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190 Cobert’s Manual of Drug Safety and Pharmacovigilance
authorities from causality judgment, should be consid-
ered in a consensus forum.
In this setting, all SAEs or the subgroup of unex-
pected SAEs should be reported rapidly (say, within 21
days), all deaths and life-threatening SAEs in 7-days
and all non-serious AEs every (say) 90 days (current
EU Regulation for spontaneous reports). When elec-
tronic medical records come into full and effective use
for safety assessment on a global basis, then all (vali-
dated one hopes) SAEs and AEs would (theoretically)
be reported immediately in real time. Or, in fact, the
data will be “pulled” by the health agency from the “big
data” database for analysis. No need to report (“push”)
cases to the health agency. This will probably not hap-
pen for many years as the technology has a long way to
go to make the interoperability of multiple international
systems and standards compatible. And then there are
detailed technical aspects of coding conventions, etc.
As displayed on the scheme below, drug safety offi-
cers can only impact the expected criteria by including
new adverse reactions in the labeling documents. For
both Seriousness and causal relationship, the assess-
ment is “fixed” thanks to their definition.
Seriousness, expectedness and causal relationship
have mainly been used until now to triage the large vol-
ume of ICSRs to be handled as quickly as possible, to
identify signals and then protect public health. Thanks
to the performance of current IT systems, to automated
data entry processes and also to AI, such criteria, will
become less and less important.
Then, at various points in time, seriousness,
expectedness, causality judgments, and relationships
to the drug or drug combinations would be made by
the companies, health agencies, and perhaps outside
experts from the big data at the same time and per-
haps independently. This would hopefully remove
“political” judgments from reporting requirements.
Maybe someday.
CHAPTER
191
16
Coding of Adverse
Events and Drug
Names
A
s pharmacovigilance becomes
more mechanized and comput-
erized, the need for standard
terminologies, formats, dictionaries,
narratives, and abbreviations grows.
The first major standardized areas are
the medical coding of adverse reac-
tions/adverse events (ARs/AEs) and
medical history and the coding of drug
names. Medical coding has become
standardized in the world of pharma-
covigilance with the use of the Medical
Dictionary for Regulatory Activities
(MedDRA
®
).
Introduction
Several other coding systems have been used. Two
prominent ones are COSTART
©
, which the US Food
and Drug Administration (FDA) used for AE coding
until transitioning to MedDRA in late 1998, and WHO-
ART
®
, from the Uppsala Monitoring Centre (UMC).
During decades, many pharmaceutical companies used
their own internal AE coding dictionary. A dwindling
number of organizations still use WHO-ART, which
is available from WHO to Regulators (only) and it is
no longer kept up to date. Thus, whether required in
regulation or not, MedDRA is now the requested stan-
dard for coding adverse reactions/adverse events (ARs/
AEs), device-related events, product quality issues,
medication errors, exposures, medical history, social
history, investigations, misuse and abuse, off label use,
192 Cobert’s Manual of Drug Safety and Pharmacovigilance
and indications. MedDRA’s structure allows for aggre-
gation of those reported terms in medically meaning-
ful groupings to facilitate analysis of safety data. Some
older drug labels in the United States and elsewhere still
have non-MedDRA terms (e.g., COSTART or CTCAE,
etc.) but most sections of newer labeling have been
converted to the MedDRA terminology. An exception
in newer US package inserts is clinical information
coded with the Clinical Observations Recordings and
Encoding (CORE) Problem List Subset of Snomed CT.
These terms are included in the “Highlights” section of
US package inserts that are formatted according to the
Physician Labeling Rule (PLR). In the detailed safety
section of PLR format inserts, MedDRA terms are gener-
ally included at the PT level stratified by System Organ
Class (SOC). In some instances, similar MedDRA terms
can be combined without losing meaning for prescrib-
ers (e.g., sedation, somnolence, drowsiness can be
grouped together in labeling). This can reduce confu-
sion on the part of prescribers. However, it is not always
possible and principles for MedDRA Labeling Group-
ings (MLGs) are being developed. Note that Common
Terminology for Adverse Events (CTCAE), with only
a few hundred terms, is not as granular as MedDRA,
but has “grades” to specify severity of the suspected
AR. CTCAE is used for many oncology studies, partic-
ularly those sponsored/conducted by the US National
Cancer Institute (NCI), the European Organization for
Research and Treatment of Cancer (EORTC), and oth-
ers. Various versions of the CTCAE are available from
the NCI website at no charge. See below. Coding is done
so that companies, regulators, and others can commu-
nicate using the same medical language. ARs/AEs are
coded so that similar cases are described (i.e., classified)
in the same consistent way and so that they can easily
be retrieved, analyzed, and compared. A standard termi-
nology and consistency in its use is invaluable for safety
signal detection and analysis.
AR/AE Coding
MedDRA
MedDRA was developed by the International Coun-
cil for Harmonization of Technical Requirements for
Pharmaceuticals for Human Use (ICH), based on ear-
lier work by the United Kingdom health authority and
others. It was owned by the International Federation of
Pharmaceutical Manufacturers and Associations, acting
as trustee for the ICH Steering Committee. When ICH
became a legal entity under Swiss law, MedDRA own-
ership was transferred to ICH. A service organization
known as the Maintenance and Support Services Orga-
nization (MSSO) serves as the repository, maintainer,
and distributor of MedDRA and the source for infor-
mation on MedDRA. The MSSO manages a formal pro-
cess for Change Requests made by subscribers. A mirror
organization, the Japanese Maintenance Organization
(JMO), functions in a similar role for the Japanese ver-
sion of MedDRA (MedDRA/J). Detailed information is
available from the MSSO and JMO websites. See https://
www.meddra.org/.
· MedDRA is a terminology developed for drugs,
vaccines, and medical devices used for standard-
ized coding of medical concepts (but not product
names). It is hierarchical, which means that it has
multiple levels (five), ranging from the most gen-
eral to very specific. MedDRA is currently available
in 18 languages (Chinese, Czech, Dutch, English,
Estonian, French, German, Greek, Hungarian, Ital-
ian, Japanese, Latvian, Polish, Brazilian Portuguese,
Portugal Portuguese, Russian, Swedish and Span-
ish). The base language is English and all transla-
tions of a medical concept have the same 8-digit
code.
Regulatory Status
European Union: MedDRA use is obligatory in the
European Union. All suspected adverse reaction reports
must be submitted electronically using the most gran-
ular MedDRA codes, i.e., the Lowest Level Term (LLT).
MedDRA is to be used for the reporting of suspected,
unexpected, serious adverse reactions (SUSARs) to
the EudraVigilance clinical trial module. In the post-
marketing phase, suspected ARs and other relevant
data must be coded with MedDRA in both serious and
non-serious case reports. Periodic Safety Update Report
(PSURs) must also have the AR/AE terms coded in
MedDRA, but they are analyzed and displayed at the
Coding of Adverse Events and Drug Names 193
Preferred Term (PT) level. Product labeling, the Sum-
mary of Product Characteristics (SmPC), and Risk
Management Plans should also use MedDRA.
“Standardized MedDRA Queries” (SMQs) are ref-
erenced in GVP Module VII as a potential tool in the
signal evaluation process. The structure intrinsic in
the hierarchy of MedDRA also supports searches, since
terms are arranged in logical groupings.
The EudraVigilance Expert Working Group has
created a list of Important Medical Event (IME) terms
to assist with the classification and assessment of sus-
pected ARs/AEs and aggregate data analysis. Use of the
IME list is voluntary. It is updated with each new ver-
sion of MedDRA and published on the EudraVigilance
website. Some companies use the terms on the IME list
as “always serious” AEs, though not everyone agrees
with this.
United States: FDA has not mandated the use of
MedDRA for reporting AEs. s. It has been implemented
on a voluntary basis by FDA, regulated medical prod-
uct manufacturers/distributors, and other stakehold-
ers. US legislation or regulation does not require use
of MedDRA by either FDA or Sponsors/Applicants/oth-
ers; there is no legally-enforceable mandate. However,
FDA issued a final rule on June 10, 2014 (effective June
10, 2015), that requires industry to submit individual
post-marketing safety reports in an electronic format
that FDA can process, review, and archive (not all in
ICH E2B format). However, the ICH E2B(R2) electronic
case report format specifies use of MedDRA and the
associated technical specifications indicate FDA’s expec-
tation for MedDRA in post-marketing ICSRs for drugs
and biologic products. So, in practice, MedDRA
should be used for all reporting of AEs/ARs.
For clinical trials, FDA also requires submissions
that the agency can review, process, and archive. CDER
and CBER submissions with study data must use the
standards specified in the Catalog posted to the FDA’s
Study Data Standards Resources Web page. Controlled
terminologies currently supported by FDA include
MedDRA. MedDRA is the default terminology for cod-
ing adverse events in clinical trial data.
In summary, MedDRA is the de facto coding standard
in the US for relevant FDA-regulated products intended
for use in humans and nearly all mandatory compliance
data are currently pre-coded in MedDRA by Sponsors/
Applicants. FDA has the expectation that MedDRA will
be used by Sponsors/Applicants as they themselves use
it in their review of the safety data.
Safety reporting for medical devices requires sepa-
rate non-MedDRA codes for Event Problem reporting
to FDA.
MedDRA is used in most AE reporting to FDA. In
practice, as MedDRA is obligatory for the European
Union, Japan, and elsewhere and has no widely used
competing regulatory terminology, it is wise to use
MedDRA consistently for AE reporting.
Note that Snomed CT, ICD, and other terminologies
are often used for observational studies when electronic
medical records are the data source. See the MSSO web-
site for updates and further regulatory information.
MedDRA is updated twice yearly (April 1st and
October 1st), and, in general, users update their own
computer systems on the first Monday of the second
month following release of each new version by the
MSSO. Users may request the addition of new codes to
future versions of MedDRA by applying to the MSSO,
which then reviews each request. Codes also may be
moved, changed, demoted, made non-current, or pro-
moted by the MSSO in the updates. The version number
“bumps up” twice a year.
MedDRA terms cover diseases, diagnoses, signs and
symptoms, therapeutic indications, medical and surgi-
cal procedures, and medical, social, and family histories.
MedDRA does not cover drug and device names, study
design, patient demographic terms, population qualifi-
ers (e.g., rare, frequent), and descriptions of severity or
numbers. It does not give definitions of AEs.
Originally, MedDRA was developed for post-
marketing AEs, but it is now used widely for clini-
cal trial AEs. This has produced complex issues with
regard to long trials that might run a year or more and
go through one or more MedDRA upgrades. When and
how to update the codes in an ongoing trial is com-
plex and has multiple solutions. Generally, however,
the most current version is used in individual expedited
reports. This is the case even when aggregate data from
a long-term study might be coded with a single version
194 Cobert’s Manual of Drug Safety and Pharmacovigilance
in a clinical study report. Methodology should be clearly
described in the study report and integrated summaries.
MedDRA in Practice
The primary purpose of coding data into a standard-
ized terminology is to analyze it. “A key benefit of Med-
DRA is its support of straightforward and sophisticated
analyses. MedDRA can therefore be used to analyze
individual medical events (e.g., “Influenza”) or issues
involving a system, organ or etiology (e.g., infections)
using its hierarchical structure. MedDRA should also
be used for signal detection and monitoring of clinical
syndromes whose symptoms encompass numerous sys-
tems or organs using its multiaxial hierarchy or through
the special feature of Standardized MedDRA Queries
(SMQs)”.
As of September 2023, MedDRA version 26 has more
than 80,000 terms arranged into five hierarchical cate-
gories (total number of LLTs includes PTs, as each PT
is represented at the LLT level. This includes current
and non-current terms) The numbers listed below were
current at the time of publishing and provided to illus-
trate the breadth and depth of the number of classified
and categorized medical terminology. One can imagine,
based on the number of terms systematically coded,
that the logical method used to classify these terms:
System organ classes (SOCs): 29
Higher-level group terms (HLGTs): >337
Higher-level terms (HLTs): >1,738
Preferred terms (PTs): 25,916
Lowest-level terms (LLTs): 86,714
An example of coding:
SOC: Cardiac disorders
HLGT: Cardiac arrhythmias
HLT: Supraventricular arrhythmias
PT: Sinus bradycardia
LLT: Bradycardia sinus, sinus bradycardia
Verbatims: Slow heart rate, sinus bradycardia, slow
pulse, and so forth
Verbatim terms are not MedDRA terms but rather
the terms used by reporters, patients, and investigators.
They may be medical, lay, or slang terms. Many compa-
nies create verbatim dictionaries in which they map the
verbatim terms to MedDRA LLT-level terms. Note that
in this example, “sinus bradycardia” is a verbatim, LLT,
and PT at the same time. Note also that all PTs are LLTs
(but not vice versa).
Each term in MedDRA has a unique eight-digit
code. This unique number is the same for each trans-
lated term in all the MedDRA languages. That is, for
example, “nausea” has a unique eight-digit number no
matter what language “nausea” is coded in.
Browsers: Because there are so many terms, it is nec-
essary to search for a needed term by computer rather
than reading through a printed version of the termi-
nology. For this, the MSSO and other companies have
developed software, called “browsers”, to allow a user
to find the terms he or she needs. The MSSO makes
available a downloadable browser to all subscribers.
Commercial browsers are also available. With the
browser, one or more words (e.g., pain in the leg) are
typed in, and the browser software determines whether
there is a direct word-for-word match at one or more
of the hierarchical levels. If so, it gives the direct “hit”
along with the hierarchical tree; that is, if the direct hit
is an LLT, it will display the PT, HLT, HLGT, and SOC
(both primary and secondary if more than one exists).
If not, most browsers suggest choices for the user to
pick from. The choices are often automatically based
on previous coding selections. Some browsers do “auto-
encoding” where one may type in a narrative (prose
paragraphs), and the browser will extract and code all
medical-sounding terms for the user to examine and
accept or reject. Machine learning has been harnessed
to gradually improve fidelity and efficiency of autoen-
coding. We may see further advances artificial intelli-
gence (AI) over the next few years.
The actual coding of AEs is a very complex sub-
ject and cannot be fully covered here, but some general
thoughts and issues on coding are addressed. The goal
of coding is to create one or more AE codes that cap-
ture the essence of the problems that the patient experi-
enced. There should not be too many or too few terms
but just enough. That is, we should follow the “Goldi-
locks Principle” and use codes that are “just right”, or
as Albert Einstein put it: “Everything should be made
Coding of Adverse Events and Drug Names 195
as simple as possible, but not simpler.” Defining “just
enough”, however, is difficult. ICH provides guidance
that coding should ordinarily be at the LLT level. Fur-
ther, a term(s) should be selected that most accurately
reflects the reported verbatim information.
There are many complexities that one encounters
when coding:
Should one be “a lumper or a splitter”? That is,
should one code “flu-like syndrome” (the lumper)
or “fever”, “malaise”, “fatigue”, “muscle aches”,
“headache”, “chills”, and “runny nose” (the split-
ter)? This may be evident to the reader for a term
such as “flu-like syndrome” but less clear for the
“Hermansky-Pudlak syndrome” (albinism, visual
problems, platelet defects with bleeding, lung dis-
ease, and often kidney and gastrointestinal disease).
When a unifying diagnosis with characteristic signs
and symptoms is reported, however, ICH recom-
mends selecting a term for the diagnosis only as a
preferred option. No reported information should
be excluded and, likewise, information should
not be added. For example, a term for a diagnosis
should not be selected if only signs or symptoms
are reported. When a diagnosis is reported along
with terms that are not consistent with the typical
presentation of that diagnosis, ICH indicates that
the outlying terms should be coded as well as the
diagnosis.
Should one code “cascade effects” or “secondary
effects”? For example, if a patient becomes dizzy
and falls, breaking his or her shoulder and abrading
his or her skin, the primary event is dizziness (and
should be coded) but should the other terms — the
fall, shoulder fracture, skin abrasions — also be
coded and thus considered as AEs associated with
the drug in question in the database and future
labeling?
Should provisional or “rule out” diagnoses be
coded? ICH recommends that provisional diagnoses
as well as reported signs and symptoms should be
coded until a diagnosis can be confirmed by the pri-
mary reporter. Signs and symptoms do not change
whereas a provisional diagnosis might. An alterna-
tive would be to code only signs and symptoms.
The organization’s approach should be documented
in a coding conventions document to facilitate con-
sistency across coders and over time.
In our experience, coding a large number of “rule
out” diagnoses is not done and is not a good idea.
For example, hypercalcemia (elevated calcium) has
a dozen causes. It is not a good idea to code all of
these or, depending on the case, any of the causes
until there is some evidence to suspect one or more
of the diagnoses (causes).
Should one code “low blood glucose” or “hypogly-
cemia”? “Low blood glucose” would code to LLT
Blood glucose decreased, which is a laboratory test
result and links to SOC Investigations. “Hypoglyce-
mia” is a medical condition and would be coded to
LLT Hypoglycemia, which links to PT Hypoglycae-
mia and SOC Metabolism and nutrition disorders.
One must understand the nuances of MedDRA to
code accurately and consistently. Should laboratory
abnormalities be coded as AEs? In the past, this
was sometimes done in an arbitrary and inconsis-
tent manner. It has been a problem in clinical study
reports or dossiers for Marketing Authorization
(MA) when the number of AEs of hypertension did
not equal the number of subjects whose recorded
blood pressure on physical exams went up, clearly
demonstrating that not all elevations in blood pres-
sure were considered to be reportable or codable by
the investigator or company as AEs. Some compa-
nies code lab abnormalities as a lab test only in the
SOC Investigations. Only if there are clinical signs
or symptoms do they also code another non-lab
term as an AE.
Coding should not be done at a less specific level,
sometimes referred to as “downcoding”. For exam-
ple, coding “edema” instead of “facial edema”
or “lung disease NOS (not otherwise specified)”
instead of a more specific diagnosis (e.g., pneu-
mococcal pneumonia). This type of “lumping” can
mask or hide certain AEs or problems.
Coding consistency and variability is often a prob-
lem, especially when there are multiple coders
or coding is done over time (e.g., in a long clini-
cal trial). One might see “elevated liver enzymes”,
“abnormal liver enzymes”, “elevated ALT”, or “ele-
vated AST”, all of which are capturing the same con-
dition in different patients at different times. This
poses problems when one is attempting to retrieve
196 Cobert’s Manual of Drug Safety and Pharmacovigilance
all the potential cases of liver injury for safety sig-
naling (see section on “Standardized MedDRA Que-
ries”) or aggregate AE tables.
Having too many codes for a particular case makes
it hard to understand what the primary or major
issues were. In practice, many users try to limit the
number of codes in each case to six or eight at most.
However, some business partners may require full
coding of all reported terms.
Cultural differences may affect coding across coun-
tries or regions. In addition, language issues may
alter coding, especially if people are coding in a lan-
guage (English) that is not their primary language.
Further, because of language nuances and cultural
aspects, complete translation of every English Med-
DRA term to all other languages is not possible.
There is, in many cases, no single correct answer
to a coding question. Rather it is necessary that cod-
ers agree on certain standards, or “conventions”, that
define (sometimes arbitrarily) how to code. The ICH
has published several versions of its coding sugges-
tions entitled “MedDRA
®
Term Selection: Points to
Consider, ICH-Endorsed Guide for MedDRA Users.
Application to Adverse Drug Reactions/Adverse
Events & Medical and Social History & Indications”.
A copy is freely available for no charge at the MedDRA
website.
The FDA, in its Guidance for Industry Premarket-
ing Risk Assessment of March 2005, has commented on
coding:
1. “Sponsors should explore the accuracy of the
coding process with respect to both investigators
and the persons who code AEs.”
2. “Investigators may sometimes choose verbatim
terms that do not accurately communicate the
adverse event that occurred.”
3. “The severity or magnitude of an event may be
inappropriately exaggerated (e.g., if an investiga-
tor terms a case of isolated elevated transaminases
acute liver failure despite the absence of evidence
of associated hyperbilirubinemia, coagulopathy,
or encephalopathy, which are components of the
standard definition of acute liver failure).”
4. “Conversely, the significance or existence of an
event may be masked (e.g., if an investigator uses
a term that is non-specific and possibly unim-
portant to describe a subject’s discontinuation
from a study when the discontinuation is due to
a serious adverse event).”
5. “Sponsors should strive to identify obvious cod-
ing mistakes as well as any instances when a
potentially serious verbatim term may have been
inappropriately mapped to a more benign coding
term, thus minimizing the potential severity of
an adverse event. One example is coding the ver-
batim term facial edema (suggesting an allergic
reaction) as the non-specific term edema; another
is coding the verbatim term suicidal ideation as
the more benign term emotional lability.”
6. “Prior to analyzing a product’s safety database,
sponsors should ensure that adverse events were
coded with minimal variability across studies,
time, and individual coders.”
To limit variability, some companies establish a
central coding group that either does all AE coding or
performs quality checks to verify that coding done by
others is consistent and correct.
Standardized MedDRA Queries
(SMQs)
Standardized MedDRA Queries (SMQs) are groupings
of terms from one or more MedDRA SOCs that relate
to a defined medical condition or area of interest.
They help in retrieving cases. This implies they were
coded correctly on data entry/input of the cases. The
included terms may relate to signs, symptoms, diag-
noses, syndromes, physical findings, and laboratory
and other physiologic test data. Examples of SMQs
that were developed and tested by CIOMS include
cardiac arrhythmias, cardiac failure, cardiomyopathy,
hepatic disorders, hostility/aggression, hyperglycemia/
new onset diabetes mellitus, malignancies, and over
100 more, including subqueries. See the current list at
the MSSO website.
A newly developing initiative at the FDA is the
development of “FMQs” or “FDA Medical Queries”.
Coding of Adverse Events and Drug Names 197
These are standard groupings of adverse event terms
designed by FDA to help identify potential safety issues
during review of clinical trial adverse event data. The
FDA announced the release of the FDA Medical Query
(FMQ) and Algorithmic FDA Medical Queries (AFMQ)
at a Duke Margolis-FDA Workshop: Advancing Premar-
ket Safety Analytics1 on Sept 14, 2022. The description
of FMQ and AFMQ can be found in this FDA presen-
tation: Advancing Premarket Safety Analytics. Tra-
ditional medical SMQs focus primarily on MedDRA
preferred terms, which clinical trial sponsors used to
classify adverse events that occur during the clinical
trial. The basis is that MedDRA PTs are highly granular
with >24000 PTs and each grouping represents a med-
ical concept. The FMQ consists of groupings of these
terms that correlate to specific broader medical condi-
tions. For example, the FMQ for “Dizziness” consists of
31 different MedDRA preferred terms. Any trial subject
that experiences one or more of these adverse events
would be captured as experiencing “Dizziness”. The
FMQ version 2.1 has over 100 of these groupings and
the most recent version is available publicly online.
The goal of the FMQ is to improve safety signal
detection in clinical trial datasets and create a standard-
ized approach to increase efficiency and consistency.
This is a newly developing concept at the FDA and their
current list of FMQs is available to the public for view-
ing and implementation if desired. One would think...
if the FDA is looking at the data this way, shouldn’t we
also?
Training
Safety departments, regulatory authorities, data entry
personnel, and others need to establish detailed coding
standards, preferably using accepted (ICH) conven-
tions, and to train the staff on their use. Because employ-
ees come and go and because MedDRA is updated twice
a year, training coders is usually an ongoing process.
The MSSO and several vendors provide basic training
courses on MedDRA coding, usually running from 1⁄2
day to 2 or 3 days. Nevertheless, periodic trainings
(internal or external) remain expected by inspectors for
both new comers in the PV business as well as for expe-
rienced PV employees.
Systematized Nomenclature
of Medicine — Clinical Terms
Systematized Nomenclature of Medicine — Clinical
Terms (SNOMED
®
CT) is a comprehensive dictionary
of clinical healthcare terminology that was created
by combining terms created by the College of Amer-
ican Pathologists and the United Kingdom National
Health Service. The main purpose of SNOMED CT is to
encode terms used in health informatics and to support
the effective clinical recording of data. It is designed
for use in clinical documentation in electronic health
records (EHRs). A SNOMED CT to ICD-10-CM map
was developed by the US National Library of Medicine
to support semi-automated generation of ICD-10-CM
codes from clinical data encoded in SNOMED CT for
reimbursement and statistical purposes. The terminol-
ogy is owned, maintained, and distributed by the Inter-
national Health Terminology Standards Development
Organization (IHTSDO), a non-profit in Denmark.
IHTSDO acquires, owns, and administers the rights to
SNOMED CT. It is the primary medical terminology
in electronic health records used for decision-support,
record-keeping, and certain billing activities. Concepts
can be combined at different levels of detail to permit
various levels of hierarchical precision. The nature
of hierarchies allows information to be selectively
retrieved to meet different requirements at various lev-
els of generalization. SNOMED CT supports not only
clinical decision-making, but also supports reuse of
clinical data for research purposes and epidemiology,
etc. Various countries including the United Kingdom,
Spain, Australia, Canada, Sweden, the United States,
and the Netherlands have joined and are in various
stages of implementing SNOMED in their countries.
Countries are linked through their National Release
Centers and translations are available in at least seven
languages. SNOMED CT can be adapted to each coun-
try’s local requirements via extensions.
It is the most comprehensive clinical vocabulary
available and has been designated by the US govern-
ment for electronic exchange of clinical data to include
electronic medical records provider order entry, includ-
ing e-prescribing, laboratory order entry, remote inten-
sive care unit monitoring, lab reporting, emergency
198 Cobert’s Manual of Drug Safety and Pharmacovigilance
room charting, cancer reporting, genetic databases,
pharmaceutical use, and more. It will be or is being
used by certain US federal agencies for exchanging
clinical information for lab result contents, non-lab
interventions and procedures, anatomy, diagnoses and
problems, and nursing terms. Other governments, par-
ticularly in the European Union, may adopt it.
AE Severity Coding
A common problem for coders is judging the severity
(mild, moderate, severe) of an AE. This is, of course,
different from the regulatory definitions of “serious”
and “non-serious”, which may be inconsistent, in a
sense, with severity. For example, mild chest pain that
is perceived by the patient as mild but which is due to a
myocardial infarction and results in hospitalization may
be classified as mild or moderate pain. But in fact, the
AE was serious according to the regulatory definition
because of hospitalization (and “medical importance”).
Severity is, perhaps, best assessed by the experienced
practitioner who sees the patient first-hand.
Most reviewers will make a subjective clinical judg-
ment on severity based on the data supplied and their
subjective conclusion about the AE or cases. There
exists one objective classification system developed by
the US National Cancer Institute for use in its proto-
cols. It is to some degree oncology related but can be
useful for other indications and trials. It is called the
“Common Terminology Criteria for Adverse Events
(CTCAE)”. New versions are released periodically. For
example, version 4.0 was released in June 2010 and
version 5.0 was released in November 2017. Version
6.0 was in progress as of early 2024, but had not yet
been released. The grading scale is 1 (mildest) to 5
(most severe, usually an outcome of death). Informa-
tion is available free and in the public domain at NCI’s
website, and the actual files, in several formats, with
background
Drug Names and Drug
Dictionaries
Another requirement in the pharmacovigilance world
is a consistent and up-to-date drug dictionary. Ideally,
such a dictionary would have all the names of all the
drugs sold throughout the world. Unfortunately, this is
not a simple task. It is far harder than developing an AE
dictionary:
Each drug may have multiple names (see below).
Drug names change.
Drug formulations change: the excipients, the active
ingredient, or both;
A drug with the same trade name may have differ-
ent formulations or strengths in different countries;
Generic brand names (when applicable) for the
same product differ;
Spelling varies, and some languages have different
alphabets and special characters that are not in the
English language;
Combination drugs have multiple names.
Drugs may be very similar, varying only in the salt.
They may have the same names or totally different
names.
Grades
Grade refers to the severity of the AE. The CTCAE
displays Grades 1 through 5 with unique clinical
descriptions of severity for each AE based on this
general guideline:
Grade 1 Mild; asymptomatic or mild symptoms;
clinical or diagnostic observations
only; intervention not indicated.
Grade 2 Moderate; minimal, local or noninva-
sive intervention indicated; limiting
age appropriate instrumental ADL*.
Grade 3 Severe or medically significant but not
immediately life-threatening; hospital-
ization or prolongation of hospitaliza-
tion indicated; disabling; limiting self
care ADL**.
Grade 4 Life-threatening consequences; urgent
intervention indicated.
Grade 5 Death related to AE.
Coding of Adverse Events and Drug Names 199
Multiple Names and Name
Changes
In January 2006, the FDA issued a warning to consum-
ers against filling US prescriptions abroad because drugs
with same or similar names may contain different active
ingredients from those sold in the United States and
may thus pose health risks. They gave two examples:
For example, in the United States, “Flomax” is a
brand name for tamsulosin, a treatment for an enlarged
prostate, while in Italy, the active ingredient in the
product called “Flomax” is morniflumate, an anti-
inflammatory drug. In the United States, “Norpramin”
is the brand name for an anti-depression drug contain-
ing desipramine but, in Spain, the same brand name,
“Norpramin”, is used for a drug that contains omepra-
zole, a treatment for stomach ulcers.
A drug, even a “simple” drug, usually has multiple
names. For example, here is a list of some of the names
for the drug cimetidine that are used around the world:
Eureceptor, Gastromet, SKF 92334, Tagamet, Tametin,
Tratul, Ulcedine, Ulcimet, Ulcomet, Acibilin, Acinil,
Cimal, Cimetag, Cimetum, Dyspamet, Edalene, Peptol,
Ulcedin, Ulcerfen, Ulcofalk, Ulcomedina, Ulhys, N-cy-
ano-N-methyl-N-((E)-2-([(5-methyl-1H-imidazol-4-yl)
methyl]sulfanyl)ethyl)guanidine,1-cyano-2-methyl-3-
(2-(((5-methyl-4-imidazolyl)methyl)thio)ethyl)guani-
dine, 2-cyano-1-methyl-3-(2-(((5-methylimidazol-4-yl)
methyl)thio)ethyl)guanidine, Acibilin, Acinil, Cimetag,
Cimetum, Dyspamet, Edalene, Eureceptor, Gastromet,
Metracin, and Brumetidina.
As noted above, brand names may change. Omepra-
zole was originally sold in the United States as Losec,
but the name was changed to Prilosec at the request of
the FDA because of possible confusion with Lasix.
In the United States, the US Adopted Names Council
(USAN), which is officially sponsored by the American
Medical Association, the US Pharmacopeial Conven-
tion, and the American Pharmacists Association, assigns
generic names that are unique and non-proprietary.
The USAN works closely with the International Non-
proprietary Name (INN) Program of the World Health
Organization (WHO), which assigns international
“generic” names. Different countries or regions may
also use different generic names for exactly the same
drug: “acetaminophen” is used in the United States
and “paracetamol” in the EU and elsewhere. Recently,
the H2 blocker ranitidine was withdrawn from the US
market. It was sold for many years as Zantac®. The
name Zantac360® is now used in the US for famotidine
(another H2 blocker).
Much attention has been paid in the last several
years to medication errors that are felt to be “low-hang-
ing fruit” in the world of drug safety, as errors in nam-
ing, prescribing, and handwriting should be more
easily rectified than finding the rare SAE. In the FDA,
the review of proposed proprietary names is con-
ducted by the Division of Medication Error Prevention
and Analysis (DMEPA) in CDER’s Office of Surveil-
lance and Epidemiology (OSE). DMEPA, in consulta-
tion with the Office of Prescription Drug Promotion
(OPDP) reviews proposed names before approval of an
IND, NDA, BLA, and ANDA. FDA does not review pro-
prietary names of products marketed under an over-
the-counter (OTC) monograph or those of a distrib-
utor or repacker. Similar systems exist in most other
countries. See, for example, Health Canada’s Guidance
for Industry: Drug Name Review: Look-alike Sound-
alike (LA/SA) Health Product Names, the United King-
dom MHRA Guideline on Naming Medicines, and the
European Union’s guideline on naming.
This is obviously a very complex situation. So, in
the example above, cimetidine is the “generic” (and the
INN and USAN, see below) name of the compound that
has a chemical name of N-cyano-N-methyl-N-[2-[[(5-
methyl-1H-imidazol-4-yl)methyl]thio]ethyl]guanidine,
which has the trade names of Tagamet, Peptol, Nu-
Cimet, Apo-Cimetidine, Novo-Cimetidine, and others.
See the website of the Institute for Safe Medication
Practices (https://www.ismp.org/) for an excellent dis-
cussion of all aspects of medication prescribing and
medication errors, including name issues. They publish
a list of Confused Drug Names.
In the drug safety world, during the preparation
of individual case safety reports and aggregate reports
(PSURs, NDA Periodic Reports, etc.), co-medications