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70 Cobert’s Manual of Drug Safety and Pharmacovigilance
CIOMS III (1995 and
1998/1999): Guidelines
for Preparing Core Clinical
Safety Information on
Drugs (1995), Including New
Proposals for Investigator’s
Brochures (1998/1999)
The CIOMS III guideline is now out of print but estab-
lished and extended several fundamental concepts now
in use in much of the world. The idea of the CDS intro-
duced in CIOMS II was extended to the Core Safety
Information (CSI). The CDS contains all key core data
(not just safety data) on a drug. The CSI contains (only)
core safety information and is a subset of the CDS. Sev-
eral fundamental concepts were introduced:
The CSI is the core safety information that should
appear in all countries’ regulator-approved label-
ing for that drug. Additional information could be
added at the national level, but the core information
should be included in all countries’ labels. The CSI
(and national labels) are guides for healthcare pro-
fessionals and contain the most relevant informa-
tion needed for the drug’s use.
Marketing considerations should not play a role in
preparing the CSI.
The CSI was proposed primarily as a medical docu-
ment and not as a legal or regulatory document.
Every drug should have a CSI prepared and updated
by the manufacturer.
Adverse events (AEs) due to excipients should be
included.
AEs that have no well-established relationship to
therapy should not be included.
The CSI should include important information that
physicians are not generally expected to know.
As soon as relevant safety information becomes
sufficiently well established; it should be included.
The specific time when it is included occurs when
the safety information crosses the “threshold for
inclusion”, which is defined as the time when “it
is judged that it will influence physicians’ decisions
on therapy”.
Thirty-nine factors were proposed that can be
ranked and weighed for an AE for a particular drug
to assess whether the information has crossed the
threshold. An extensive discussion on the threshold
is given as follows:
1. The threshold should be lower if the condition
being treated is relatively trivial, if the drug is
used to prevent rather than to treat disease, if the
drug is widely used, or if the ADR is irreversible.
2. Hypersensitivity reactions should be noted early.
3. Substantial evidence is required to remove or
downgrade safety information.
Ten general principles were proposed as follows:
1. In general, statements that an adverse reaction
does not occur or has not yet been reported
should not be made.
2. Generally, clinical descriptions of specific cases
should not be part of the CSI.
3. If the mechanism is known, it should be stated
whether a potentially major, new safety signal
signifies a shift, calling for significant action in
the established relationship between benefits
and risks; it also provides guidance for deciding
what options for action should be considered
and on the process of decision-making should
such action be required.
4. As a general rule, secondary effects or sequelae
should not be listed.
5. In general, a description of events expected as a
result of progression of the underlying treated
disease should not be included in the CSI.
6. Unlicensed or “off-label” use should be men-
tioned only in the context of a medically
important safety problem.
7. The wording used in the CSI to describe
adverse reactions should be chosen carefully
and responsibly to maximize the prescriber’s
understanding. For example, if the ADR is part
of a syndrome, this should be made clear.
8. The terms used should be specific and medi-
cally informative.
9. The use of modifiers or adjectives should be
avoided unless they add useful important
information.
10. A special attribute (e.g., sex, race) known to
be associated with an increased risk should be
specified.
Council for International Organizations of Medical Sciences (CIOMS) 71
Where possible, frequencies should be provided,
although it is admitted that this is very difficult with
spontaneous safety data. A proposed classification is as
follows:
Very common: >1/10 (10%);
Common (frequent): 1/100 and <1/10 (1% and
<10%);
Uncommon (infrequent): 1/1000 and <1/100 (0.1%
and <1%;
Rare: 1/10,000 and <1/1000 (0.01% and <0.1%);
Very rare: <1/10,000 (<0.01%).
Many of these recommendations have been adopted
in one form or another around the world, though not
in their totality. The revised edition (1998/1999) of this
document appeared as CIOMS V (see below).
CIOMS IV (1998): Benefit–
Risk Balance for Marketed
Drugs: Evaluating Safety
Signals
From the preface of the report: “CIOMS IV is to some
extent an extension of CIOMS II and III. It examines the
theoretical and practical aspects of how to determine
whether a potentially major, new safety signal signifies
a shift, calling for significant action in the established
relationship between benefits and risks; it also provides
guidance for deciding what options for action should
be considered and on the process of decision-making
should such action be required.”
The report looks at the general concepts of bene-
fit–risk analysis and discusses the factors influencing
assessment, including stakeholders and constituen-
cies, the nature of the problem (risk), the indication
for drug use and the population under treatment,
constraints of time, data and resources, and economic
issues. Several examples of benefit–risk analyses are
given (quinine and allergic hematologic events, fel-
bamate and blood dyscrasias, dipyrone and agran-
ulocytosis, temafloxacin and renal impairment and
hypoglycemia, remoxipride and blood dyscrasias,
clozapine and agranulocytosis, sparfloxacin and
phototoxicity).
No example of a real benefit–risk report is given
using this format. This type of report seems eminently
possible in situations where the risk is small and there
is no urgent or immediate action needed to protect the
public health. However, in situations in which immedi-
ate action is needed, usually in multiple markets around
the world, the preparation of such a report is probably
not feasible.
Since this CIOMS IV report, several other guide-
lines and documents on benefit–risk analysis have been
published by the FDA, European Medicines Evaluation
Agency, ICH, and others. Most of these documents use
similar conceptual frameworks for benefit–risk analy-
ses but do not follow or propose the rigid CIOMS IV
format. Clearly, however, this document served as a
stimulus to a much closer and intense examination of
benefit–risk analyses around the world. The document
is worth reading, particularly for the case studies noted
above.
CIOMS V (2001):
Current Challenges in
Pharmacovigilance:
Pragmatic Approaches
The CIOMS V report is a 380-page document that cov-
ers a wide variety of issues in drug safety. A summary of
some of the proposals follows. Not all these recommen-
dations are universally accepted or required.
The sources of individual case reports are recom-
mended as follows:
Traditionally, the primary source of safety informa-
tion on marketed drugs has been spontaneous reports,
with occasional literature reports also appearing. New
types of reports are now appearing, including Internet
reports, solicited reports from patient support programs,
surveys, epidemiologic studies, disease registries, reg-
ulatory and other databases, and licensor and licensee
interactions. In the past, consumer reports were often
not analyzed unless medical validation was obtained.
72 Cobert’s Manual of Drug Safety and Pharmacovigilance
The CIOMS V report makes various recommenda-
tions, some of which are as follows:
1. Consumer reports
a. Consumer reports should be scrutinized and
should receive appropriate attention.
b. The quality of a report is more important than
its source.
c. Spontaneous reports are always considered
to have an implied causal relationship to the
drug.
d. Respect privacy and the laws and regulations
governing it.
e. If a report is received from a third party, that
party should be asked to encourage the con-
sumer to report the information to his or her
physician or to authorize the sponsor/author-
ity to contact the physician directly.
f. All efforts should be made to obtain medical
confirmation of serious unexpected consumer
reports. The regulators may be in a better
position to get this information if companies
have been unsuccessful.
g. If an event is considered not to be drug related,
it should be retained in the company database
but not reported.
h. Even in the absence of medical confirmation,
any ADR with significant implications for the
medicine’s benefit–risk relationship should be
submitted on an expedited or periodic basis.
i. Consumer reports should be included in
PSURs in an appendix or as a statement indi-
cating they have been reviewed and do or do
not suggest new findings.
2. Literature
a. Cases may appear in letters to the editor.
b. There may be a long lag time between the first
detection of a signal by a researcher and his or
her publication of it.
c. Publications may be a source of false informa-
tion and signals.
d. Companies should search at least two interna-
tionally recognized literature databases using
the International Normalized Nomenclature
name at least monthly.
e. Broadcast and lay media should not ordinarily
be monitored. If such information is made
available to the company, it should be fol-
lowed up.
f. Judgment should be used in regard to fol-
low-up, with the strongest efforts made for
serious unexpected ADRs.
g. If the product source or brand is not specified, a
company should assume it was its product. The
company should indicate in any report that the
specific brand was not identified if this is the
case.
h. If there is a contractual agreement between
two or more companies (e.g., for co-market-
ing), the contract should specify the responsi-
bility for literature searches and reporting.
i. English should be the standard language for
literature report translations.
j. Regulators should accept translation of an
abstract or pertinent sections of a publication.
k. References cited in a publication on appar-
ently unexpected/unlisted and serious reac-
tions should be checked against the company’s
existing database of literature reports. Articles
not previously reported should be retrieved,
translated to English (as needed), and reviewed
as usual. Routine tracking down of all such
sources is unrealistic unless faced with a major
safety issue.
l. The clock starts when a case is recognized to
be a valid case (reporter, patient, drug, event).
3. The Internet
a. Protection of privacy is particularly important
regarding Internet cases.
b. A blank ADR form should be provided on a
website to facilitate reporting.
c. A procedure should be in place to ensure daily
screening of a company’s or regulator’s web-
site(s) to identify potential case reports.
d. Companies and regulators do not need to
routinely surf the net beyond their own sites
Council for International Organizations of Medical Sciences (CIOMS) 73
other than to actively monitor relevant special
home pages (e.g., disease groups) if there is a
significant safety issue.
e. The message should be consistent around the
world because the Internet does not respect
geographic (or linguistic) boundaries.
4. Solicited reports
a. Solicited ADR reports arising in the course of
interaction with patients should be regarded
as distinct from spontaneous unsolicited
reports.
b. They should be processed separately and so
identified in expedited and periodic reporting.
c. To satisfy post-marketing regulations, solic-
ited reports should be handled in the same
way as study reports: causality assessments
are needed. Serious unexpected ADRs should
be reported on an expedited basis.
d. Serious, expected and non-serious solicited
reports should be kept in the safety database
and reported to regulators on request.
e. Signals may arise from solicited reports, so
they should be reviewed on an ongoing basis.
5. Aspects of clinical trial reports
a. In general, safety information reported expe-
ditiously to regulatory authorities should be
reported to all phase I, II, and III investigators
who are conducting research with any form of
the product and for any indication.
b. It is less important to notify phase IV inves-
tigators; they should ordinarily use the avail-
able up-to-date local official data sheet as part
of the investigator’s brochure.
c. Quality of life studies should be handled like
clinical trial data.
6. Epidemiology: Observational studies
and use of secondary databases
a. Structured epidemiologic studies should have
the same reporting rules for suspected ADR
cases as clinical trials.
b. For epidemiologic studies, unless there is
specific attribution in an individual case,
its expedited reporting is generally not
appropriate.
c. If relevant, studies should be summarized in
PSURs.
d. Promptly notify regulators (within 15 days) if
a study result shows an important safety issue
(e.g., a greater risk of a known serious ADR
for one drug versus another).
e. For manufacturers, expedited reports from
comparator drug data should be forwarded to
the relevant manufacturer(s) for their regula-
tory reporting as appropriate.
7. Disease-specific registries and regula-
tory ADR databases
a. A registry is not a study. Cases should be
treated as solicited reports (causality assess-
ment required).
b. Although there are numerous ADR databases
created by regulatory authorities, it is unnec-
essary to attempt to routinely collect them for
regular review. If a company possesses data
from a regulatory database, it should review
those data promptly for any required expe-
dited reporting. Careful screening should be
done to avoid duplicates.
c. It is advisable to mention in the PSUR that the
databases have been examined even if no rele-
vant cases have been found.
8. Licenser–licensee interactions
a. When companies co-develop, co-market,
or co-promote products, it is critical that
explicit contractual agreements specify pro-
cesses for exchange of safety information,
including timelines and regulatory reporting
responsibilities.
b. The time frame for expedited regulatory
reporting should normally be no longer than
15 calendar days from the first receipt of a
valid case by any of the partners.
c. The original recipient of a suspected ADR
should ideally conduct any necessary fol-
low-up; any subsequent follow-up informa-
tion sent to the regulators should be submitted
74 Cobert’s Manual of Drug Safety and Pharmacovigilance
by the same company that reported the case
originally.
9. Clinical case evaluation
a. The company or regulatory authority staff can
propose alternate clinical terms and interpre-
tations of the case from those of the reporter,
but unless the original reporter alters his or
her original description in writing, the origi-
nal terms must also be reported.
b. When a case is reported by a consumer, his
or her clinical description should be retained
even if confirmatory or additional information
from a healthcare professional is obtained.
c. There is an important distinction between a
suspected ADR and an “incidental” event. An
incidental event occurs in reasonable clinical
temporal association with the use of the drug
product but is not the intended subject of the
spontaneous report (it did not prompt the
contact with the company or regulator). There
is also no implicit or explicit expression of
possible drug causality by the reporter or the
company’s safety review staff. They should be
included as part of the medical history and not
be the subject of expedited reporting. Inciden-
tal events should be captured in the company
database.
10. Assessing patient and reporter identities
a. When cases do not meet the minimum crite-
ria (patient, reporter, event, drug) even after
follow-up, the case should be kept in the
database as an “incomplete case”.
b. The regulatory reporting clock starts when
a valid case is initially reported to the com-
pany, even by a consumer.
c. One or more of the following pieces of infor-
mation automatically qualify a patient as
identifiable: age, age category (e.g., teen-
ager), sex, initials, date of birth, name, or
patient number.
d. Even in the absence of such qualifying
descriptors, a report referring to a defi-
nite number of patients should be regarded
as a case as long as the other criteria for
validity are met. For example, “Two patients
experienced…” but not “A few patients
experienced....”
e. For serious, unexpected, suspected reactions,
the threshold for reporting in the absence of
confirmatory identity should be lowered.
11. Criteria for seriousness
a. Hospitalization refers to admission as an
inpatient and not to an examination or treat-
ment as an outpatient.
b. All congenital anomalies and birth defects,
without regard to their nature or severity,
should be considered serious.
c. There is a lack of objective standards for
“life threatening” and “medical judgment” as
seriousness criteria; both require individual
professional evaluation that invariably intro-
duces a lack of reproducibility.
d. Within a company, the tools, lists, and deci-
sion-making processes should be harmo-
nized globally.
12. Criteria for expectedness
a. The terminology associated with expected-
ness depends on which reference safety doc-
ument is being used and for what purpose:
“Listed” or “unlisted” refers to the ADRs
contained in the CSI for a marketed
product or within the development CSI
(DCSI) in the investigator’s brochure.
“Labeled” or “unlabeled” refers to the
ADRs contained in official regulator-ap-
proved product safety information for
marketed products (e.g., summary of
product characteristics in the European
Union or the package insert in the United
States).
b. Determining whether a reported reaction is
expected is a two-step process: first, is the
reaction term already included in the CSI?
Second, is the ADR different regarding its
nature, severity, specificity, or outcome?
c. Expectedness should be strictly based on
inclusion of a drug-associated experience
in the ADR section of the CSI. Special types
Council for International Organizations of Medical Sciences (CIOMS) 75
of reactions, such as those occurring under
conditions of overdose, drug interaction, or
pregnancy, should also be included in this
section.
d. Disorders mentioned in “contraindications”
or “precautions” as reasons for not treating
with the drug are not expected ADRs unless
they also appear in the ADR section.
e. If an ADR has been reported only in associ-
ation with an overdose, it should be consid-
ered unexpected if it occurs at a normal dose.
f. For a marketed drug CSI, events cited in
data from clinical trials are not considered
expected unless they are included in the
ADR section.
g. For expedited reporting on marketed drugs,
local approved product information is
the reference document for expectedness
(labeledness).
For periodic reporting (PSUR), the CSI
is the reference document for expectedness
(listedness).
Disclaimer statements for causality (e.g.,
“X has been reported but the relationship
with the drug has not been established”) are
discouraged; however, even if used, the reac-
tion X is still unexpected.
Class labeling does not count as “expected”
unless the event in question is included in
the ADR section.
Lack of expected efficacy is not relevant to
whether an AE is expected.
If the treatment exacerbates the target
indication, it would be unexpected unless
already detailed in the CSI.
Unless the CSI specifies a fatal outcome
for an ADR, the case is unexpected as long
as there was an association between the reac-
tion and the fatality.
13. Case follow-up approaches
a. Highest priority for follow-up are cases that
are serious and unexpected; followed by seri-
ous, expected; and non-serious, unexpected.
b. Cases “of special interest” (e.g., ADRs under
active surveillance at the request of the
regulators) also deserve high priority, as do
any cases that might lead to a labeling change.
c. For any cases with legal implications, the com-
pany’s legal department should be involved.
d. When the case is serious and if the ADR has
not resolved at the time of the initial report,
it is important to continue follow-up until
the outcome has been established or the con-
dition stabilized. How long to follow up such
cases requires judgment.
e. It is recommended that collaboration with
other companies be done if more than one
company’s drug is suspected as a causal agent
in a case.
f. Follow-up for unexpected deaths and
life-threatening cases should be done within
24 hours.
g. If a reporter fails to respond to the first fol-
low-up attempt, reminder letters should be
sent as follows:
h. A single follow-up letter for any non-serious
expected case.
i. For all other cases, a second follow-up letter
should be sent no later than four weeks after
the first letter.
j. In general, when the reporter fails to respond
or is incompletely cooperative, the two fol-
low-up letters should reflect sufficient due
diligence.
14. Role of narratives
a. A company case narrative is different from
the reporter’s clinical description of a case,
though the reporter’s comments should be
an integral part of the company narrative.
The reporter’s verbatim words should be
included for the adverse reactions.
b. Alternate causes to that given by the reporter
should be described and identified as a com-
pany opinion.
c. The same evaluation should be supplied to
all regulators.
d. Narratives should be prepared for all serious
(expected and unexpected) and non-seri-
ous unexpected cases but not for non-seri-
ous expected cases.
76 Cobert’s Manual of Drug Safety and Pharmacovigilance
e. Narratives should be written in the third
person past tense. All relevant information
should be in a logical time sequence.
f. In general, abbreviations (except laboratory
parameters and units) and acronyms should
not be used.
g. Time to onset of an event from the start of
treatment should be given in the most appro-
priate time units (e.g., hours), but actual
dates can be used if helpful to the reader.
h. If detailed supplementary records are
important to a case (e.g., autopsy report),
their availability should be mentioned in the
narrative.
i. Information may be supplied by more than
one person (e.g., initial reporter and supple-
mentary information from a specialist); all
sources should be specified.
j. When there is conflicting information pro-
vided from different sources, this should be
mentioned and the sources identified.
k. If it is suspected that an ADR resulted from
misprescribing (e.g., wrong drug or wrong
dose) or other medication error, judgmental
comments should not be included in the nar-
rative because of legal implications. Only the
facts should be stated (e.g., “four times the
normal dose was administered”, “the prescrip-
tion was misread and a contraindicated drug
for this patient was given”).
l. The narrative should have eight sections that
serve as a comprehensive stand-alone “med-
ical story”:
Source of the report and patient
demography.
Medical and drug history.
Suspect drug(s), timing and conditions
surrounding the onset of the reaction(s).
The progression of the event(s) and their
outcome in the patient.
If the outcome is fatal, provide relevant
details.
Rechallenge information, if applicable.
The narrative preparer’s medical evalua-
tion and comment.
15. PSURs: Content modification
a. For reports covering long time periods (e.g.,
5 years), it is more practical to use the CSI
current at the time of PSUR preparation.
b. Clinical trial data should be supplied only if
they suggest a signal or are relevant to a pos-
sible change in the benefit–risk relationship.
c. If there are more than 200 individual case
reports, submit only summary tabulations
and not line listings (which may be supplied
on request by the regulator).
d. For 5-year reports, follow-up information on
cases described in the previous report should
be provided only for cases associated with
new or ongoing safety issues.
e. Inclusion of literature reports should be
selective and cover publications relevant to
safety findings, independent of listedness.
f. For PSURs with large numbers of cases, dis-
cussion and analysis for the overall safety
evaluation should be by system organ class
rather than by listedness or seriousness.
g. An PSUR saves time and resources if little
or no new safety information is generated
during the time period covered. Criteria for
an abbreviated report:
No serious unlisted cases
Few (e.g., 10) serious listed cases
No significant regulatory actions for
safety
No major changes to the CSI
No findings that lead to a new action
The term “abbreviated PSUR” as used
here should not be confused with “abbre-
viated PSURs” prepared at short inter-
vals, e.g., monthly line listings during
pandemic influenza outbreaks.
16. PSURs: A bridging report
a. A summary bridging report is a concise doc-
ument that provides no new information and
integrates two or more previously prepared
PSURs to cover a specified period.
b. Its format follows that of a regular PSUR,
but the content should consist of summary
Council for International Organizations of Medical Sciences (CIOMS) 77
high-lights of the reports being summarized.
Note that bridging PSURs no longer have a
role per the ICH E2C(R2) guideline.
17. PSURs: An addendum report
a. This report is prepared on special request
of the regulators to satisfy regulators who
require reports covering a period outside
the routine PSUR reporting cycle (e.g., if the
reports are based on the local approval date
in that country rather than on the IBD).
b. It updates the most recently completed
PSUR.
c. It follows the usual PSUR format.
18. PSURs: Miscellaneous proposals
a. A brief (e.g., one-page) stand-alone overview
(executive summary) should be provided.
b. Manufacturers should be allowed to select
the IBDs for their older products to facilitate
synchronization of PSURs.
c. If there is no CSI for an old product, the most
suitable local labeling should be considered
for use.
d. The evaluation of cases in a PSUR should
focus on unlisted ADRs, with analyses orga-
nized primarily by system organ class (body
system).
e. Discussion of serious unlisted cases should
include cumulative data.
f. Complicated PSURs and those with exten-
sive new data may require more than 60 days
to prepare adequately and the regulators
should be flexible.
g. The possibility of “resetting” the PSUR clock
(from annual to semiannual reports as the
result of a new indication or dosage form)
should be allowed by the regulators.
19. PSURs: Population data
a. Detailed calculations on exposure (the
denominator) are ordinarily unnecessary,
especially given the unreliability of the
numerator; rough estimates usually suffice,
but the method and units used should be
explained clearly.
b. Drug exposure data are approximate and
usually represent an overestimate.
c. For special situations, such as dealing with
an important safety signal, attempts should
be made to obtain exposure information cov-
ering the relevant covariates (e.g., age, gen-
der, race, indication, dosing details).
CIOMS VI (2005):
Management of Safety
Information from Clinical
Trials
The CIOMS VI working group focused on clinical trial
safety, which represents a departure from the focus of
the earlier working groups that concentrated primar-
ily on post-marketing safety issues. The report, avail-
able from the CIOMS office in Geneva, like the CIOMS
V report, runs some 300 pages. The most important
points are summarized here. The reader is referred to
the report for further detail. Keep in mind that these
recommendations have not been put into regulations in
all jurisdictions.
20. General Principles and Ethical
Considerations
a. The concepts of pharmacovigilance pre-
sented here apply to trials in phase I–IV.
b. Any study that is not scientifically sound
should be considered unethical.
c. Informed consent is the cornerstone of
human subject research, but there are situ-
ations in which it is either not possible or
appropriate (such as in anonymous tissue
sample studies, epidemiologic research, or
emergency treatment protocols).
21. Systematic Approach to Managing
Safety Data
a. The concepts of pharmacovigilance, risk
management, assessment, and minimization
should be applied to the study phases and
78 Cobert’s Manual of Drug Safety and Pharmacovigilance
the post-marketing period. Sponsors must
have in place a well-defined process to read-
ily identify, evaluate, and minimize potential
safety risks. The process should start before
the first phase I study. A formal development
risk management plan should be developed.
b. A dedicated safety management team should
be formed for each development program to
review safety information on a regular basis
so that decisions can be made in a timely
manner. The review should be at least quar-
terly, and the team should consider changes
to the investigator’s brochure, informed con-
sent, and protocol as needed.
c. When licensing partners are involved, a joint
safety committee should be created, with
clear roles and responsibilities. This should
ideally be defined in the initial contract. A
project management function should be
set up to ensure scheduling, tracking, and
timelines.
d. All pertinent data must be readily available
from the clinical trial and safety databases as
well as non-clinical toxicology, mutagenicity,
pharmacokinetic, pharmacodynamic, and
drug interaction data.
e. Epidemiology should be incorporated into
the planning process.
f. Certain toxicities should be considered for
all new drugs, including abnormalities of
cardiac conduction, hepatotoxicity, drug
interactions, immunogenicity, bone marrow
toxicity, and reactive metabolite formation.
22. Data Collection and Management
a. The investigator should report to the sponsor
(immediately if judged critical) any informa-
tion considered to be important regarding
safety even if the protocol does not call for it.
The sponsor must carefully train the investi-
gative site in this matter.
b. The collection of “excessive” data can have a
negative impact on data quality. Case report
form fields should collect only those data
that can be analyzed and presented in tabular
form. All other data should be collected as
text comments.
c. Safety monitoring in phase IV studies may
not require the same intensity as for phase
I–III trials, but the same principles and prac-
tices should apply.
d. If a company provides any support for an
independent trial it does not sponsor (inves-
tigator-initiated studies/trials), the company
should still obtain at a minimum all serious
suspected adverse reactions. The company
should do its own causality assessment and, if
appropriate, report it to the health authorities,
even if the investigator has already done so.
e. In the early phases of drug development, it
is often necessary to collect more compre-
hensive safety data than in post-marketing
studies. Some studies may require longer
follow-up.
f. Phase I data are especially important because
these data are collected in healthy volunteers
and are critical to the future development of
the drug.
g. There is no definitive way to determine cau-
sality of a particular AE. That is, its attribu-
tion to the drug or to a background finding
with only a temporal association cannot be
definitively done. Thus, the following is
recommended.
h. All AEs, both serious and non-serious, are
collected whether believed to be related
or not. This applies to the experimental
product, placebo, no treatment, and active
comparators.
i. Similarly, studies initiated during the imme-
diate post-approval period should continue
this practice. Once the safety profile is judged
to be well understood, it may be possible to
collect less data (e.g., omitting non-serious
AEs believed not to be due to the drug).
23. Other Points
a. The use of herbal and other non-traditional
treatments should be sought when data are
being collected in all studies.
Council for International Organizations of Medical Sciences (CIOMS) 79
b. Although causality assessments based on
aggregate data or case series are usually more
meaningful than those based on individual
cases, the investigator causality assessment
should be done and may play a role in the
early detection of significant safety events,
especially rare ones.
c. The investigator should be asked to use a
“simple binary decision” for drug causality
of serious AEs: related or not related, rea-
sonable possibility or no reasonable pos-
sibility, and so on. The use of the words
“unknown” or “cannot be ruled out” should
be avoided.
d. Causality for non-serious AEs should not be
requested from investigators routinely.
e. Where appropriate, the investigator should
supply a diagnosis rather than signs and
symptoms. However, when a diagnosis is
supplied for a serious AE, the accompanying
signs and symptoms should be recorded.
f. Before starting a study, AEs of special inter-
est and anticipated AEs (if known) should
be communicated to the investigator. This is
less critical for non-serious AEs unless they
are prodromes of more serious conditions
(e.g., muscle pain and creatine phosphoki-
nase elevation as a possible prodrome of
rhabdomyolysis).
g. Medically serious clinical events recorded in
a trial as clinical efficacy outcomes or end-
points should be reviewed by the sponsor
and data monitoring committee even though
they are not considered AEs.
h. It is preferable to frame questions to patients
in general terms rather than suggest that the
study treatment was responsible for reported
AEs. Althougha “laundry list” of AEs
should not be read to the patient, patients
should be alerted to known issues of medi-
cally important suspected or established AEs
so they can alert the investigator as soon as
possible.
i. Data collection should start from the time
the informed consent is signed.
j. Safety data event collection should continue
after the last dose of the drug for at least an
additional five half-lives of the experimental
product.
24. General Rules for Data Quality
a. Cases should be as fully documented as
possible.
b. There should be diligent follow-up of each
case.
c. The reporter’s verbatim terms should be cap-
tured and retained.
d. If the reporter’s terms are considered inaccu-
rateor inconsistent with standard medical
terminology, attempts should be made to
clarify them. If disagreement continues, the
sponsor should code the AE terms according
to its judgment but identify them as distinct
from the reporter’s terms and note reasons
for differences.
e. Primary analyses of the data should be
done using the reporter’s terms. Additional
analyses may be done using the sponsor’s
terms. Any differences must be noted and
explained.
f. Individual case safety reports should be cat-
egorized and assessed by the sponsor, using
trained individuals with broad experience.
Investigators should obtain specialist con-
sultation for clinically important events that
fall outside their expertise.
g. AE tables may display both the reported
investigator’s verbatim term and the spon-
sor’s terms.
h. The sponsor (as well as health authorities)
may wish to consider the use of a listing of
event terms always regarded as serious and
important. Such events then routinely trig-
ger special attention and evaluation.
i. Cases should not be “overcoded” using more
terms than minimally necessary to ensure
retrieval of the cases. Similarly, cases should
not be “undercoded”, where the terms cho-
sen downgrade the severity or medical
importance of events.