significant safety issue is identified, either on
receipt of an ICSR or on review of aggregate data, the
sponsor should immediately notify all investigators.
A safety issue that affects the course of the clinical
study or development project, including suspension
of the study program or safety-related amendments
to study protocols, should also be reported to the
investigators (Volume 10).
Note: No time frame is specified. Many companies use
the 15-day requirement used in the US.
The US regulations are also somewhat ambiguous,
particularly in terms of format:
“IND safety reports. The sponsor must notify FDA
and all participating investigators (i.e., all investiga-
tors to whom the sponsor is providing drug under
its INDs or under any investigator’s IND) in an IND
safety report of potential serious risks, from clinical
trials or any other source, as soon as possible, but in
no case later than 15 calendar days after the sponsor
determines that the information qualifies for report-
ing…” (21CFR312.32(c)(1)).
21CFR312.32(c) also requires that “In each IND
safety report, the sponsor must identify all IND
safety reports previously submitted to FDA con-
cerning a similar suspected adverse reaction, and
must analyze the significance of the suspected
adverse reaction in light of previous, similar reports
or any other relevant information.”
In regard to investigator notification, FDA indicated
that:
All participating investigators filed to open INDs
(including investigator initiated studies) should be
notified in an IND safety report of potential serious
risks;
How an Individual Case Safety Report (ICSR) is Handled from Start to Finish 175
Follow-up reports should be sent to investigators
to inform and update them about an important sus-
pected adverse reaction if it significantly affects the
care of the subjects or conduct of the study;
Minor refinements that do not significantly affect
care of subjects or conduct of the study need to be
sent to FDA but need not be sent to investigators;
and
Such information may be communicated to inves-
tigators in a routine update of the investigator
brochure.
These requirements have been interpreted in vari-
ous ways. “Participating Investigators” is ambiguous.
Many companies take a conservative view and report all
expedited reports to all investigators in all phase I, II,
and III trials, as well as to investigators in investigator-
initiated studies using this study drug whether for
this indication or not. Some sponsors will also send
spontaneous reports for this drug to investigators if it
is also on the market. The drug safety group prepares
the analysis of similar cases from the safety data-
base and sometimes from the clinical trial database if
cases are present there that are not in the drug safety
database.
15 Calendar Days and Day 0
versus Day 1
The FDA in its draft guidance Post-marketing Safety
Reporting for Human Drug and Biological Products
Including Vaccines of March 2001, refers to the com-
pletion of box G4 on the MedWatch 3500A form as the
date the company first awareness of the four criteria for
a valid AE (reporter, patient, event, drug) and that this
is day 0 of the 15-day time clock. This has been car-
ried over to field A.1.6 (date report was first received
from source) in the E2B message. It is important to pay
attention to this because it triggers compliance metrics.
This date then gives up to 16 calendar days for a case.
Depending on the time the case is received, day 0 is
usually less than 24 hours. The document also notes
clearly that the case must be received by FDA no later
than day 15. If the 15th calendar day is a weekend or a
US federal holiday, the report may be submitted on the
first working day after the weekend or holiday. How-
ever, if a company has submission obligations in coun-
tries outside the United States, the federal holiday (and
possibly even the weekends) should not be allowed to
permit a delay in submission.
The EU is more explicit and states in GVP module
VI.B.7: “The clock for the submission of a valid ICSR
starts as soon as the information containing the mini-
mum criteria has been brought to the attention of the
national or regional pharmacovigilance center of a com-
petent authority or of any personnel of the marketing
authorization holder, including medical representatives
and contractors. This date should be considered as day
0.” The same applies if new information on the case
is received by the MAH, i.e., the reporting time clock
begins again for the submission of the follow-up report
from the day the MAH receives relevant follow-up
information. The clock for expedited reporting starts
(day 0) as soon as the minimum information has been
brought to the attention of any personnel of the MAH or
an organization holding a contractual agreement with
the MAH including medical representatives.
CHAPTER
177
15
Seriousness,
Expectedness, and
Causality
T
he drug safety staff involved
in individual case evaluation
generally have to make several
decisions regarding each case. These
decisions must be made rapidly on
receipt of an Individual Case Safety
Report (ICSR) because this deter-
mines how the case is handled in the
drug safety department and whether,
how, and when it is reported to health
agencies and business partners. Seri-
ousness and expectedness are key crite-
ria to classify, analyze and report ICSRs
to the appropriate bodies. Causality has
key consequences as well, but mainly for
clinical trial case reports. During clin-
ical development, these three criteria
actually support the selection of ICSRs,
which are SUSARs to be reported on an
urgent basis to health agencies.
Introduction
The concept and practice of assessing and reporting if an
event is serious, if it is expected, and if it has a causal rela-
tionship to a medical product, should be clearly defined in
internal procedures such as SOPs, as the process of these
assessment have an enormous impact on the reporting
requirements to agencies as well as the interpretation of
impact of the event in the patient population. Standard pro-
cedures should define and match the regulatory definition of
seriousness and state that these definitions will be included
in all clinical development protocols. The SOP should also
define how expectedness will be determined. If the com-
pany has both developmental and approved products (per-
haps the same product in different regulatory jurisdictions),
178 Cobert’s Manual of Drug Safety and Pharmacovigilance
then the procedure should reference the appropriate refer-
ence material such as the Investigator Brochure for devel-
opmental products, or the appropriate Labeling document
(SmPC, Package Insert, Label, etc.) for the approved prod-
uct. If a company does not want to put this language in a
procedure (not recommended), then the protocol should
at a minimum define how these criteria will be defined and
determined.
Seriousness
Is an event Serious? This is one of the first questions asked
when we receive safety information regarding an adverse
event either in a clinical trial or in the post-market setting.
These definitions are fairly set-in-stone, have not changed
over the course of several years and are one of the major
building blocks of assessing and categorizing a case.
The generally accepted definition of seriousness is as
follows:
A serious adverse event (AE) (experience) or seri-
ous adverse reaction is any untoward medical occur-
rence that at any dose:
Results in death;
Is life-threatening;
Requires inpatient hospitalization or prolongation
of existing hospitalization;
Results in persistent or significant disability/
incapacity;
Is a congenital anomaly/birth defect;
Is medically significant; Medical and scientific judg-
ment should be exercised in deciding whether expe-
dited reporting is appropriate in other situations,
such as important medical events that may not
be immediately life-threatening or result in death
or hospitalization but may jeopardize the patient
or may require intervention to prevent one of the
other outcomes listed in the previous definition.
These should also usually be considered serious.
“Examples of such events are intensive treatment in
an emergency room or at home for allergic broncho-
spasm; blood dyscrasias or convulsions that do not
result in hospitalization; or development of drug
dependency or drug abuse” (ICH E2A).
Important Medical Events
The EudraVigilance Expert Working Group has
coordinated the development of an Important Med-
ical Event (IME) terms list based on the Medical
Dictionary for Regulatory Activities (MedDRA
®
)
(see GVP Annex IV in the EMA PV Modules). This
IME list aims to facilitate the classification of sus-
pected adverse reactions, the analysis of aggregated
data and the assessment of ICSRs in the framework
of day-to-day pharmacovigilance activities. The IME
list is intended for guidance purposes only and is
available on the Agency website to stakeholders who
wish to use it for their pharmacovigilance activities.
It is regularly updated in line with the latest version
of MedDRA. Note: The EU and Japan also note that
any suspected transmission via a medicinal prod-
uct of an infectious agent is also considered serious
(GVP Module VI C.2.2.5).
Over the years, these definitions have been dis-
cussed, parsed, and clarified by health agencies, com-
panies, and other interested observers. In general, the
most conservative interpretation is the one drug safety
groups should use.
Some comments are as follows:
Death: Although one would believe this binary
concept (alive–dead) would be rather straightfor-
ward, there have been some discussions relating
to the timing of the death and the circumstances
around the AE and the death.
A note on death: It is generally accepted that
death is an outcome and not an actual event, which
is true; something must have caused the patient’s
death, be it cardiac arrest or progressive disease,
but something did cause the death. As scientists,
we want to explore the cause of the death once it
has been reported, To understand whether the event
that caused the death was a result of the product
use, some companies in the past have failed to
report cases where the only event reported was
“death” citing that they didn’t have the minimum
criteria to report, and that this situation did not ful-
fill case reporting. If during clinical develop-
ment, or even in the post-marketing period,
an event of “death” is reported, a company
Seriousness, Expectedness, and Causality 179
must regard this as valid information and
report what is known and attempt to assess
the case as best as possible while obtaining
additional information. Companies should
have clear procedures in place and language within
protocols that outline how events of “death” will be
handled to avoid any confusion.
It is fairly clear that if a patient has a myocardial
infarction (the SAE) and then over the next several
hours or days goes into shock, has severe arrhyth-
mias, and dies, this death is related to the SAE and
this is a “fatal myocardial infarction”. It gets trickier,
however, if the patient has a myocardial infarction
and during a cardiac catheterization goes into an
intractable ventricular arrhythmia and dies. Is the
myocardial infarction to be classified as a fatal one
or is the death a sequela of the catheterization? Some
will argue that the catheterization was performed
because of the myocardial infarction. There is no
clear answer, and it may vary from case to case. The
most conservative call is often used by drug safety
units; that is, the death is a part of (or consequence
of) the SAE. However, if a medically defensible call is
made that is less conservative, this should be noted
somewhere in the case along with the reasoning
behind the decision.
Another example would be that of a fall. If a patient
trips while walking on a level surface, falls, and
scrapes his or her knee, this is most probably a
non-serious AE. If, however, he or she falls while
standing on a ledge or walking down a staircase and
dies as a result of the fall, the case should be reported
as a serious and fatal case but how to classify it is
tricky. The fall may be non-serious, but the sum of
the case is clearly serious and fatal because of the
fatality occurring after the fall, not the actual fall.
Again, there is no clear answer; many would take
the conservative approach and consider this case (if
occurring during a clinical trial) as a serious, fatal,
unlabeled fall (presuming “fatal fall” is not in the
investigator brochure), and unrelated to the study
drug (unless it is believed to be related, perhaps due
to accompanying dizziness, which should also be
coded). Others would argue that the AE was the fall
and everything that happened after it was due to the
circumstances of standing near the ledge. Had the
fall occurred on the level surface none of the events
leading to the death would have occurred.
In a 1996 report on a survey done at the US and EU
Drug Information Association meetings in 1993,
Dr. Win Castle and Dr. George Phillips reported
marked transatlantic differences in the interpreta-
tion of seriousness and expectedness. For example,
“total blindness for 30 minutes” was believed to be
serious by 89% in the European Union survey and
44% in the US survey compared with “mild anaphy-
laxis”, which was believed to be serious by 37% of
the EU responders and 98% of the US responders.
Whether this is still the case remains to be seen,
but the results nonetheless are most interesting and
suggest the need for harmonization and training of
safety reviewers.
1
Life-threatening: Note: The term life-threaten-
ing in the definition of serious refers to an event
in which the patient was immediately at risk of
death at the time of the event; it does not refer to
an event that hypothetically might have caused
death if it were more severe. This concept also has
interpretation issues revolving around whether
the SAE would truly kill the patient if untreated.
A non-severe myocardial infarction with no car-
diac function compromise or arrhythmias might be
considered serious (medically significant if not hos-
pitalized) but not life-threatening, whereas a myo-
cardial infarction that progresses over the next hour
or two to pulmonary edema would be considered
life-threatening. This definition thus may overlap to
a degree with “medically significant”. Again, most
would take a conservative approach. Note that for
clinical trials, FDA changed the definition effective
March 2011 to include the requirement that the
idea of whether an AE is life-threatening should be
commented upon by both the investigator and the
sponsor and that if either one feels it is, then the AE
should be so considered.
Hospitalization: Much debate occurred over what
actually constitutes “hospitalization” or “inpatient
1
Castle, Phillips, Standardizing “expectedness” and “seriousness” for
adverse experience case reporting. Drug Inform J 1996; 30: 73–81.