DRUG DICTIONARIES AND

CODING IN
PHARMACOVIGILANCE
MRS. MACVEENA M. MARTIN
ASST. PROFESSOR
ST. JOHN INSTITUTE OF PHARMACY AND RESEARCH
 CONTENTS
WHO adverse reaction terminologies
MedDRA and Standardized MedDRA queries
WHO drug dictionary
Information resources in pharmacovigilance, drug information resources
Specialized resources for ADRs
Basic terminologies used in pharmacovigilance
Terminologies of adverse medication related events
Regulatory terminologies
Drug utilization: Need, types of drug utilization studies, Drug use evaluation
Medication safety data: Safety data generation
✓Pre-clinical phase
✓Clinical phase
✓Post approval phase
WORLD HEALTH
ORGANIZATION ADVERSE
REACTION TERMINOLOGY
WHO-ART
WHAT IS WHO-ART???
The WHO Adverse Reaction Terminology was developed and maintained by
Uppsala Monitoring Centre (UMC) over approximately 30 years to serve as a
terminology for coding adverse reaction terms, covering most medical terms
needed in adverse reaction reporting.

Until 2008, when MedDRA was implemented, WHO-ART was the only available
terminology for coding adverse drug reactions in VigiBase.

Today, WHO-ART is no longer actively maintained, and the last release was in
2015.
FEATURES OF WHO-ART
Four-level hierarchical structure
Open-ended - new terms added as necessary
Computer suitable record number system
Developed in English
Translations into French, German, Spanish, Portuguese and Italian
Used by drug regulatory agencies and pharmaceutical manufacturers in many
countries
FOUR LEVEL HIERARCHICAL STRUCTURE
SYSTEM
ORGAN
CLASS (SOC) HIGH LEVEL
TERM (HLT)
PREFERRED
TERM (PT)
INCLUDED
TERM (IT)
STRUCTURE (2015Q1)
ITs
PTs
3925 Included
HLTs 2123 Preferred
SOCs terms
339 High level terms: principal
32 System-organ synonyms to
terms for terms for
classes body Preferred terms
grouping describing
organ groups
Preferred terms adverse
reactions
DEFINITIONS
Preferred terms:
These are the principal terms used for describing drug adverse reactions. They are the
main terms used at the input side, but may also be used for output purposes.

High level terms:

These are group terms of related or similar conditions, which are used for easy retrieval
of information.

E.g. thrombophlebitis leg and thrombophlebitis arm represent two different Preferred
terms but are both grouped under thrombophlebitis as a high level term. All Preferred
terms may not have been assigned a high level term.
DEFINITIONS
System-organ classes:
These are groups of adverse reaction Preferred terms pertaining to the same system-
organ, and are for some purposes used at the output side.
A Preferred term can be allocated to a maximum of three different system-organ
classes, e.g. respiratory depression is coded both under Respiratory disorders and
Central nervous system disorders.
The allocation of a Preferred term to system-organ classes is fixed and does not change
with specific reports.
The first System Organ class listed for each Preferred term is considered the most
important one.
DEFINITIONS
Included terms:
These are terms closely related to Preferred terms.
They are used to assist in finding the corresponding Preferred term for proper coding of
the adverse reaction reported.
DEFINITIONS
Record number system:
Each Preferred term is designated a record number (ARECNO), in consecutive order as
they are introduced.
Preferred terms are always assigned the sequence number (SEQ) 001.
Included terms get the same record number as their corresponding Preferred terms,
but with a higher sequence number.
Where high level terms exist, a high level term link (HL LINK) is assigned from all
relevant Preferred terms.
A high level term is always in itself also a Preferred term.
A high level term link is a pointer to the record number of the Preferred term that is
also the high level term.
DEFINITIONS
Example showing the structure of the Adverse Reaction Terminology and the relationship
between the different types of terms
 THE COMPLETE LIST OF SYSTEM-ORGAN
CLASSES AND CODES
SYSTEM ORGAN CLASS CODE SYSTEM ORGAN CLASS CODE
Skin and appendages disorders 0100 Musculo-skeletal system disorders 0200
Collagen disorders 0300 Central & peripheral nervous system disorders 0410
Autonomic nervous system disorders 0420 Vision disorders 0431
Hearing and vestibular disorders 0432 Special senses other, disorders 0433
Psychiatric disorders 0500 Gastro-intestinal system disorders 0600
Liver and biliary system disorders 0700 Metabolic and nutritional disorders 0800
Endocrine disorders 0900 Cardiovascular disorders, general 1010
Myo-, endo-, pericardial & valve disorders 1020 Heart rate and rhythm disorders 1030
Vascular (extracardiac) disorders 1040 Respiratory system disorders 1100
Red blood cell disorders 1210 White cell and RES* disorders 1220
 THE COMPLETE LIST OF SYSTEM-ORGAN
CLASSES AND CODES
SYSTEM ORGAN CLASS CODE SYSTEM ORGAN CLASS CODE
Platelet, bleeding & clotting disorders 1230 Urinary system disorders 1300
Reproductive disorders, male 1410 Reproductive disorders, female 1420
Foetal disorders 1500 Neonatal and infancy disorders 1600
Neoplasms 1700 Body as a whole - general disorders 1810
Application site disorders 1820 Resistance mechanism disorders 1830
Secondary terms – events 2000 Poison specific terms 2100

Secondary terms: events not likely to be a direct effect of a drug, e.g. medication error, wound infection,
burn, fall
Poison terms: e.g. foetal alcohol syndrome, silicosis, chemical burn
CRITICAL TERMS
Some of the terms in the WHO ART file are indicated by asterisk as Critical Terms.
Critical terms are a subset of adverse reaction terms referring to, or possibly being
indicative of, serious disease states, which have been regarded as particularly important
to follow up.
If a Preferred term is indicated as a Critical Term, its linked Included terms are also
regarded as Critical Terms.

E.g. Death, anaphylactic shock, convulsions, erythema multiforme

MedDRA AND
STANDARDIZED MedDRA
QUERIES
MedDRA: An Overview
ICH recognized that the use of different terminologies at different stages in the
course of developing medicines made it difficult to cross-reference and analyze
data.
Converting data from one terminology to another cost time, resources and
resulted in the inevitable loss or distortion of data.
In view of these challenges, ICH created the Medical Dictionary for Regulatory
Activities (MedDRA) to facilitate the exchange of information through
standardization.
MedDRA: An Overview
Used by regulators and industry for more than a decade, MedDRA is an
important tool for product evaluation, monitoring, communication, electronic
records exchange and oversight.
MedDRA was created to manage clinical information about pharmaceuticals,
biologics, vaccines and drug-device combinations for the entire lifespan of
products.
It is a rich, highly specific, hierarchical, medically oriented, and rigorously
maintained terminology designed to meet the needs of drug regulators and the
pharmaceutical industry as a shared international standard.
MedDRA Definition
MedDRA is a clinically-validated international medical terminology used by
regulatory authorities and the regulated biopharmaceutical industry.

The terminology is used through the entire regulatory process, from pre-
marketing to post-marketing, and for data entry, retrieval, evaluation, and
presentation.
HISTORY OF MedDRA
It began life in the early 1990s as a refinement of the dictionary being developed for the
UK regulatory agency’s post-marketing safety database.

Developed by an international committee of regulators and industry staff, the new

terminology had its first incarnation as MEDDRA (Medical Dictionary for Drug
Regulatory Affairs) in 1993, then being nurtured and transformed by the International
Conference on Harmonization (ICH) M1 Expert Working Group into the subtly renamed
MedDRA (Medical Dictionary for Regulatory Activities)
HISTORY OF MedDRA
Its release as an international ICH-approved standard took place in March 1999.
By this time, its ownership had been taken over by the International Federation of
Pharmaceutical Manufacturers and Associations (IFPMA) acting as trustee for ICH, with
oversight by the MedDRA Management Board answerable to the ICH Steering Committee.
However, the interface with users, who purchase access rights through a system of
licensing, is via the MedDRA Maintenance and Support Services Organization (MSSO;
http://www.meddra.org) and the corresponding, but distinct, Japanese Maintenance
Organization (JMO).
The MSSO and JMO release to subscribers updated versions of MedDRA (currently) every 6
months by Internet download.
Where MedDRA is Used

Regulatory Authority and Industry Databases

Individual Case Safety Reports and Safety Summaries
Clinical Study Reports
Investigators’ Brochures
Core Company Safety Information
Marketing Applications
Publications
Prescribing Information
Advertising
CONTENTS OF MedDRA

The MedDRA terminology contains more than 70,000 terms for

medical conditions, syndromes, diagnoses, clinical signs, symptoms,
laboratory and clinical investigations, social circumstances, device
related issues, medication errors, and product quality issues.

It should be noted that MedDRA is limited to human experience:

animal pharmacology and toxicology and veterinary terms are
outside its scope.
MedDRA DOES NOT INCLUDE
➢terms for drug or device names (unless, exceptionally, these represent a typical medical
diagnosis, such as Digoxin toxicity).
➢definitions of terms
➢demographic descriptors within the text of the terms, such as those describing gender, age
or race- unless these are a component of a discrete medical condition, such as Infantile
spasms or Cancer of male breast.
➢numerical expressions within the terms, although there are again some exceptions such as
Type II hyperlipidemia;
➢measures of severity
TRANSLATIONS
MedDRA is available in English: British English spelling appears in all term levels of the
MedDRA hierarchy, whilst American English spelling is present only as LLTs.
Translations are available in Chinese, Czech, Dutch, French, German, Hungarian, Italian,
Japanese, Portuguese, and Spanish.
Preservation of the unique MedDRA numerical code associated with each term
facilitates translation from one language to another.
APPLICATION
From its inception, MedDRA was intended for use throughout the regulatory process of the
development of medicines in humans and also during their subsequent marketed use.
In clinical studies, it can be used for recording baseline medical and social history, the
names of clinical investigations and for recording and reporting adverse events.
Used to describe adverse events in the Investigator Brochure, in Development Safety
Update Reports, and in the safety sections of interim and final study reports.
The ICH M4E(R1) guideline (ICH Harmonized Tripartite Guideline, 2002) on the Common
Technical Document recommends the use of MedDRA in summary tables of adverse events
to be included in the registration dossier for a new product.
For marketed medicines, MedDRA may be used to present adverse reactions in the
Company Core Safety Information and in reference safety information such as the package
insert and Summary of Product Characteristics (SmPC)
APPLICATION
The scope of MedDRA for use in ICSRs is summarized in the ICH E2B(R2) guidelines (ICH,
2001), to include coding of the following data fields: medical history of disease and surgical
procedures; past drug history – indications and reactions; adverse reaction or event;
therapeutic indication for suspect drug; effects of re-challenge; reported and autopsy-
determined cause of death; and sender’s diagnosis.
An additional use is in the recording of findings of investigations of the adverse event.
MedDRA is also required for use in the periodic safety update report in summary event
tabulations.
STRUCTURE
The structure of MedDRA can be represented diagrammatically as having a five-level
hierarchy

Number of terms Level of term Example

26 System Organ Class (SOC) Respiratory, thoracic, and mediastinal
Disorders
334 High Level Group Terms (HLGT) Lower respiratory tract disorders
1717 High Level Terms (HLT) Lower respiratory tract inflammatory and
immunologic Conditions
20057 Preferred Terms (PT) Alveolitis allergic
71326 Lowest Level Terms (LLT) Pneumonitis allergic
STRUCTURE
Each MedDRA term is presented as words and also comprises an eight-number code.
The terms are organized within 5 hierarchical levels:
1. LLTs;
2. Preferred Terms (PTs);
3. High Level Terms (HLTs);
4. High Level Group Terms (HLGTs); and
5. System Organ Classes (SOCs).
Conceptually, it can also be considered that the terms are arrangedinto 26 vertical axes, each
represented by an SOC.
STRUCTURE
LLTs – around 71,000 in number are at the bottom of the hierarchy and consist of synonyms,
lexical variants, and other similar representations of specified medical or associated
conditions.
These terms are intended for entry onto a database for purposes of “coding” the data.
The large number of available LLTs provides a high degree of probability that the words used
by the individual (the verbatim or “as reported” term) – for example, from a doctor
reporting an adverse reaction – will be represented in MedDRA as an identical, or very
similar, LLT.
However, some LLTs are referred to as “non-current.” These are obsolete, ambiguous or
misspelt terms, sometimes inherited from other terminologies, or ones that breach
MedDRA’s rules in some way, or that are in some other way unacceptable for routine use.
They are retained in MedDRA to facilitate conversion of historical coded data but should not
be used for coding new data.
STRUCTURE
The PT level is that favored for use in case retrieval and data presentation, each PT
ostensibly representing a unique medical concept or a medically robust combination
concept (e.g., PT Diabetic nephropathy).
“Preferred Terms” (PTs) are single concepts for symptoms, signs, disease diagnoses,
therapeutic indications, investigations, surgical or medical procedures, and medical, social
or family history characteristics.

Related PTs are grouped together into over 1,700 “High Level Terms” (HLTs) based upon
anatomy, pathology, physiology, etiology or function.
HLTs are in turn linked to over 330 “High Level Group Terms” (HLGTs).
STRUCTURE
Finally, HLGTs are grouped into 26 “System Organ Classes” (SOCs) which are grouped by
etiology (e.g., Infections and infestations), manifestation site (e.g., Gastrointestinal
disorders) or purpose (e.g., Surgical and medical procedures).

There is also a SOC accounting for social circumstances.

MULTIAXIAL STRUCTURE
Multi-axial = the representation of a medical concept in multiple SOCs

Even a single medical concept can be examined from several points of view.
For example, the PT Influenza represents an important respiratory tract problem as well
as an infection.
For this reason, each PT is assigned to a primary SOC, but may also be assigned to one
or more secondary SOCs.
The multiaxial structure of MedDRA supports signal detection and signal monitoring.
The PT Influenza is primary to the SOC Infections and infestations, but this PT is also
secondary to the SOC Respiratory, thoracic and mediastinal disorders.
STANDARIZED MedDRA QUERIES
Standardized MedDRA Queries (SMQs) are groupings of MedDRA terms, ordinarily at
the Preferred Term (PT) level that relate to a defined medical condition or area of
interest.
SMQs are intended to aid in the identification and retrieval of potentially relevant
individual case safety reports.
The included terms may relate to signs, symptoms, diagnoses, syndromes, physical
findings, laboratory and other physiologic test data, etc.
STANDARIZED MedDRA QUERIES
Standardized MedDRA queries (SMQs) are tools developed to facilitate retrieval of
MedDRA coded data as a first step in investigating drug safety issues in PV and clinical
development.
SMQs are validated, pre-determined sets of MedDRA terms grouped together after
extensive review, testing, analysis and expert discussion.
SMQs are a unique feature of MedDRA and provide a strong tool to support safety
analysis and reporting.
The SMQ topics are intended to address the important PV topics needed by regulatory
and industry users.
The SMQs are maintained with each release of MedDRA by the MSSO.
STANDARIZED MedDRA QUERIES
Currently, over 100 SMQs have been created as the need arises. The following are a small
sampling of SMQs that are available to users today:
➢Anaphylactic reaction
➢Central nervous system vascular disorders
➢Convulsions
➢Depression and suicide/ self injury
➢Drug abuse, dependence and withdrawal
➢Hyperglycaemia/ new onset DM
➢Hypersensitivity
➢Ischaemic heart disease
➢Lack of efficacy/ effect
➢Medication errors
➢Severe cutaneous adverse reactions
SMQ DESIGN CONCEPT
SMQs may include very specific as well as less specific terms that are consistent with
description of the overall clinical syndrome.
While some SMQs are a straightforward collection of terms; others have been designed
to accommodate combination of terms from more than one group.
SMQs have certain specific design futures which user can take advantage of as per
need.
SMQ DESIGN CONCEPT
NARROW SEARCH
This search is geared towards identifying cases that are highly likely to represent the
condition of interest. Narrow search consists of all PTs that indicate the condition with
great certainty.
BROAD SEARCH
This search is geared towards identifying all possible cases, including some that may
prove to be of little or no interest on closer inspection. A broad search includes both the
“narrow” terms and the additional “broad” terms, often of less-specific nature
SMQ DESIGN CONCEPT
A narrow search on SMQ “Acute Renal Failure” (MedDRA ver 15.1) yields 17 PTs and a
broad search yields 43 PTs.
As you can see there is a substantial difference between results of narrow search vs
broad.
The difference is because narrow search is more specific (cases highly likely related to a
specific condition) while broad search is more sensitive (all possible case).
SMQ DESIGN CONCEPT
ALGORITHM
In addition to narrow and broad searches, for some SMQs an algorithmic search
approach is available.
Algorithmic search is a combination of search terms from various sub categories of the
broad search terms.
Algorithmic searches are more likely to identify case of interest than isolated broad
search.
An algorithmic search may reduce amount of noise (non-relevant cases) which may be
present in broad searches.
However, algorithmic search is not available for all SMQs.
SMQ DESIGN CONCEPT
ALGORITHM
An example of algorithmic SMQ is Acute Pancreatitis where the broad search terms are
grouped into two categories: Category B which is a list of laboratory values and
Category C which is a list of signs and symptoms.
The algorithm for Acute Pancreatitis defines a case of interest as a record coded with a
combination of at least one term of Category B and one term of Category C.
SMQ DESIGN CONCEPT
HIERARCHY
Some SMQs are related to each other in hierarchical relationship.
These SMQs consists of one or more subordinate SMQs that could be combined to
create a super ordinate, more inclusive SMQ.
In some of these hierarchical SMQs, there are no “narrow” and “broad” categories
within the subordinate SMQs (sub-SMQs).
The hierarchy is to provide flexibility to users.
For example a user may wish to apply entire scope of the SMQ topic (Haematopoietic
cytopenia SMQ including all sub SMQs - see figure) to retrieve cases related to
Haematopoietic cytopenia or a user can elect to apply a single sub-SMQ (e.g.
Haematopoietic leucopenia) or a combination of sub-SMQ as per need.
SMQ DESIGN CONCEPT
HIERARCHY
WHO DRUG
DICTIONARY
BACKGROUND
The WHO Drug Dictionary was developed by the WHO Collaborating Centre for
International Drug Monitoring – the Uppsala Monitoring Centre – as a tool for
signal detection in the program’s database of international ICSRs – VigiBase™.

The dictionary is used by the program to code medical information in ICSRs

(currently comprising over 7 million case reports from 106 countries).

Because of the international nature of the data, there was a need for a
dictionary with trade name and substance synonyms from all contributing
countries.
BACKGROUND
The dictionary was designed for signal detection based on the VigiBase data, but
since the 1980s it has increasingly been used by pharmaceutical companies for
clinical trial and post-marketing pharmacovigilance, and additional data and
tools have been developed for these uses.
The dictionary contains a code system known as the Drug Code as well as the
anatomical therapeutic chemical (ATC) classification.
Additional classifications are being added to the dictionary – both for post-
marketing signal detection and for use in clinical trials.
DICTIONARY TYPE/FORMAT
Dictionary Types
– WHO Drug Dictionary (WHO DD)
– WHO Drug Dictionary Enhanced (WHO DDE)
– WHO Drug Dictionary Enhanced extended with the Herbal Dictionary (WHO
DDE+HD)
Dictionary Formats
– B-2 Format
– C Format
THE DRUG CODE
The most important code in the dictionary is the Drug Code.
Once a Drug Code is selected it is possible to learn more about the selected drug, such
as its active ingredients and ATC classification.
A Drug Code identifies a name – a trade name, generic name, or drug class.
The Drug Code is a three-tier hierarchy that is an aggregation of Drug Record Number
(Drecno), Sequence Number 1 and Sequence Number 2.
The code is not only a unique identifier of a name; it also gives information about the
active ingredient(s) and salt/ester form of the substance.
With herbal products and insulins, the Drug Code can identify other subclassifications of
the main ingredient.
THE DRUG CODE
The two examples have different Drug Record Numbers, which means that they contain
different active ingredients: ampicillin and paracetamol.
THE DRUG CODE
All entries containing only ampicillin will have the same Drug Record Number –
regardless of the salts of the substance, different trade names and different countries.
THE DRUG CODE
In Table 7.11, the three entries all have the same active ingredient, ampicillin, but in
different salt forms: sodium and trihydrate.
They all have the same Drug Record Number, 000005, but different Sequence Number
1.
All entries containing only ampicillin sodium will have the same Drug Record Number
and Sequence Number 1, regardless of the different trade names and different
countries: 00000502.
THE DRUG CODE
The first sequence number is used for single constituent drugs, to distinguish between
salts or esters of a substance,

the second sequence number distinguishes between trade names with the same
ingredients or alternative names for the same ingredients—for example, paracetamol
(rINN) versus acetaminophen (USAN), glibenclamide (rINN) versus glyburide (USAN),
and rifampicin (rINN) versus rifampin (USAN)
THE DRUG CODE
In Table 7.12, all the entries in the example contain ampicillin.
The first three entries contain ampicillin in its base form but the following three contain
ampicillin sodium.
THE ANATOMICAL–THERAPEUTIC–
CHEMICAL CLASSIFICATION
The ATC classification is an integral part of the WHO drug dictionaries.
The ATC classification is maintained by the WHO Collaborating Centre for Drug Statistics
Methodology in Oslo, Norway.
All drugs in the dictionary are assigned to at least one ATC class.
In most cases the official ATC classification is used, but drugs of natural origin are often
assigned to classes from the Herbal ATC classification that was developed for the WHO
Herbal Dictionary.
THE ANATOMICAL–THERAPEUTIC–
CHEMICAL CLASSIFICATION
In the ATC classification, drugs are divided into different groups according to the
organ or system in which they act and their chemical, pharmacological, and
therapeutic properties (WHO Collaborating Centre for Drug Statistics
Methodology).

The ATC classification hierarchical levels are as follows:

THE ANATOMICAL–THERAPEUTIC–
CHEMICAL CLASSIFICATION
1. Fourteen anatomical groups designated by the letters A–V (one letter).
THE ANATOMICAL–THERAPEUTIC–
CHEMICAL CLASSIFICATION
2. Therapeutic main groups (two figures).
3. Therapeutic/pharmacological subdivision (one letter).
4. Therapeutic/pharmacological/chemical subgroup. In this level the
pharmacological properties and the chemical nature of the substance are taken
into account (one letter).
5. Individual substance designated by numbers. This level is not used in the
WHO drug dictionaries (two figures).
The hierarchical classification makes it possible to aggregate statistics and to
produce queries and listings on different levels.
THE DICTIONARY FORMATS
The B-2 Format dictionary is a dictionary of The C Format dictionary is a dictionary of
Drug Codes (drug names and their Medicinal Products
corresponding ingredient etc.) Medicinal Product ID
A unique combination of
Drug Code • Drug Code
– Ingredient(-s) • Name
– Salt(-s) • Name Specifier
– Names • Country
• Marketing Authorisation Holder
• Strength
• Dosage form