2. INTRODUCTION
The International Conference on Harmonisation(ICH) is
a unique project that brings together the regulatory
authorities of Europe, Japan and the United States and
experts from the pharmaceutical industry in the three
regions to discuss scientific and technical aspects of
product registration.
3. The ICH Topics are divided into four major categories and ICH
Topic Codes are assigned according to these categories.
Q S E M
"Quality"
i.e., those
relating to
chemical and
Pharmaceutic
al Quality
Assurance
(Stability
Testing,
Impurity
Testing,
etc.)
"Safety"
i.e., those
relating
to in vitro and
in vivo pre-
clinical
studies
(Carcinogenici
ty
Testing,
Genotoxicity
Testing, etc.)
"Efficacy"
i.e., those
relating
to clinical
studies in
human
subject
(Dose
Response
Studies, Good
Clinical
Practices,
etc.)
"Multidisciplina
ry”
i.e.,
crosscutting
Topics
which do not
fit uniquely
into one
of the above
categories
(MedDRA,
ESTRI, M3,
CTD,
M5)
4. Multidisciplinary
M1-MedDRA Terminology
M2-Electronic Standards
M3-Non-clinical Safety Studies
M4-Common Technical Document
M5-Data elements & Standards for Drug dictionaries
M6-Gene Therapy
M7-Genotoxic Impurities
M8-Electronic common Technical Document (eCTD)
M9-Biopharmaceutics Classification System (BCS)-based
Biowaivers
M10-Bioanalytical method validation
M11-Clinical electronic Structured Harmonised Protocol
(CeSHarP)
M12-Drug Interaction Studies
M13-Bioequivalence for Immediate-Release Solid Dosage
Form
5. MedDRA Terminology(M1)
MedDRA is a rich and highly specific standardised medical
terminology developed by ICH to facilitate sharing of regulatory
information internationally for medical products used by humans.
MedDRA was developed by the working group of ICH and is owned
by the International Federation of Pharmaceutical Manufacturers
and Associations (IFPMA) acting as trustee for the ICH steering
committee
The development of a Medical Dictionary for Regulatory Activities
(MedDRA) was approved by the ICH Steering Committee in 1997,
and the terminology was launched in 1999
6. It is used for registration, documentation and safety monitoring of
medical products both before and after a product has been
authorised for sale.
Products covered by the scope of MedDRA include
pharmaceuticals, vaccines and drug-device combination products.
The current ICH M1 Points to Consider Working Group develops
and maintains two documents on the use of MedDRA for data
entry (coding) and data retrieval/analysis
The latter includes guidance on the use of SMQs, Standardised
MedDRA Queries, as powerful tools for assisting with safety signal
detection.
Both documents are updated twice a year, with every MedDRA
release.
7. Electronic Standards for the Transfer of Regulatory Information
(ESTRI)(M2)
The M2 Expert Working Group (EWG) was established by the ICH Steering
Committee in 1994 with the objective of facilitating international electronic
communication by evaluating and recommending the specifications
The first Specification developed by the M2 EWG was the Individual Case Safety
Report (ICSR), created as the electronic message for the ICH E2B(R2)
The second Specification developed by the M2 EWG was the Electronic Common
Technical Document (eCTD) created as the electronic message for the
CommonTechnical Document developed by the ICH M4
ICH development of specifications for electronic messages for the E2B(R2) ICH
Guideline on Clinical Safety Data Management for Transmission of Individual Case
Safety Reports, as well as the M4 Common Technical Document (CTD)
In November 2010, the ICH Steering Committee modified the mandate of the
M2 EWG, which responsible for the evaluation and recommendation of standards
8. M3(R2): Guidance on Non-Clinical Safety Studies for the
Conduct of Human Clinical Trials and Marketing
Authorization for Pharmaceuticals
The present guidance represents the consensus that exists
regarding the type and duration of nonclinical safety studies and
their timing to support the conduct of human clinical trials and
marketing authorization for pharmaceuticals.
The nonclinical safety assessment for marketing approval of a
pharmaceutical usually includes pharmacology studies, general
toxicity studies, toxicokinetic and nonclinical pharmacokinetic
studies, reproduction toxicity studies, genotoxicity studies and for
drugs that have special cause for concern are intended for a long
duration of use
9. The goals of the nonclinical safety evaluation generally include a
characterisation of toxic effects with respect to target organs, dose
dependence, relationship to exposure, and, when appropriate,
potential reversibility
This information is used to estimate an initial safe starting dose
and dose range for the human trials and to identify parameters for
clinical monitoring for potential adverse effects.
10. M4 Common Technical Document
The agreement to assemble all the Quality, Safety and Efficacy
information in a common format (called CTD - Common Technical
Document ) has revolutionised the regulatory review processes,
enabled implementation of good review practices.
The Common Technical Document provides a harmonised structure
and format for new product applications. The Common Technical
Document was agreed upon in November 2000 in San Diego, USA
This Common Technical Document is divided into four separate
sections. The four sections address the application organisation
(M4 organise), the Quality section (M4Q), the Safety section (M4S)
and the Efficacy section (M4E) of the harmonised application
11. QUALITY SECTION(M4Q)
The Quality section of the Common Technical Document (M4Q)
provides a Harmonised structure and format for presenting CMC
(Chemistry, Manufacturing and Controls) information in a
registration dossier.
The table of contents includes sections on Drug Substance and
Drug Product.
A new section on Pharmaceutical Development has been included
to replace the Development Pharmaceutics Report (currently a
part of the EU submission requirements).
Also, a new CMC summary document, the Quality Overall
Summary, has been developed.
12. SAFETY SECTION M4S(R2)
The CTD Safety (M4S) Guideline delineates the structure and
format of the nonclinical summaries in Module 2 of the Common
Technical Document, and provides the organisation of Module 4,
the Nonclinical Study Reports.
The Nonclinical Overview should present an integrated and critical
assessment of the pharmacologic, pharmacokinetic, and toxicologic
evaluation of the pharmaceutical, and generally should not exceed
30 pages.
The Nonclinical Written Summaries (100 - 150 pages) are
recommended to provide more extensive summaries and
discussion of the nonclinical information on pharmacology,
pharmacokinetics and toxicology
13. EFFICACY SECTION M4E(R2)
CTD Efficacy (M4E) describes the structure and format of the
clinical data in an application, including summaries and detailed
study reports.
There are two high level clinical summaries in Module 2 of the CTD:
the Clinical Overview, a short document that provides a critical
assessment of the clinical data; and the Clinical Summary, a longer
document that focuses on data summarisation and integration.
Clinical Study Reports and raw data (where applicable) are
included in Module 5 of the CTD.
15. M5: Data Elements and Standards for Drug Dictionaries
This document provides guidance on the harmonized standards
related to core sets of medicinal product information and
medicinal product terminology.
Facilitate the exchange and practical use of medicinal product data
by regulators and pharmaceutical industry.
In particular, a need was identified to harmonise product
information that would facilitate the electronic exchange of
Individual Case Safety Reports (ICSRs) within and across ICH
regions using the ICH E2B format in post-marketing
pharmacovigilance.
16. M6 GENE THEARPY
VIRUS AND GENE THERAPY VECTOR SHEDDING
This new topic was endorsed by the ICH Steering Committee in
September 2009.
In September 2009, following the finalisation by the ICH Gene
Therapy Discussion Group (GTDG) of the ICH Consideration
document “General Principles to Address Virus and Vector
Shedding”
The ICH Steering Committee endorsed the development of an ICH
Guideline on this topic with the aim of providing more extensive
information to improve harmonisation amongst the ICH regions.
This new topic was subsequently assigned the code “M6”. In April
2011, this topic was ceased following the ICH Steering Committee
discussion.
17. M7 MUTAGENIC IMPURITIES
M7(R1)ASSESSMENT AND CONTROL OF MUTAGENIC
IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL
CARCINOGENIC RISK
The ICH M7 Guideline was finalised in 2014 offering guidance on
analysis of Structure Activity Relationships (SAR) for genotoxicity.
It is intended to resolve questions such as whether impurities with
similar alerts that potentially have similar mechanism of action
should not be combined in calculating a Threshold of Toxicological
Concern (TTC) and whether the TTC may differ based on differences
in the approved duration of use.
The intent of this Addendum is to provide useful information
regarding the acceptable limits of known mutagenic
impurities/carcinogenic and supporting monographs
18. M7(R2)ASSESSMENT AND CONTROL OF MUTAGENIC
IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL
CARCINOGENIC RISK
The M7(R2) Maintenance EWG is currently undertaking a
maintenance of the M7(R1) Guideline to incorporate acceptable
limits (Acceptable Intakes (AIs) or Permitted Daily Exposures
(PDEs)) for new DNA reactive (mutagenic) impurities and revising
acceptable limits for impurities already listed in the Addendum as
new data becomes available, which will result in the future ICH
M7(R2) version.
As a result, Q&As will be developed to clarify and address Quality
and Safety issues and concerns that have been identified from
experience through implementation of M7 since its publication in
2014.
19. M8 ELECTRONIC COMMON TECHNICAl
DOCUMENT(eCTD)
An electronic version of the Common Technical Document (eCTD)
developed by the eCTD Implementation Working Group.
The Electronic Common Technical Document (eCTD) allows for the
electronic submission of the Common Technical Document (CTD)
by an applicant to regulator.
Implemented 6 months behind CTD on May 2001, Tokyo, Step 2 of
the eCTD ICH process was agreed by Multidisciplinary Group 2
Expert Working Group (ICH M2 EWG).
Specifications developed by ICH M2 EWG
Maintained by eCTD IWG
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25. M9 Biopharmaceutics Classification System (BCS)-based
biowaivers.
This topic was endorsed by the ICH Assembly in October 2016.
This new multidisciplinary Guideline is proposed to address
Biopharmaceutics Classification System (BCS)-based biowaivers.
BCS-based biowaivers may be applicable to BCS Class I and III
drugs, however BCS-based biowaivers for these two classes are not
recognised worldwide.
This Guideline applies to the systems supporting the development
and manufacture of pharmaceutical drug substances and drug
products, including biotechnology and biological products
This Guideline will provide recommendations to support the
biopharmaceutics classification of medicinal products and will
provide recommendations to support the waiver of bioequivalence
studies
26. M10 BIOANALYTICAL METHOD VALIDATION
This topic was endorsed by the ICH Management Committee in
October 2016.
This new multidisciplinary guideline will apply to the validation of
bioanalytical methods and study sample analyses in non-clinical
and clinical studies.
This guideline will provide recommendations on the scientific
regulatory requirements for bioanalysis conducted during the
development of drugs of both chemical and biological origins.
It will also address issues on method validation by considering the
characteristics of the analytical methods used in bioanalysis, e.g.,
chromatographic assay and ligand binding assay.
