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180 Cobert’s Manual of Drug Safety and Pharmacovigilance
hospitalization”. Some patients may be kept over-
night (even up to 24–36 hours) in the emergency
department for observation and treatment but not
“formally” admitted to the hospital as an inpatient.
Thus, this patient would not qualify as serious based
on a stay in the emergency room (see the Food
and Drug Administration’s 2001 draft guidance on
AE reporting, Section IV.A.3). In the EU, Directive
2001/83/EC refers to the definition of SAE, includ-
ing “inpatient” hospitalization. Generally, an event
meets the criteria for hospitalization if the patient
was admitted to the hospital for more than 24 hours.
Most clinical trial protocols will even go so far to
state that if the hospitalization was due to an elective
procedure, or pre-planned operation not relevant to
the disease under study, that these events would not
meet the criteria for hospitalization. The easiest way
to figure this out is to ask “Was the person hospital-
ized unexpectedly for an adverse event or procedure
that was unanticipated or unplanned?”
Significant or persistent disability/inca-
pacity: A relatively uncommon criterion in prac-
tice andnot formally defined. The FDA gives an
interesting example in its 2001 draft guidance:
Persons incarcerated because of actions allegedly
caused by a drug (e.g., psychotropic drugs and rage
reactions) have sustained a substantial disruption in
their ability to conduct normal life functions. Thus,
these adverse experiences would qualify for the sig-
nificant or persistent disability/incapacity outcome.
Note the change referred to earlier in this chapter
about FDA’s addition of this concept directly into
the definition of “serious”. The FDA slightly altered
the definition of “serious” effective March 2011 for
clinical trials by adding the concept of “disability”
directly into the definition, including the phrase:
“substantial disruption of the ability to conduct
normal life functions”.
Congenital anomaly/birth defect: Usu-
ally rather straightforward. It would include even
mild birth defects, when detected. The FDA also
notes that this includes those defects “occurring
in a fetus”, thus covering abnormalities discovered
before birth.
Important Medical Events (IME): This crite-
rion has often been difficult to handle for pharma-
covigilance departments because the definition relies
on medical judgment. The examples given (allergic
bronchospasm, blood dyscrasias, or convulsions) do
not necessarily help to clarify other less dramatic sit-
uations. The FDA also gives the examples of drug
dependency or drug abuse as important events.
Often, cases elicit hours of debate in drug safety units
on whether to consider them medically important. Is
a mild focal seizure medically important? Is a plate-
let count 10% below the lower level of normal med-
ically important? Other examples abound. Various
rules of thumb have developed as follows:
If it happened to you or a family member, would
you consider it important or medically signifi-
cant?
If you discuss or debate whether a case is medi-
cally important, it is.
The EudraVigilance Working Group developed
an IME (Important Medical Events) list\https://
eudravigilance.ema.europa.eu/human/textfor
IME.asp which is updated twice a year in step
with new versions of MedDRA and can be down-
loaded at the site listed above. Use of the IME list
is voluntary and not required by regulation.
If a member of the marketing or sales depart-
ment or a non-medical professional believes it
is not important, it is important. This “rule”,
though somewhat jocular and cynical, has
developed to note the real observation that
sometimes there are non-medical pressures put
on personnel in the safety department to inter-
pret cases or make decisions based on sales,
financial, or other non-medical criteria. This
is an unfortunate fact of life — not just in the
pharmaceutical world but in the world of clin-
ical medicine, where many judgments are now
made on a cost-effectiveness basis. Always keep
in mind that the primary mission of the drug
safety department is to protect public health.
As a rule, we must never forget the purpose of
such criteria: the goal is not just to ensure we are
(or not) sticking to the regulations (obviously
we must); but to select the cases which are the
most clinically-relevant/important to identify a
signal, if any, to protect the public health. More-
over, if one of the seriousness criteria can be
Seriousness, Expectedness, and Causality 181
checked off, then the others are less important
as the case report becomes serious. The point
is to ensure that the case is correctly assessed
as serious or not. Therefore, in case of doubt, it
is wise to call the case/AE as serious and avoid
endless discussions between co-workers; let’s
not waste any more time!
Expectedness
Is the event expected? Have we seen this event before
in the nature and severity is has occured? Is this event
known to occur in the patient population or in asso-
ciation with the product in use? These are some of
the questions we aim to answer when determining
Expectedness.
The regulations governing expectedness are fairly
straightforward:
For a pre-marketed product: Any adverse
drug experience, the specificity or sever-
ity of which is not consistent with the cur-
rent investigator’s brochure; or, if an investigator
brochure is not required or available, the specificity or
severity of which is not consistent with the risk informa-
tion described in the general investigational plan or else-
where in the current application, as amended. For exam-
ple, under this definition, cerebral thromboembolism
and cerebral vasculitis would be unexpected (by virtue
of greater specificity) if the investigator brochure only
listed cerebral vascular accidents (21CFR312.32(a)).
FDA added to this definition effective March 2011 by
noting in 21CFR312 that “Unexpected, as used in this
definition, also refers to AEs or suspected adverse reac-
tions that are mentioned in the investigator brochure as
occurring with a class of drugs or as anticipated from
the pharmacological properties of the drug, but are not
specifically mentioned as occurring with the particular
drug under investigation”. That is, an AE in the class
labeling section of the brochure without specific men-
tion for the study drug is considered unexpected.
For marketed products: Any adverse drug
experience that is not listed in the current
labeling (PI or SmPC or local labeling) for the
drug product. This includes events that may
be symptomatically and pathophysiologically
related to an event listed in the labeling, but dif-
fer from the event because of greater severity or
specificity, outcome, or frequency. For example,
under this definition, hepatic necrosis would
be unexpected (by virtue of greater severity)
if the labeling only referred to elevated hepatic
enzymes or hepatitis.
AEs that are “class-related” (i.e., allegedly seen
with all products in this class of drugs) and
mentioned in the labeling (PI or SmPC) or
Investigator Brochure, but which are not specif-
ically described as occurring with this product,
are considered unexpected” (21CFR314.80(a)).
In the European Union, expectedness is addressed
in Regulation 536/2014 for clinical trials and Directive
2001/83 for registered products. “Unexpected seri-
ous adverse reaction means a serious adverse reaction,
the nature, severity or outcome of which is not con-
sistent with the Reference Safety Information” (RSI)
(i.e., Investigator Brochure for an unauthorized investi-
gational product and SmPC for an authorized product).
In addition, the regulation specifies that “Expectedness
shall be determined on the basis of events previously
observed with the active substance and not on the
basis of the anticipated pharmacological properties of a
medicinal product or events related to the subject’s dis-
ease”. Severe must not be misunderstood or confused
with serious: the word severe is used to assess medi-
cal intensity while serious helps to identify regulatory
reporting obligations.
In theory, this concept is rather straight forward,
but in practice, it becomes somewhat harder when syn-
onyms and overlapping concepts are considered. In the
report cited previously by Castle and Phillips, 72% of
the EU responders believed that if the labeled event is
“dizziness”, then “vertigo” would also be considered
expected (labeled), but only 50% of the US responders
believed vertigo was labeled. Similarly, 18% of the EU
responders and 3% of the US responders believed that if
“hypotension, wheezing, and urticaria” are labeled, then
a reported term of anaphylaxis would also be expected.
Whether these differences persist, many years after the
survey, is unclear. However, it does highlight the fact
that well-trained experienced medical personnel doing
182 Cobert’s Manual of Drug Safety and Pharmacovigilance
pharmacovigilance can take the same set of facts and
come up with differing and even opposing views. This
study also highlighted the potential differences of inter-
pretation due to language: non-native English speakers
may actually misinterpret case-reports.
In general, one should decide expectedness with-
out thought to seriousness. That is, just because a case
is non-serious and the AE in question is mildly severe
and of little medical import (e.g., a maculopapular rash)
compared with a serious AE (e.g., severe hepatitis), the
decision on expectedness should be made purely on the
basis of the wording in the label and not on the serious-
ness. Give each AE its due.
With clinical trial drugs, especially those not yet
marketed, there may be minimal or no human experi-
ence (e.g., the first study in humans or the first phase II
study after phase I studies showed no AEs). In this case,
there are no labeled events in the investigator brochure,
and everything is thus “new” and unexpected. Antici-
pated events based on the pharmacologic properties of
the drug should not be considered expected until actu-
ally reported in a patient and put into the brochure.
In some cases, it is necessary to consider the route
of administration, dosage, or indication being studied
when assessing the expectedness. This usually depends
on how the investigator brochure or marketed labeling
is written. Some describe a different set of AEs for dif-
ferent indications, dosages, or routes of administration.
Care must be taken to apply the correct label to each
case when doing expectedness. Note that benefit–risk
assessments are performed indication-by-indication,
both for marketing approval and in the post-market-
ing phase. The general advice would be, as with seri-
ousness, to decide on the side of conservatism. Thus,
if there are questions on whether an AE is expected,
consider it unexpected.
Relatedness (Causality)
Was the event associated with the use of the product?
Did the product cause the event to occur?
Of the three criteria revolving around the regulatory
reportability of an individual case (seriousness, expect-
edness, and relatedness), this one is often the most
difficult to do for the multiple reasons explained next.
Causality may be determined initially at the individual
case level, after the receipt of an individual case safety
report, but probably more importantly, again after the
review of aggregate data in a case series as for signaling,
risk management, and various regulatory reports with
aggregate data, such as PSURs/PBRERs.
First, some basic “housekeeping” points should be
cleared up to ensure that cases are always handled and
collected in the same manner. In doing case assessment
of ICSRs, one should be sure that cases are coded using
the current MedDRA
®
version and codes (some older dic-
tionaries may still be used outside the ICH regions and
some labeling for older drugs may not be in MedDRA).
Coders should be trained on coding conventions aligned
with the current version of MedDRA and there should be
consistent methodology, current coding conventions, and
synonym lists. MedDRA Labeling Groupings, when used,
should have clear (updated) lists of included terms.
For aggregate reports, the search criteria for the
case series should be complete and normalized to the
current (i.e., same) MedDRA version and drug dictio-
nary for all ICSRs in the aggregate analysis. This may
require migration from earlier versions if the aggregate
report spans more than one MedDRA version. If queries
are required to obtain similar cases for a specific medi-
cal concept of interest, Standardized MedDRA Queries
(SMQs) developed by CIOMS and published by the
MSSO in step with each version of MedDRA, should be
used in accord with CIOMS guidance. Cases should be
followed up (rapidly upon receipt, not at a later date),
as appropriate, to ensure the maximum amount of
high-quality and useful data.
In practice, many companies have two sets of stan-
dards and classifications for causality assessment of
individual case safety reports. The first is used in clin-
ical trials by the medical research group and the inves-
tigator (a separate causality assessment for each case
should be done by the investigator and the sponsor as
noted by many health authorities FDA, EMA, etc.). The
second is used in the drug safety unit. In the EU, “The
causality assessment given by the investigator shall not
be downgraded by the sponsor. If the sponsor disagrees
with the investigator’s causality assessment, the opinion
of both the investigator and the sponsor shall be pro-
vided (to health authorities) with the report.”
Seriousness, Expectedness, and Causality 183
A decision on causality for regulatory reporting is
binary: yes or no, a causal relationship is possible or
not. The NCI CTCAE Guidance on AE reporting sug-
gests and simplifies causality using the bimodal assess-
ment of yes and no.
RELATIONSHIP ATTRIBUTION DESCRIPTION
Unrelated to
investigational
agent/intervention
1
Unrelated
The AE is clearly
NOT related to the
intervention
Unlikely
The AE is doubtfully
related to the
intervention
Related to
investigational
agent/intervention
1
Possible
The AE may be
related to the
intervention
Probable
The AE is likely
related to the
intervention
Definite
The AE is clearly
related to the
intervention
For other reasons, however, as explained below,
various categories (usually three to six) are included in
clinical trial protocols and case reports, as follows:
Related
Probably related
Possibly related
Unlikely related
Unrelated
Unassessable
This methodology is useful in later analyzing sig-
nals and in creating tables for Investigator Brochures,
product labeling, and monographs to give a feel for
the certainty or lack thereof about the causality of AEs
by the drug in question. However, for the drug safety
group, which must determine whether a clinical trial
case meets the three criteria (seriousness, expectedness,
causality) for expedited reporting, the decision is yes or
no. That is, the drug safety group must make the choice
between unrelated and related. There is no middle
ground or gray zone for causality here. Thus, the drug
safety group has to make a rapid decision on whether
the case is clearly unrelated (absolutely, positively) or
everything else (possibly, probably, unlikely, weakly,
etc.). Some drug safety groups consider “unlikely
related” to be unrelated and other groups consider it in
the broad “related” category. Whichever way is decided,
it should be made clear what will be done in the SOP or
working document (or the protocol for clinical trials)
to everyone in the company. Many drug safety officers
believe that unless a case is clearly and absolutely unre-
lated, the causality should be, for reporting purposes,
“related”. To put it another way, the default causality
for all cases is “possibly related” until there is evidence
that the case is “unrelated”. It is realized that this may
not ultimately agree with the case analysis in the final
clinical research study report, where a more nuanced
opinion may be recorded. So, to summarize, in drug
safety there are two causality choices for reporting pur-
poses: unrelated (thus making the case not reportable as
an expedited case) and everything else (viz. related for
reporting purposes).
In March 2011, the FDA changed the causality
regulations, introducing the concept of “reasonable
possibility” (21CFR32): Suspected adverse reaction
means any AE for which there is a reasonable possi-
bility that the drug caused the AE. For the purposes of
IND safety reporting, ‘‘reasonable possibility’’ means
there is evidence to suggest a causal relationship
between the drug and the AE. Suspected adverse reac-
tion implies a lesser degree of certainty about causal-
ity than adverse reaction, which means any AE caused
by a drug. This wording changes the older concept of
“possible association” to “reasonable possibility”. It
is not clear that this has made a major difference in
practice.
Methodology
Because there are no clear standards or classifications
for causality, two broad methods have been developed
for causality assessment. (Bayesian analysis is a third
method, but this has not proved practical yet.)
Global Introspection
The first (and most widely used) method for causal-
ity is known as “global introspection.” This is a some-
what jocular description of having one or more smart
184 Cobert’s Manual of Drug Safety and Pharmacovigilance
experienced drug safety experts (usually physicians)
read the case details, in particular the narrative, and
decide on “introspective” grounds whether the case
was caused by the drug. Obviously, all the anticipated
difficulties exist when the decision is left to one or
more human beings using subjective criteria: differ-
ent training, different experience, untested inter-rater
reliability, biases, and pressure from others within the
company or institution. A French group in a 2005 pub-
lication on causality found that the overall agreement
among five senior experienced experts using global
introspection was poor and varied according to level
of causality.
2
So, in practice, companies try to get solid,
smart, ethical individuals with thick skin and a strong
desire to protect the public health to do the job of mak-
ing the causality judgments.
These criteria are used in global introspection:
1. Reasons to suspect the AE was caused by the
drug.
2. The AE occurred in the expected time frame (as
a function of the drug’s pharmacologic or clini-
cal half-life);
3. No problems or symptoms before exposure;
4. No other medical conditions that could cause
this AE;
5. No concomitant medications that could cause
this AE;
6. A positive dechallenge and (better) a positive
rechallenge;
7. The AE is consistent with the established mech-
anism of action of the product (“biologic plausi-
bility”);
8. A known class effect;
9. Lack of alternative explanation;
10. A dose response;
11. A “typical” adverse drug reaction (e.g., low
background rate), such as a fixed drug reaction
that would not generally be seen except when
due to a drug;
12. A “clean subject” (e.g., a child);
2
Arimone, Bégaud, Miremont-Salamé, et al., Agreement of expert
judgment in causality assessment of adverse drug reactions, Eur J
Clin Pharmacol 2005; 61(3): 169–173.
13. Consistency of time to onset (e.g., early for
immediate hypersensitivity or long term for tum-
origenesis);
14. Similar findings in toxicity studies;
15. Positive in vitro test (e.g., immunoglobulin E
antibodies to allergen and elevated serum trypt-
ase in anaphylaxis);
16. Positive in vivo test (e.g., intradermal or prick
test for immediate hypersensitivity or patch test
for delayed hypersensitivity);
17. Identified subset at risk or pre-disposing factor;
18. Lack of protopathic bias: a drug given to treat
early symptoms may appear temporally asso-
ciated with the subsequent illness, particularly
if the drug’s efficacy is low. Source: Adapted
from the Report of CIOMS Working Group III,
Guidelines for Preparing Core Clinical Safety
Information on Drugs 1995.
Algorithms
Algorithms represent the second method and the usual
alternative to global introspection. They have in general
not succeeded as well as global introspection when used
alone, though they can be useful when used in conjunc-
tion with global introspection. Algorithms represent a
decision tree that is computerizable and allows yes/no
answers to preset questions to determine a causality
result. Obviously, the algorithm is only as good as the
questions asked and the data provided. Because of the
inability to make a “one size fits all” algorithm, there is
usually a final human review to ensure that the algo-
rithm results are “reasonable” for the situation. More
than 30 algorithms have been developed for both man-
ual and computerized causality assessment of individ-
ual cases in pharmacovigilance. One of the earlier used
algorithms was developed by Professor J. Venulet in
1980 and updated in 1986.
3
In a study to evaluate agreement between various
algorithms and those obtained from an expert panel
using the World Health Organization method, 200
reports were studied. The rates of concordance between
assessments made using the algorithms and those of the
expert panel were 45% for “certain”, 61% for “probable”,
3
Venulet, Ciucci, Berneker, Int J Clin Pharmacol Ther Toxicol 1986;
24: 559.
Seriousness, Expectedness, and Causality 185
46% for “possible”, and 17% for drug-unrelated terms.
Correcting for confounding variables did not signifi-
cantly improve the results. The authors concluded that
full agreement with global introspection was not found
for any level of causality assessment.
4
This area continues to become more robust with
advances in artificial intelligence and its application to
causality and signaling.
Comment
Finally, there is another general rule: If there is disagree-
ment between two or more evaluators (e.g., the clini-
cal research team, the investigator, and the drug safety
department), the most conservative judgment should
be used; that is, if one believes the case is not related
and the other believes it is possibly related, the case
is considered to be related. The European Regulation
536/2014 for clinical trials notes that “If the sponsor
disagrees with the investigator’s causality assessment,
the opinion of both the investigator and the sponsor
shall be provided with the report”; therefore, the more
conservative causality is used for reporting purposes
and both opinions should be provided in the narrative
of the case when submitted.
FDA also wants both the investigator and the
sponsor to make a judgment, but only the spon-
sor is responsible for the final determination.
Although this has been clarified for situations in which
the investigator disagrees with the company, it probably
should also apply within the company when there is
disagreement.
Some sponsors have organized an adjudication
committee (with rules and SOP) for escalation of dis-
agreements so that timely resolution can be reached,
including for possible 7- and 15-day reporting. It
is not recommended to engage in dialogue with an
investigator to convince them to change his/her
opinion when it differs from the company’s position.
Conservatism and over-reporting is preferable to
underreporting of SAEs in our view. The FDA, how-
ever, does allow the sponsor to override the investiga-
tor’s judgment of possibly/probably related and NOT
4
Macedo, Marques, Ribeiro, et al., J Clin Pharm Ther 2003; 28: 137.
report the case as an expedited report. In our view this
can be problematic.
The first highly unlikely SAE (e.g., vaginal cancer
in the daughter of a woman taking DES 14 years ear-
lier) is often felt to be unrelated to the study drug but
after the second and third and additional cases, the
causality now becomes possible or even probable. It is
again our view that overriding an investigator’s related
call is often not a good path to take; it should be jus-
tifiable, taken deliberately, and with an abundance of
caution. In practice, this occurs rarely, if ever. After
all, the investigator knows the study subject from the
bedside perspective. Another problem is that if the
ICSR is reported as an expedited report in the EU but
not in the US, the company is saying different things
to different regulators at the same time — always an
unfortunate and dangerous thing to do. The regulators
talk to each other!
Criteria Table
Comparison of EU and US application of causality
determination to expedited single case reporting from
interventional clinical trials.
Table 1. Causality Table
Investigator
causality
Sponsor
causality
Causality
for
regulatory
reporting
=
Not related
Not
related
Not
related
=
Related Related Related
=
Not related Related Related
Related
Not
related
Not
related
Related
Not
related
Related
For a short and useful summary on how an expert
on pharmacovigilance approaches causality from
a clinical, pharmacologic, and epidemiologic per-
spective, see the article article by Diemont.
5
and the
2012 article by Edwards (Int J Risk Saf Med,
5
Diemont, Netherlands J Med 2003; 63: 7.
186 Cobert’s Manual of Drug Safety and Pharmacovigilance
2012;24(1):41–54. Considerations on causality in
pharmacovigilance, Ralph Edwards).
Health Authority Guidance
and Requirements
There is no international standard for causality assess-
ment or classification. The US and EU recommenda-
tions are summarized in the following sections.
United States FDA
Current United States regulations require a causality
assessment for IND expedited 7- and 15-day reports. These
regulations require an IND safety report (21CFR312):
The sponsor must notify FDA and all participat-
ing investigators (i.e., all investigators 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 possi-
ble, but in no case later than 15 calendar days
after the sponsor determines that the informa-
tion qualifies for reporting. In each IND safety
report, the sponsor must identify all IND safety
reports previously submitted to FDA concern-
ing 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.
An unexpected AE or unexpected suspected
adverse reaction is defined by FDA in the reg-
ulations as unexpected if it is not listed in the
investigator brochure or is not listed at the
specificity or severity that has been observed;
or, if an investigator brochure is not required or
available, is not consistent with the risk infor-
mation described in the general investigational
plan or elsewhere in the current application, as
amended. For example, under this definition,
hepatic necrosis would be unexpected (by virtue
of greater severity) if the investigator brochure
referred only to elevated hepatic enzymes or
hepatitis. Similarly, cerebral thromboembolism
and cerebral vasculitis would be unexpected
(by virtue of greater specificity) if the investiga-
tor brochure listed only cerebral vascular acci-
dents. ‘‘Unexpected’’, as used in this definition,
also refers to AEs or suspected adverse reactions
that are mentioned in the investigator brochure
as occurring with a class of drugs or as antic-
ipated from the pharmacological properties of
the drug, but are not specifically mentioned as
occurring with the particular drug under inves-
tigation (21CFR312.32).
For NDA 15-day expedited reports, there is
“implied” causality for spontaneous reports. What this
means is that if a healthcare professional or consumer
takes the time to report an AE to the manufacturer of the
drug or to the FDA, the implication is that the reporter
believes that to some degree the drug may have caused
the AE. This is not clearly stated in the regulations that
require 15-day expedited reports:
For post-marketing 15-day “Alert reports”, the
applicant shall report each adverse drug expe-
rience that is both serious and unexpected,
whether foreign or domestic, as soon as possi-
ble but in no case later than 15 calendar days of
initial receipt of the information by the appli-
cant” (21CFR314.80(1)(i)).
In the draft, Guidance for Industry Post-marketing
Safety Reporting for Human Drug and Biological Products
Including Vaccines of March 2021, the FDA notes the
following:
For spontaneous reports, the applicant should
assume that an adverse experience or fatal out-
come was suspected to be due to the suspect
drug or biological product (implied causality).
For clinical studies, an adverse experience or
fatal outcome need not be submitted to the
FDA unless the applicant concludes that there
is a reasonable possibility that the product
caused the adverse experience or fatal outcome
(see §§ 310.305(c)(1)(ii), 337.314.80(e)(1),
and 600.80(e)(1)).
Seriousness, Expectedness, and Causality 187
Causality Assessment — Determination of
whether there is a reasonable possibility that the
product is etiologically related to the adverse
experience. Causality assessment includes, for
example, assessment of temporal relationships,
dechallenge/rechallenge information, associa-
tion with (or lack of association with) under-
lying disease, presence (or absence) of a more
likely cause, and physiologic plausibility.
In the draft, Guidance for Industry: Good Phar-
macovigilance Practices and Pharmacoepidemio-
logic Assessment of March 2005, the FDA notes the
following:
For any individual case report, it is rarely pos-
sible to know with a high level of certainty
whether the event was caused by the product.
To date, there are no internationally agreed
upon standards or criteria for assessing cau-
sality in individual cases, especially for events
that often occur spontaneously (e.g., stroke,
pulmonary embolism). Rigorous pharmaco-
epidemiologic studies, such as case-control
studies and cohort studies with appropriate
follow-up, are usually employed to further
examine the potential association between a
product and an AE.
The FDA does not recommend any specific catego-
rization of causality, but the categories probable, pos-
sible, or unlikely have been used. The WHO uses the
following categories: certain, probably/likely, possible,
unlikely, conditional/unclassified, and unassessable/
unclassifiable. Although the FDA does not advocate a
particular categorization system, if a causality assess-
ment is undertaken, the FDA suggests that the causal
categories are specified.
In contrast to causality assessment at the individual
case level, it may be possible to assess the degree of causal-
ity between use of a product and an AE when a sponsor or
health authority gathers and evaluates all available safety
data in aggregate, including the following:
1. Spontaneously reported and published case
reports;
2. Relative risks or odds ratios derived from phar-
macoepidemiologic safety studies;
3. Biologic effects observed in pre-clinical stud-
ies and pharmacokinetic or pharmacodynamic
effects;
4. Safety findings from controlled clinical trials; and
5. General marketing experience with similar prod-
ucts in the class.
FDA concludes: “After the available safety informa-
tion is presented and interpreted, it may be possible to
assess the degree of causality between use of a product
and an adverse event”.
European Union
The EU position on causality is explained in the,
“Detailed guidance on the collection, verification and
presentation of AE/AR reports arising from clinical trials
on medicinal products for human use (‘CT-3’) (2011/C
172/01/7.2.1 (45))”.
Causality: “The definition implies a reason-
able possibility of a causal relationship between
the event and the IMP. This means that there are
facts (evidence) or arguments to suggest a causal
relationship”. All AEs judged by either the
investigator or the sponsor as having a reason-
able suspected causal relationship to an inves-
tigational medicinal product qualify as adverse
reactions. The causality assessment given by the
investigator should not be downgraded by the
sponsor. If the sponsor disagrees with the inves-
tigator’s causality assessment, both the opinion
of the investigator and the sponsor should be
provided with the report.
Post-registration causality: Any sponta-
neous report is considered as having a possible
relationship; the EU health authorities actually
consider an ICSR would not be reported by a
healthcare professional or a patient if this per-
son felt there was a non-drug causal agent.
Since the end of the seventies, the French govern-
ment has used an “imputabilité” decision table based on
188 Cobert’s Manual of Drug Safety and Pharmacovigilance
a combination of chronological criteria (timing, dechal-
lenge, rechallenge), and semi logical criteria (specific
laboratory findings, suggestive clinical picture, other
explanations likely) leading to a five-degree global
score (0, unrelated; 1, doubtful; 2, possible; 3, probable;
4, definite). An additional “bibliographic” score (from
never reported to well known) is also considered.
6
The
updated method has been published in 2013
7
leading to
an increase of the degrees (5–7) for the global score, a
new informativeness scale and a clearer scoring for bib-
liographic assessment. It is legally required to assess all
spontaneous case reports occurring in France according
to this method. It is not used outside of France.
The French causality method has one very use-
ful aspect which is to help determine the appropriate
and useful documentation to be used in a case report.
For example, during a phone call this methodology
helps the pharmacovigilance specialist determine
the most useful and appropriate data to capture for
appropriate case analysis. As regards delivering a
robust conclusion about causal relationship, experts
are still debating...
Overall, a frequently used method for post-market-
ing case reports remains the Naranjo scale or a variant
of it. In published case reports, authors frequently use
this method which is known worldwide.
8
6
Begaud, Therapie 1985; 40(2): 111–118.
7
Arimone, Therapie 2013; 68(2): 69–76.
8
Naranjo CA, et al., A method for estimating the probability of adverse
drug reactions, Clin Pharmacol Ther 1981; 30(2): 239–245.
CIOMS I Assessment
of Causality
It should be emphasized that manufacturers should not
separate out those spontaneous reports they receive
into those that seem to themselves to be causally related
to drug exposure and those they consider not causally
related. A physician in making a spontaneous report to
a manufacturer is indicating that the observed event
may be due to the drug, i.e., the physician suspects that
the event is a reaction. In such a case, it would be inap-
propriate for a manufacturer to impute to the reporting
physician an assessment of causality. Thus, all sponta-
neous reports of serious unlabeled reactions made by
medical professionals should be considered as CIOMS
reports. However, submission of such a report does not
necessarily constitute an acceptance of causality by a
manufacturer. That is clearly the position of the US
FDA.
Uppsala Monitoring Centre
(WHO)
The Uppsala Monitoring Centre uses six categories: (1)
certain, (2) probably/likely, (3) possible, (4) unlikely, (5)
conditional/unclassified, and (6) unassessable/unclassi-
fiable. They note that these categories are widely used,
although not everyone uses all of them. See the chapter
in this Manual on the Uppsala Monitoring Centre.
Judgment of Cases When
Received Versus at the Time
of Periodic Reporting and
Signaling
Most of this chapter dealt with judging cases at the time
of receipt. For causality, this is primarily for clinical
trial cases, but also applies to other types of “solicited”
reports. Judgment of seriousness, expectedness, and
causality in the acute phase upon receipt is often done
with incomplete information and in a “vacuum.”
Seriousness, Expectedness, and Causality 189
At the time of signaling or PSUR/PBRER prepara-
tion, the reviewers now have the benefit of complete (or
at least more complete) information on each case, a case
series, perhaps a review of animal and other pre-clinical
data, a literature review, both interval and cumulative
data, and so on. This allows a more nuanced and rea-
soned judgment. It is not uncommon for causality and
the view of the case to change entirely as more data and
more cases come in. For example, in the early first in
human clinical trials, every AE is unexpected and new.
It is very hard to judge causality. With hindsight, later
on and with more data, the judgment may be easier. It
is highly unlikely that the first case of valvular heart
disease seen with Fen-Phen was felt to be due to the
drugs. Only when several occurred did this SAE appear
to be linked causally to the drug. For cases where there
is a high background incidence, assessment of causal-
ity may take years and major epidemiological studies to
make a valid judgment.
Summary and Comments
For IND or clinical trial ICSRs, a binary causality assess-
ment (related versus not related) is needed in order to
comply with current regulations.
For post-marketing/post-registration case reports,
it is considered that if a reporter takes the trouble to
send the ICSR, there is an implied/inferred link between
drug intake and AE occurrence. There is no offi-
cial method accepted worldwide. One single country
(France) requests that all spontaneous domestic cases
are assessed according to the French Causality Assess-
ment method. As regards causal relationship conclu-
sions, none of the published methods is strongly useful
on a case-by-case basis. In addition, pharmacoepidemi-
ology methods are today often considered to be more
valid to assess causal relationship for a suspected signal
rather than combining “possibly/probably related” case
reports. Getting a clear and robust conclusion about
drug-induced causal relationship for each case report
remains a dream!
Combining seriousness, expectedness and causal
relationship on a case-by-case basis allows the drug
safety specialist to prioritize case management and
reporting to health authorities for pre-registration as
well as for post-registration case reports.
But for signal detection purposes, thanks to the
current IT systems and the use of AI (artificial intel-
ligence) methodology, considering only the serious
unexpected and causally related case reports does not
make sense. For example, case reports assessed as
non-serious, expected and causally related can generate
a signal if these cases together mean an AE frequency
increase. By putting aside such case reports, we would
miss safety signals. It is clear that many case reports
are either expected and/or not related; these reports
generate background noise which is useless for signal
identification; but they are useful for pharmacoepide-
miologic studies among others (case control studies,
for example).
Even if PV regulations have similar objectives in dif-
ferent jurisdictions, many countries have their specific
requirements. Thus, the EU and US, for example, have
slight differences regarding the seriousness or expect-
edness definitions. However, each Agency requires that
their definitions apply to all ICSRs (i.e., domestic and
foreign) submitted to them. Moreover, labeledness must
be assessed according to the local reference safety infor-
mation (US PI and EU SmPC), even for foreign ICSRs
submitted to them. Unfortunately, the content of both
documents can vary for many reasons. As a result, some
companies expedite all spontaneous cases that are cate-
gorized as serious, without regard to labeledness.
The system for determining seriousness, expected-
ness, and causality is, to say the least, messy and com-
plicated. One thing that seems to have become clear
over the years is that judging causality, particularly for a
new drug or for an AE with any drug in an indication or
patient population for which there is a high background
rate of that AE, is exceedingly difficult on a case-by-case
basis. Some drugs in this category take years, millions of
patients exposed, and multiple trials and meta-analyses
(e.g., Avandia
®
and cardiac AEs) before an understand-
ing of whether the drug produced a particular AE or
group of AEs. Even so, experts may arrive at somewhat
differing interpretations of the same data and regula-
tory actions may be implemented or constrained based
on available regulatory tools. The authors’ view is that
a simpler system, which separates reporting to health