ISO/TS 5499:2024

Health informatics - Clinical particulars - Core principles for the harmonization of therapeutic indications terms and identifiers

The objective of this document is to establish common principles for the creation, assessment, selection and maintenance of maps between terminological resources used to describe and code IDMP therapeutic indications for investigational and medicinal products, medical devices, combination products, biologics and companion diagnostics. Core maintenance principles, such as reliability, reproducibility and quality assurance of the maps for future indication terminology use, are also discussed. The intended audience for this document includes: a) Global regulators, pharmaceutical/biopharmaceutical companies, Clinical Research Organizations (CROs) and universities/scientific institutes involved in the development, authorization and marketing of medicinal products b) Implementers of IDMP seeking more information about coding of Therapeutic Indications c) Healthcare providers d) Standards Organizations e) Implementers and software vendors developing and implementing terminology map sets f) Patients

Informatique de santé — Spécificités cliniques — Principes fondamentaux pour l'harmonisation des termes et identifiants des indications thérapeutiques

General Information

• Status: Published
• Publication Date: 30-Jan-2024
• ICS: 35.240.80 - IT applications in health care technology
• Technical Committee: ISO/TC 215 - Health informatics
• Drafting Committee: ISO/TC 215 - Health informatics
• Current Stage: 6060 - International Standard published
• Start Date: 31-Jan-2024
• Due Date: 01-Sep-2023
• Completion Date: 31-Jan-2024

Relations

• Consolidates: ISO/IEC 10373-6:2020 - Cards and security devices for personal identification - Test methods - Part 6: Contactless proximity objects
• Effective Date: 06-Jun-2022

Overview

ISO/TS 5499:2024 - "Health informatics - Clinical particulars - Core principles for the harmonization of therapeutic indications terms and identifiers" - defines common principles for creating, assessing, selecting and maintaining maps between terminological resources used to describe and code therapeutic indications under the IDMP (Identification of Medicinal Products) data model. The Technical Specification addresses terminologies, use cases and core maintenance principles (reliability, reproducibility, quality assurance) needed to harmonize indication terms and identifiers for medicinal products, biologics, medical devices, combination products and companion diagnostics.

Key topics and requirements

• Terminology coverage: Guidance for common clinical terminologies used for indication coding, including SNOMED CT, MedDRA, ICD, MeSH and drug classification systems (e.g., ATC).
• Use-case driven mapping: Mandates that maps be developed and validated against explicit use cases (e.g., regulatory submission, clinical trials, pharmacovigilance), because semantic tolerances differ by purpose.
• Mapping prerequisites and processes: Defines required processes and best-practice conventions for building maps between terminologies, including handling of national/regional terms and hierarchy differences.
• Quality and maintenance principles: Emphasizes map reliability, reproducibility and quality assurance, with ongoing governance and stakeholder engagement for map updates.
• Safety considerations: Highlights that semantic shifts acceptable for aggregation (statistics, billing) may be unacceptable for patient-level clinical care - maps must reflect this distinction.
• Stakeholder engagement: Encourages involvement of regulators, clinicians, industry and implementers from project inception through maintenance.

Applications and who uses this standard

ISO/TS 5499:2024 supports implementation and interoperability where coded therapeutic indications are needed:

• Global regulators and health authorities for consistent IDMP data exchange and coded labelling.
• Pharmaceutical / biopharmaceutical companies and CROs for clinical trials, regulatory submissions and product labelling.
• Healthcare providers and EHR implementers to improve recording of medication indications and support safe prescribing.
• Pharmacovigilance teams to link adverse event monitoring with therapeutic uses.
• Standards organizations and software vendors building terminology map sets and clinical decision support.
• Researchers and registries requiring harmonized indication data across datasets.
• Patients and public health stakeholders benefiting indirectly from clearer, comparable safety and efficacy information.

Related standards

• ISO/TR 14872 - maintenance of identifiers and terms
• ISO/TR 12300 - principles of mapping between terminological systems
• ISO/TS 21564 - terminology resource map quality measures (MapQual)

ISO/TS 5499 is essential for any organization implementing IDMP-based coding of therapeutic indications, ensuring interoperability, regulatory compliance and safer, more consistent clinical and regulatory data exchange. Keywords: therapeutic indications, IDMP, terminology mapping, SNOMED CT, MedDRA, health informatics, regulatory submission, pharmacovigilance.

Standards Content (Sample)

Technical
Specification
ISO/TS 5499
First edition
Health informatics — Clinical
2024-01
particulars — Core principles for
the harmonization of therapeutic
indications terms and identifiers
Informatique de santé — Spécificités cliniques — Principes
fondamentaux pour l'harmonisation des termes et identifiants
des indications thérapeutiques
Reference number
© ISO 2024
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on
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or ISO’s member body in the country of the requester.
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Published in Switzerland
ii
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms, definitions and abbreviated terms . 1
3.1 Terms and definitions .1
3.2 Abbreviated terms .3
4 Terminologies used for the coding of Therapeutic Indications . 4
4.1 General .4
4.2 SNOMED CT .4
4.3 MedDRA .4
4.4 ICD .4
4.5 MeSH .5
5 Use Cases for Coding of Therapeutic Indications . 5
5.1 General .5
5.2 IDMP data exchange between global regulators and bio/pharmaceutical companies
during regulatory processes .6
5.2.1 Clinical Trials (Medicinal Product Development Lifecycle) .6
5.2.2 Regulatory Submission and Coded Labelling Information .6
5.2.3 Clinical protocol .8
5.2.4 Risk Management.8
5.3 Pharmacovigilance .9
5.3.1 General .9
5.3.2 Clinical information in the EHR supporting regulation for Pharmacovigilance .9
5.3.3 Identify potentially inappropriate prescribing/off-label use .10
5.4 Registries.10
6 Mapping principles specific to therapeutic indications .10
6.1 Maps between Terminologies .10
6.1.1 General .10
6.1.2 Mapping Prerequisites .10
6.1.3 Required Processes . .11
6.2 Therapeutic Indications - Mapping best practice principles and conventions .11
6.3 General mapping guidance . 13
6.3.1 General . 13
6.3.2 Mapping of national and regional terms . 13
6.3.3 Regulatory agencies . 13
Annex A (informative) Implementations of the IDMP Therapeutic Indications Data Model .16
Bibliography .22

iii
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out through
ISO technical committees. Each member body interested in a subject for which a technical committee
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with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are described
in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the different types
of ISO document should be noted. This document was drafted in accordance with the editorial rules of the
ISO/IEC Directives, Part 2 (see www.iso.org/directives).
ISO draws attention to the possibility that the implementation of this document may involve the use of (a)
patent(s). ISO takes no position concerning the evidence, validity or applicability of any claimed patent
rights in respect thereof. As of the date of publication of this document, ISO had not received notice of (a)
patent(s) which may be required to implement this document. However, implementers are cautioned that
this may not represent the latest information, which may be obtained from the patent database available at
www.iso.org/patents. ISO shall not be held responsible for identifying any or all such patent rights.
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and expressions
related to conformity assessment, as well as information about ISO's adherence to the World Trade
Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 215, Health informatics, in collaboration with
the European Committee for Standardization (CEN) Technical Committee CEN/TC 251, Health informatics, in
accordance with the Agreement on technical cooperation between ISO and CEN (Vienna Agreement).
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.

iv
Introduction
The need for improved communication between health agencies, hospitals, pharmacies, pharmaceutical
companies and the general public about drug safety and efficacy information requires migration from manual
text entry and unstructured data that cannot be coded, to a structured data model that is interoperable
[1]
across the health care ecosystem . The clinical particulars conceptual class of the ISO 11615 Identification
of Medicinal Products (IDMP) data model captures information about a medicinal product’s indication(s),
contraindication(s), undesirable effect(s) and interactions. Within this conceptual class, the Therapeutic
Indication subclass captures information about the therapeutic indication for the target disease or condition
for which a medicinal product is authorized, under investigation, or utilized in clinical practice. Therapeutic
indications can be described using free text as presented in approved product labelling documents, and as
terms and codes from standard terminologies. Consistent and accurate coding of therapeutic indication
terms is needed to support a variety of processes and is found in various terminological resources and
official documents, which include epidemiological and real-world databases, electronic health records and
health authority reporting processes. Therefore, a key principle for terminology mapping is that maps are
based on specific use cases, and stakeholders who can provide feedback on the form, content and scope of
the mapping should be engaged from the beginning of and throughout the mapping exercise.
A universally accepted terminology for coding therapeutic indications does not yet exist and is not feasible
due to differing international medicinal product and healthcare regulations and reporting requirements.
There is a difference between the therapeutic indication of a specific medicinal product and the diseases,
conditions or problems listed in an electronic health record (EHR). While most EHRs will manage a problem
list and/or a list of findings and diagnoses and a medication list, it is less frequent that the indication (or
indications) for each specific medication is specified for a particular patient.
In medicinal product labels, a range of authorized indications is listed, often with qualifiers (diagnostic,
preventive, curative, disease-modifying) or specified patient target groups. Sometimes, diseases or
conditions are explicitly listed as not being indications for a specific drug. For example, “drug x” is not
indicated in von Willebrand disease, or “drug y” is contraindicated with Haemophilia A. Use of medicinal
products outside the authorized indications is considered off-label.
The indication wording, and thus the related coding, is based on a highly complex process over the years-long
development of a pharmaceutical product. The relationship between a medicinal product and an indication
is based on evidence from clinical trials, which are often comparative in nature (e.g. placebo versus active
substance, or active substance A versus active substance B). Evidence synthesis in systematic reviews is
often constrained by a Patient/intervention/comparator/outcome (PICO) statement, which results in a
clinical recommendation to prefer or not to prefer the use of a particular medicinal product over another
intervention for a particular patient (with a specific disease or condition), aiming at a specific outcome.
In a regulatory document, this information is often reduced to a statement that “this medicinal product is
indicated for ….”.
In regulatory documents, the relationship is specified between a particular medicinal product (with specific
substance(s), dose form(s), strength(s) and pack sizes), on the one hand and the indication(s), which are
often specified in a detailed form. The formulation of this detailed indication often results from strong
and intricate debate between the medical department of a pharmaceutical company, medical experts and
regulators. The finesse of such formulation is often difficult to catch by any of the existing terminologies. For
example, the therapeutic indications for a preparation that is licensed for over-the-counter (OTC) use can be
more restrictive than the indications for the same preparation when prescribed by a clinician. For example,
treatment of candidiasis in pregnancy using a clotrimazole must be under the direction of a physician; an
OTC preparation is not authorized for this indication.
In handbooks of pharmacology and in drug classifications, indications might be formulated at a higher level
of aggregation, and substances can be aggregated to drug classes. Hence, relationships between high level
indications and drug classes (rather than individual substances) can be described.

v
Terminologies describing drug classes (e.g. the Anatomical Therapeutic Chemical (ATC) codes, SNOMED
1)
CT® , Standard Drug Groups from WHO Drug, etc.) are built using different principles and dimensions
(chemical class, anatomical target, therapeutic intent, mechanism of action, molecular target site), and
exhibit variable levels of granularity. The same is true for terminologies describing diseases, conditions and
signs and symptoms as proxies for indications. Therefore, using different terminologies (and maps between
these terminologies) to establish relationships between medicinal products/drug classes and specific
indications/high level indications can be bewilderingly complex. Hence, harmonization of terminologies
for therapeutic indications should account for both the specific level of regulatory listing of authorized
indications for specific medicinal products, as well as the relationship between high level aggregations of
indications and substances.
The most common standard terminological resources used to describe and code medicinal product
2)
indication terms are the Medical Dictionary for Regulatory Activities (MedDRA® ), SNOMED CT, the
3)
International Statistical Classification of Diseases and Related Health Problems (ICD™ ) and Medical Subject
Headings (MeSH). Mappings between these terminological resources are necessary for documentation and
reporting purposes; however, the different hierarchy levels and variation in the number of terms for each
resource introduce significant complexity in the creation and maintenance of terminology maps. Map usage
is often restricted by the limited availability of centrally provided and approved map sets and contributes
to inefficiencies and redundant manual curation by individual stakeholders for specific use cases. Creation
and maintenance of comprehensive maps between clinical terminologies to support coding of indication
terms will thus liberate workforce effort and enable more efficient processes, responses and comprehensive
reporting.
There are safety and maintenance implications when creating and applying maps that directly impact clinical
care and decision-making. Therefore, a key principle is the requirement to identify the use case for any map
before creating or using mappings. For example, there is an allowable semantic shift during mapping such as
for statistics and billing because of aggregation to a group level, whereas in use cases to support clinical care
at the individual (patient) level, no semantic shift can be tolerated because of potential safety issues. Thus,
mappings between e.g. SNOMED CT and MedDRA are semantic maps of total meaning focused on adverse
events. However, additional maps between these two terminologies with use cases focused on therapeutic
indications are possibly needed, so a use case will need to be developed and tested against existing maps
before deciding on next steps.
This document describes use cases and principles that are applicable for creation, assessment and selection
of maps specific to Therapeutic Indications. This document thus refers to and builds on the following
documents regarding terminologies and mapping:
— ISO/TR 14872 on core principles for maintenance of identifiers and terms
— ISO/TR 12300 on principles of mapping between terminological systems
— ISO/TS 21564 on terminology resource map quality measures (MapQual)
1) SNOMED CT® is the registered trademark of a product supplied by the International Health Terminology Standards
Organization (IHTSDO). This information is given for the convenience of users of this document and does not constitute
an endorsement by ISO of the product named.
2) MedDRA is the registered trademark of a product supplied by the International Federation of Pharmaceutical
Manufacturers & Associations (IFPMA) on behalf of the International Council for Harmonization of Technical Requirements
for Pharmaceuticals for Human Use (ICH). This information is given for the convenience of users of this document and
does not constitute an endorsement by ISO of the product named.
3) ICD™ (International Classification of Diseases) maintained by the World Health Organization is an example of a
suitable product available commercially. This information is given for the convenience of users of this document and does
not constitute an endorsement by ISO of this product.

vi
Technical Specification ISO/TS 5499:2024(en)
Health informatics — Clinical particulars — Core principles
for the harmonization of therapeutic indications terms and
identifiers
1 Scope
The objective of this document is to establish common principles for the creation, assessment, selection
and maintenance of maps between terminological resources used to describe and code IDMP therapeutic
indications for investigational and medicinal products, medical devices, combination products, biologics
and companion diagnostics. Core maintenance principles, such as reliability, reproducibility and quality
assurance of the maps for future indication terminology use, are also discussed. The intended audience for
this document includes:
a) Global regulators, pharmaceutical/biopharmaceutical companies, Clinical Research Organizations
(CROs) and universities/scientific institutes involved in the development, authorization and marketing
of medicinal products
b) Implementers of IDMP seeking more information about coding of Therapeutic Indications
c) Healthcare providers
d) Standards Organizations
e) Implementers and software vendors developing and implementing terminology map sets
f) Patients
2 Normative references
There are no normative references in this document.
3 Terms, definitions and abbreviated terms
3.1 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https:// www .iso .org/ obp
— IEC Electropedia: available at https:// www .electropedia .org/
3.1.1
comorbidity
concurrent condition or co-infection described as part of the indication
3.1.2
electronic health record
EHR
repository of information regarding the health status of a subject of care, in computer processable form
[SOURCE: ISO/TR 20514:2005, 2.11, modified]

3.1.3
electronic health record system
EHR system
system for recording, retrieving and manipulating information in electronic health record
3.1.4
individual map
map
cross map
index from one term to another, sometimes using rules that allow translation from one representation to
another indicating degree of equivalence
Note 1 to entry: Entry in a map which indicates how to translate from an individual source concept to a target concept.
The term map is often used to indicate a table of individual map entries. It is for this reason that the individual and
map tables are being differentiated.
Note 2 to entry: The use of this term is often used in ways which are confusing. It is essential to always make it clear
whether you are referring to an individual map or a map table (or set).
Note 3 to entry: In SNOMED CT, each individual map is represented as a row or group of rows in a map Reference Set.
It links a single map source concept code (e.g. SNOMED CT Concept ID) to one or more codes in a map target (e.g. ICD
Code).
Note 4 to entry: A map is often computable and is the outcome of the mapping process.
[SOURCE: ISO/TR 12300:2014, 2.1.9]
3.1.5
maintenance organization
formal and recognized group or legal business entity involved in the direct or indirect provision of
terminology services such as the creation, reconciliation, maintenance and distribution of IDMP controlled
vocabularies
[SOURCE: ISO/TR 14872:2019, 3.7]
3.1.6
mapping
process of defining a relationship between concepts in one coding system to concepts in another coding
system, in accordance with a documented rationale, for a given purpose
Note 1 to entry: Quality mapping will produce a usable map table, be a reproducible and understandable process.
[SOURCE: ISO/TR 12300:2014, 2.1.12]
3.1.7
map set
map table
map reference set
group of individual maps used to convert a range of entries from source to target code system
[SOURCE: ISO/TR 12300:2014, 2.1.11]
3.1.8
real-world data
RWD
data collected in a non-experimental, non-virtual situation
[SOURCE: ISO/TR 21934-1:2021, 3.9]

3.1.9
structured product labelling
SPL
document markup standard that specifies the structure and semantics of the content of authorized published
information that accompanies any medicine licensed by a medicines licensing authority
[SOURCE: Reference [10]]
3.1.10
target population
type of patients or consumers for which the indication of a medicinal product is authorized or is under
investigation
[SOURCE: ISO 11615:2017, 3.1.81]
3.1.11
term
linguistic representation of a concept
Note 1 to entry: A term can contain symbols and have variants, e.g. different forms of spelling
[SOURCE: ISO/TR 12300:2014, 2.2.8]
3.1.12
terminology
structured, human readable and machine-readable representation of concepts
Note 1 to entry: This includes the relationship of the terminology to the specifications for organizing, communicating
and interpreting such a set of concepts.
[SOURCE: ISO/TS 23541-1:2021, 3.1.5, modified — Note added.]
3.1.13
therapeutic indication
definition of the target disease or condition for which the Medicinal Product is authorized or under
investigation
[SOURCE: ISO 11615:2017, 3.1.82]
3.1.14
vocabulary
terminological dictionary which contains designations and definitions from one or more domains or subjects
[SOURCE: ISO 1087:2019, 3.7.5, modified]
3.1.15
off-label
prescribing of a medicinal product for an unapproved/unauthorized indication when a health care provider
determines that it is medically appropriate for their patient
3.2 Abbreviated terms
ADR Adverse Drug Reaction
CT Clinical Trials
ERP Enterprise resource planning
ICSR Individual Case Safety Report
PSUR Periodic Safety Update Reports

PV Pharmacovigilance
RIM Regulatory Information Management
4 Terminologies used for the coding of Therapeutic Indications
4.1 General
The following terminologies are commonly used in various jurisdictions and are required by regulatory
agencies for coding medicinal product therapeutic indications.
4.2 SNOMED CT
SNOMED CT is a comprehensive, multilingual clinical healthcare terminology, used in more than eighty
countries. It is a resource with comprehensive, scientifically validated clinical content that enables consistent
representation of clinical content in electronic health records and is mapped to other international
standards. SNOMED CT is owned, administered and developed by SNOMED International, a not-for-profit
organization.
The primary purpose of SNOMED CT is to encode the meanings that are used in health information and to
support the effective clinical recording of data with the aim of improving patient care. SNOMED CT provides
the core general terminology for electronic health records. SNOMED CT provides for consistent information
interchange and is fundamental to an interoperable electronic health record. It allows a consistent way to
index, store, retrieve and aggregate clinical data across specialties and sites of care. SNOMED CT is used
to represent Medical Condition in Structured Product Labelling to facilitate informed decision-making and
support long-term patient care. Thus, it is the required terminology for the coding of indications reported to,
[14]
e.g. the U.S. FDA .
4.3 MedDRA
The Medical Dictionary for Regulatory Activities (MedDRA), which is owned by the International Council
for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) and maintained
and distributed by the MedDRA Maintenance and Support Services Organization (MSSO) and the Japanese
Maintenance Organization (JMO), is an international standardized terminology used to exchange regulatory
information on medical products in both pre- and post-authorization phases. In developing and continuously
maintaining MedDRA, the ICH endeavours to provide a single standardized international, multi-lingual
medical terminology which can be used for regulatory communication and evaluation of data pertaining to
medicinal products for human use. As a result, MedDRA is designed for use in the registration, documentation
and safety monitoring of medicinal products through all phases of the development cycle (i.e. from clinical
trials to post-marketing surveillance). Furthermore, MedDRA supports ICH electronic communication
within the ICH’s Electronic Common Technical Document (eCTD) and the E2B Individual Case Safety Report.
[15] [16]
MedDRA is the required terminology for the coding of indications for EMA .
4.4 ICD
The International Statistical Classification of Diseases and Related Health Problems (ICD) is a global
standard classification for reporting diseases and health conditions that is developed and maintained by
the World Health Organization (WHO). It is used worldwide in systems such as patient registries, insurance
claims systems, mortality and morbidity statistics, and patient health records. ICD is the foundation for the
identification of health trends and statistics globally, and the international standard for reporting diseases
and health conditions. It is the diagnostic classification standard for all clinical and research purposes.
ICD defines the universe of diseases, disorders, injuries and other related health conditions, listed in a
[17]
comprehensive, hierarchical fashion .
In addition, the International Classification of Primary Care (ICPC) is accepted within the WHO Family of
nd
International Classifications (FIC) as a classification for primary care or general practice. ICPC, 2 edition
(ICPC-2) classifies patient data and clinical activity in the domains of General/Family Practice and primary

care; it allows classification of the patient’s reason for encounter (RFE), the problems/diagnosis managed,
[18]
interventions, and the ordering of these data in an episode of care structure .
Since the diagnosis and interventions assigned by the healthcare provider and coded with ICD and ICPC
are related to the indications of a pharmaceutical product, mappings between disease terms within these
classifications to those used for coding the therapeutic indications are useful in the healthcare domain.
4.5 MeSH
The Medical Subject Headings (MeSH) thesaurus is a controlled and hierarchically organized vocabulary
produced by the National Library of Medicine (NLM). It is used for indexing, cataloguing, and searching of
biomedical and health-related information. The usage of appropriate descriptors from NLM's Medical Subject
Headings (MeSH)-controlled vocabulary thesaurus or terms from another vocabulary, such as SNOMED
CT, that has been mapped to MeSH within the Unified Medical Language System (UMLS) Metathesaurus,
is required when posting the primary disease or condition being studied in a clinical trial at clinicaltrials.
[19][20]
gov .
5 Use Cases for Coding of Therapeutic Indications
5.1 General
Medicinal product therapeutic indications are initially proposed for clinical trials and can be further
detailed and refined for regulatory submissions, and, if successful, will be included in product labels as part
of the marketing authorization process. Details of the indications are recorded and exchanged as text and
codes, via regulator and pharmaceutical company systems. Once authorized for distribution, the medicinal
products enter the supply chain along with the authorized indication information. This information can then
be used within the healthcare domain, including during the prescribing, dispensing, administering cycle,
with data stored and processed in clinical support systems, medicinal product dictionaries and electronic
health records. If adverse reactions to a medication are encountered, indication information can be sent
back to regulators and pharmaceutical companies in reports as part of the pharmacovigilance process.
Indication data are also be used as part of the reimbursement process and for pharmaco-epidemiological or
other statistical analyses. A high-level view of the flow of indication data is shown in Figure 1. This section
describes some of the use cases for indications and the need for harmonization of indication-related data.
Figure 1 — Processes & Systems Involving Product Indication Data Across Regulatory &
Healthcare4
5.2 IDMP data exchange between global regulators and bio/pharmaceutical companies
during regulatory processes
5.2.1 Clinical Trials (Medicinal Product Development Lifecycle)
During the development lifecycle of a medicinal product, clinical trials must be conducted to prove the
safety and efficacy of the medicine, and indications must be submitted by the pharmaceutical company to
the regulator as part of the clinical trial application process (e.g. clinical trial application (CTA) in Europe,
Investigational new drug (IND) application for the US). Clinical trials for the same medicinal product are
often conducted in multiple countries. Requirements for the description of the indication text and how
it is coded vary between regions, so the indication data for the same medicinal product can be recorded
differently between regions. The availability of maps between terminologies would facilitate exchange of
this data between regions.
5.2.2 Regulatory Submission and Coded Labelling Information
After the successful completion of clinical trials, a regulatory submission for authorization of the medicinal
product can be submitted to the regulator. The data submitted will include details of the therapeutic
indication(s) to be approved/authorized and to be included in the product label as well as coding of the
indication terms.
According to health authority guidance for labelling documents used as the basis for information to health
care professionals and patients, therapeutic indications should be clearly stated to reflect in which disease/
condition and target population the benefit-risk balance was established to be positive.
Nevertheless, defining the therapeutic indication is quite complex and requires a multidimensional analysis
of aspects that influence the benefit/risk assessment with respect to the interpretation of wording in
different therapeutic areas. The therapeutic indication is the primary information on the use of a medicine,
and it should clearly state the disease/condition and population that a medicine is intended to treat.
Examples of such areas of common interest refer to the description of the target population, the severity
of the disease, the aim of the treatment (diagnostic indication, prevention, or treatment), the place of the
medicinal product in the therapy, the use in combination therapy, as well as the consistency of wording
within and across therapeutic areas.
Study data standards describe principles for the exchange of clinical and nonclinical research data between
computer systems and provide a framework for the organization of study data. For example, the Clinical
Data Interchange Standards Consortium-Study Data Tabulation Model (CDISC-SDTM) provides a standard
for organizing and formatting data to streamline processes in collection, management, analysis and
reporting. CDISC SDTM is a required standard in certain regulatory regions (i.e. US, Japan) and promotes the
use of common dictionaries to be utilized across clinical studies adverse events, concomitant medications,
procedures, indications, study drug names, and medical history. More specifically, SDTM requires SNOMED
CT to identify the medical condition or problem that the investigational product in a clinical study is intended
[21]
to affect (treat, diagnose or prevent, i.e. the indication) .
5.2.2.1 Coded Labelling Information
Maps between the terminologies commonly used for coding therapeutic indications within each domain, i.e.
SNOMED CT in the clinical space, MedDRA for safety reporting, and ICD in the healthcare domain, enable the
transformation of unstructured information, e.g. in labelling documents, to structured (coded) information.
In this way, by making that data interoperable, further use cases can be supported, from the tracking of off-
label usage to identification of unmet medical needs.
5.2.2.2 Use Case: Structured Electronic Product Information
Clinical particulars such as indications and contra-indications are key for enabling clinical decision support
systems to be able to use product information and the patient’s health records to alert the prescriber or
dispenser to potential issues or harm with the chosen medicines for a specific patient.

Structured electronic product information (ePI) enables the easy checking of product information for
products concerning the same substances and linkage to other systems.
Online repositories of product information and linkage to this data through use of barcodes on packaging
will enable patients to benefit from the latest information for their medicines and translations of this
information into other languages.
Certain health authorities have implemented or have current initiatives to structure electronic product
information. These initiatives have leveraged data standards to structure and code medicinal product
information that includes therapeutic indications. For example, in 2005 the U.S. FDA implemented HL7
[22]
Structured Product Labeling to structure and code medicinal product information (i.e. ePI). In 2019,
Health Canada initiated their transition to a structured XML format for their product monograph templates
[23]
also utilizing HL7 SPL. The European Medicines Agency (EMA) have also initiated an ePI initiative
utilizing HL7 Fast Healthcare Interoperability Resources (FHIR), which also lends itself to the coding of
[24]
medicinal product information to include therapeutic indications. Of note, U.S. FDA and Health Canada
have identified SNOMED CT as the terminology for the identification of therapeutic indications whereby EMA
has identified MedDRA. This introduces an additional use case in the application of the general principles
identified within this document for additional mapping between SNOMED CT and MedDRA beyond the
pharmacovigilance use case.
5.2.2.3 Clinical Decision Support
Clinical decision support systems use indication information extensively. Firstly, they provide this
information “as data” – to allow a clinician to look up the set of medications that can be used to treat a
particular condition. For example, a clinician might know that "alpha-blocker medication” can be used to
relieve chronic urinary retention in men with benign prostatic hyperplasia; the Clinical Decision Support
(CDS) can list the products that have this indication (e.g. alfuzosin, tamsulosin) rather than other indications
(such as treatment of hypertension – terazosin).
Secondly, CDS use indication information to provide accurate dosage checking. Some medicinal products
have quite different dosage regiments depending on indication. For example, for phosphate binding in renal
failure, an antacid containing aluminium hydroxide can be used in a dosage of up to 20 capsules per day (in
5 divided doses), but when used as an antacid, the maximum dosage is only 5 capsules per day. (Another
example, penicillamine is used to treat rheumatoid arthritis and for Wilson’s disease at different dosage
regimens.)
Thirdly, CDS use diagnosis information in decision rules, as one of the patient characteristics to determine
the appropriate usage of a medicine. For example, if a patient has rheumatoid arthritis, this is a risk factor
that will be part of the consideration to prescribe gastric protection for a non-steroidal anti-inflammatory
drug (NSAID).
As an additional consideration, contra-indications are a special subgroup referring to diseases, which when
present, prohibit the use of that medicine in this patient.
A standard terminological resource for indication terms in a machine-readable format allows users with
clinical decision support tools, electronic health records (EHRs), registries, and electronic prescribing
systems to rapidly search and sort product information. A fully automated health information exchange
system requires the ability to uniquely define and identify clinical particulars within an automated health
information exchange system and the adoption of internationally accepted data standards (i.e. ISO IDMP) and
message exchange standards such as Health Level Seven (HL7) Fast Healthcare Interoperability Resources
(FHIR). The application of data and message exchange standards enables the inclusion of machine-readable
data elements for the electronic exchange of clinical particulars for health care providers, patients, and
relevant regulated and healthcare product information use cases. This will greatly enhance users' ability
to automatically search and sort product information, which allows for patients, healthcare professionals
(HCPs), and providers to support a more robust electronic health records, electronic prescribing systems,
and an array of clinical decision support systems and tools at their disposal.

5.2.3 Clinical protocol
The standardization of the representation of therapeutic indications based on information in the EHR along
with drug information enables the users to retrieve and analyse information for clinical review and audit.
This also allows the re-use of clinical data for additional statistical purposes where required.
A clinical protocol describes the processes and procedures directing the conduct and analysis of a clinical
study. Currently there is no internationally harmonized standard template for the format and content of the
clinical protocol document to support consistency across sponsors and exchange of protocol information.
This lack of harmonization contributes to inefficiencies and difficulties in reviewing and assessing clinical
protocols by regulators, sponsors, ethical oversight bodies, investigators, and other stakeholders. The
standardization of the representation of therapeutic indications based on information in the EHR along with
drug information enables the users to retrieve and analyse information for clinical review and audit. This
also allows the re-use of clinical data for additional statistical purposes where required.
The ICH is an organization comprised of regulatory authorities and pharmaceutical industry to discuss
scientific and technical aspects of pharmaceuticals and develop ICH guidelines. ICH established a formal
[25]
working group, M11: Clinical electronic Structured Harmonized Protocol (CeSHarP). CeSHarP
describes the general design principles, format, and structure of the protocol for the broad adoption of an
internationally harmonized clinical protocol supported by electronic content structured for exchange. All
steps within the conduct of a study are within scope (e.g. trial design, investigator on-boarding, study setup,
study reporting, and review). Identification and coding of indications within a clinical protocol is paramount
and relevant to the primary/secondary objectives, study design, subject selection (e.g. inclusion/exclusion
criteria), concurrent medications and overall study treatment(s) methodology.
The core principles identified within this document are fully in line with the global identification of
indications to support an internationally harmonized clinical protocol exchange; SDOs engaged in the
global identification of indications (e.g. SNOMED CT) are relevant stakeholders in the promotion of an
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