Ichguidelines imp

2
 ICH is the “International Conference on
Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use”.
 ICH is a joint initiative involving both regulators
and research-based industry representatives of the
EU, Japan and the US in scientific and technical
discussions of the testing procedures required to
assess and ensure the safety, quality and efficacy of
medicines.

Objectives of ICH
 To increase international harmonization of technical
requirements to ensure that safe, effective and high
quality medicines are developed.
 To harmonize technical requirements for registration
or marketing approval.
 To develop and register pharmaceuticals in the most
efficient and cost effective manner.
 To promote public health.
 To prevent unnecessary duplication of clinical trials on
humans.
 To minimize the use of animal testing without
compromising safety and effectiveness of drug.
3

ICH located
The ICH Secretariat is based in Geneva. The
biennial meetings and conferences of the ICH
Steering Committee rotate between the EU, Japan,
and the USA.
4

Goal of ICH
 To promote international harmonization by
bringing together representatives from the three
ICH regions (EU, Japan and USA)
 To discuss and establish common guidelines.
 To make information available on ICH, ICH
activities and ICH guidelines to any country or
company that requests the information
 To promote a mutual understanding of regional
initiatives in order to facilitate harmonization
processes related to ICH guidelines regionally and
globally
 To strengthen the capacity of drug regulatory
authorities and industry to utilize them.
5

Members of ICH
• ICH is comprised of representatives from six parties that
represent the regulatory bodies and research-based industry
in the European Union, Japan and the USA.
• In Japan, the members are the Ministry of Health, Labour and
Welfare (MHLW), and the Japan Pharmaceutical
Manufacturers Association (JPMA).
• In Europe, the members are the European Union (EU), and
the European Federation of Pharmaceutical Industries and
Associations (EFPIA).
• In the USA, the members are the Food and Drug
Administration (FDA), and the Pharmaceutical Research and
Manufacturers of America (PhRMA).
• Additional members include Observers from the World Health
Organization (WHO), European Free Trade Association
(EFTA), and Canada. The Observers represent non-ICH
countries and regions. 6

ICH structure
The ICH structure consists of the ICH Steering Committee,
ICH Coordinators, ICH Secretariat and ICH Working
Groups.
ICH Steering Committee
The Steering Committee is the body that governs the ICH,
determines the policies and procedures for ICH, selects
topics for harmonization and monitors the progress of
harmonization initiatives. Each of the six ICH parties has
two seats on the ICH Steering Committee.
ICH Coordinators
The Coordinators are fundamental to the smooth running of
the ICH and are nominated by each of the six parties. An
ICH Coordinator acts as the main contact point with the
ICH Secretariat.
7

ICH Secretariat
The Secretariat is primarily concerned with preparations
for, and documentation of, meetings of the Steering
Committee as well as coordination of preparations for
Working Group and Discussion Group meetings.
Information on ICH Guidelines and the general ICH
process can be obtained from the ICH Secretariat.
ICH Working Group
Depending on the type of harmonization activity needed,
the Steering Committee will endorse the establishment of
one of three types of working group i.e., Expert Working
Group (EWG), Implementation Working Group (IWG) or
Informal Working Group.
8

ICH OPERATION
ICH operates through the ICH Steering Committee with
administrative support from the ICH Secretariat and ICH
Coordinators.
The Steering Committee meets at least twice a year . During these
meetings, new topics will be considered for adoption, reports are
received on the progress of existing topics, and maintenance and
implementation of the guidelines are discussed.
The topics identified for harmonization by the Steering Committee
are
selected from Safety, Quality, Efficacy, and Multidisciplinary
matters.
9

Steps in the ICH process
Step-1: Drafts are prepared and circulated through
many revisions until a "final harmonised draft" is
completed
Step-2: This draft is signed by the EWG as the agreed-
upon draft and forwarded to the Steering Committee
for signing which signifies acceptance for
consultation by each of the six co-sponsors
Step-3: The three regulatory sponsors initiate their
normal consultation process to receive comments.
10

 Step-4 is reached when the Steering Committee
agrees that there is sufficient scientific consensus on
the technical issues. This endorsement is based on
the signatures from the three regulatory parties to
ICH affirming that the Guideline is recommended
for adoption by the regulatory bodies of the three
regions.
 Step-5: The process is complete when the guidelines
are incorporated into national or regional internal
procedures(implementation in the 3 ICH regions.)
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MULTIDISCIPLINARYMULTIDISCIPLINARY
EFFICACYEFFICACY
SAFETYSAFETY
QUALITYQUALITY

 "Quality" Topics, i.e., those relating to chemical
and pharmaceutical Quality Assurance (Stability
Testing, Impurity Testing, etc.)
 Efficacy" Topics, i.e., those relating to clinical
studies in human subject (Dose Response
Studies, Good Clinical Practices, etc.)
 Safety" Topics, i.e., those relating to in vitro and
in vivo pre-clinical studies (Carcinogenicity
Testing, Genotoxicity Testing, etc.)
 Multidisciplinary" Topics, i.e., cross-cutting
Topics which do not fit uniquely into one of the
above categories.
13

 Quality Guidelines "Quality" Topics, i.e., those
relating to chemical and pharmaceutical Quality
Assurance (Stability Testing, Impurity Testing,
etc.)
14

 Q1A-Q1F---STABILITY:
 Q1A (R2): Stability Testing of New Drug Substances
and Products
 The purpose of stability testing is to provide evidence
on how the quality of a drug substance or drug product
varies with time under the influence of a variety of
environmental factors such as temperature, humidity,
and light, and to establish a re-test period for the drug
substance or a shelf life for the drug product.
 Q1B: Photostability Testing of New Drug Substances
and Products
• Give guidance on the basic testing protocol required to
evaluate the light sensitivity and stability of new
drugs and products
15

 Q1C: Stability Testing for New Dosage Forms
 Gives guidelines for new formulations of already
approved medicines and defines the circumstances
under which reduced stability data can be accepted.
 Q1D: Bracketing and Matrixing Designs for Stability
Testing of New Drug Substances and Products
 Q1E: Evaluation of Stability Data
• This guideline addresses the evaluation of stability
data that should be submitted in registration
applications for new molecular entities and associated
drug products. The guideline provides
recommendations on establishing shelf lives for drug
substances and drug products intended for storage at
or below “room temperature”.
16

 Q1F: Stability Data Package for Registration
Applications in Climatic Zones III and IV
• Describes harmonised global stability testing
requirements in order to facilitate access to medicines
by reducing the number of different storage conditions.
WHO conducted a survey amongst their member
states to find consensus on 30°C/65% RH as the long-
term storage conditions for hot-dry and hot-humid
regions.
17

 Q2-Analytical validation
 Q2(R1): Validation of Analytical Procedures:
Text and Methodology
 The objective of validation of an analytical procedure
is to demonstrate that it is suitable for its intended
purpose
 Gives validation parameters needed for a variety of
analytical methods.
 It also discusses the characteristics that must be
considered during the validation of the analytical
procedures
18

• Types of Analytical Procedures to be validated
are:
 Identification tests;
 Quantitative tests for impurities content;
 Limit tests for the control of impurities;
 Quantitative tests of the active moiety in
samples of drug substance or drug product or
other selected components in the drug product.
• Typical validation characteristics of analytical
procedures
Accuracy, Precision(Repeatability, Intermediate
Precision), Specificity, Detection Limit,
Quantitation Limit, Linearity, Range.
19

 Q3A- Q3D----Impurities
 Q3A(R2): Impurities in New Drug Substances
 The guideline addresses the chemistry and safety
aspects of impurities, including the listing of
impurities, threshold limit, identification and
quantification.
 Classification of Impurities: are of 3 types
 Organic impurities (process- and drug-related)
 Inorganic impurities
 Residual solvents
20

 Q3B(R2): Impurities in New Drug Products
 Q3C(R4): Impurities: Guideline for Residual
Solvents
21
Benzene 2ppm
Carbon tetrachloride 4ppm
Dichloromethane 5ppm
Dichloroethane 8ppm
Acetonitrile 410ppm
Chloroform 60ppm
Chlorobenzene 360ppm
Formamide, Hexane 290ppm
Toulene 890ppm
Pyridine 200pm
Nitromethane 50ppm
Methanol 3000ppm

 Q4: Pharmacopoeias
 Q4A: Pharmacopoeial Harmonisation
 Q4B: Evaluation and Recommendation of
Pharmacopoeial Texts for Use in the ICH
Regions
 This document describes a process for the
evaluation and recommendation given by the
Q4B Expert Working Group (EWG) for
selecting pharmacopoeial texts to facilitate
their recognition by regulatory authorities for
use, interchangeable in the ICH regions.
22

• Q4B Annex 1: Evaluation and Recommendation of Pharmacopoeial Texts for
Use in the ICH Regions on
Residue on Ignition/Sulphated Ash
• Annex 2:Test for Extractable Volume of Parenteral Preparations
• Annex 3: Test for Particulate Contamination: Sub-Visible Particles
• Annex 4A: Microbiological Examination of Non-Sterile Products: Microbial
Enumeration Tests
• Annex 4B: Microbiological Examination of Non-Sterile Products: Tests for
Specified Micro-organisms
• Annex 4C: Microbiological Examination of Non-Sterile Products: Acceptance
Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical
Use
• Annex 5:Disintegration Test
• Annex 6: Uniformity of Dosage Units
• Annex 7: Dissolution Test
• Annex 8: Sterility Test
• Annex 9: Tablet Friability
• Annex 10: Polyacrylamide Gel Electrophoresis
• Annex 11: Capillary Electrophoresis
• Annex 12: Analytical Sieving
• Annex 13: Bulk Density and Tapped Density of Powders
• Annex14 :Bacterial Endotoxins Test
23

 Q5A-Q5E---Quality of biotechnological
products:
 Q5A(R1): Viral Safety Evaluation of
Biotechnology Products Derived from Cell
Lines of Human or Animal Origin
• This document is concerned with testing and
evaluation of the viral safety of biotechnology products
derived from cell lines of human or animal origin (i.e.,
mammalian, avian, insect)
• The objective is to provide a general framework for
virus testing experiments for the evaluation of virus
clearance and the design of viral tests and clearance
evaluation studies.
24

• Three principal, complementary approaches have
evolved to control the potential viral contamination of
biotechnology products:
a) selecting and testing cell lines and other raw
materials, including media components, for the
absence of undesirable viruses which may be infectious
and/or pathogenic for humans;
b) Testing the capacity of the processes to clear
infectious viruses;
c) testing the product at appropriate steps for absence of
contaminating infectious viruses.
25

 Q5B: Quality of Biotechnological Products :
Analysis of the Expression Construct in Cells
Used for Production of r-DNA Derived Protein
Products
 This document presents guidance regarding the
characterization of the expression construct for the
production of recombinant DNA protein products in
eukaryotic and prokaryotic cells.
 expression construct should be analysed using nucleic
acid techniques.
26

 Q5C: Quality of Biotechnological Products :
Stability Testing of
Biotechnological/Biological Products
 Q5D: Derivation and Characterisation of
Cell Substrates Used for Production of
• The objective of this guideline is to provide
broad guidance on appropriate standards for
cell substrates.
27

 Q5E: Comparability of Biotechnological/
Biological Products Subject to Changes in
Their Manufacturing Process
• The objective of this document is to provide principles
for assessing the comparability of biotechnological/
biological products before and after changes are made
in the manufacturing process for the drug substance or
drug product.
• Therefore, this guideline is intended to assist in the
collection of relevant technical information which
serves as evidence that the manufacturing process
changes will not have an adverse impact on the
quality, safety and efficacy of the drug product.
28

 Q6 : Specifications for New Drug Substances
and Products
• Bulk drug substance and final product
specifications are key parts of the core
documentation for world-wide product license
applications.
• This leads to conflicting standards for the
same product, increased expenses and
opportunities for error as well as a potential
cause for interruption of product supply.
29

 Q6A: Specifications : Test Procedures and
Acceptance Criteria for New Drug Substances and
New Drug Products : Chemical Substances
• The main objective of this guideline is to establish
a single set of global specifications for new drug
substances and new drug products.
• A specification is defined as a list of tests,
references to analytical procedures, and
appropriate acceptance criteria, which are
numerical limits, ranges
• This guideline addresses specifications, i.e., those
tests, procedures, and acceptance criteria which
play a major role in assuring the quality of the
new drug substance and new drug product during
shelf life.
30

• Universal Tests:
• The following tests are considered generally applicable
to all new drug substances and drug products.
 Description
 Identification
 Assay
 Impurities
• Specific Tests for drug substances :
 Physicochemical properties
 Particle size
 Polymorphic forms
 Tests for chiral new drug substances
 Water content
 Inorganic impurities
 Microbial limits
31

• Specific Tests for drug products(oral dosage form):
 Particle size distribution:
 Dissolution
 Disintegration
 Hardness/friability
 Uniformity of dosage units:
 Microbial limits
 Antioxidant preservative content:
 Alcohol content:
 Rheological properties:
 Redispersibility
32

• Specific Tests for drug products (Parenteral Drug
Products):
• Uniformity of dosage units
• Particle size distribution
• pH (Osmolarity)
• Sterility
• Endotoxins/Pyrogens
• Particulate matter
• Water content
• Antimicrobial preservative
• Antioxidant preservative content
• Functionality testing of delivery systems
33

 Q6B: Specifications : Test Procedures and
Acceptance Criteria for
• This document provides guidance on justifying and setting
specifications for proteins and polypeptides which are
derived from recombinant or non-recombinant cell cultures.
• A valid biological assay to measure the biological activity
should be provided by the manufacturer.
• Examples of procedures used to measure biological activity
include:
 Animal-based biological assays, which measure an
organism's biological response to the product;
 Cell culture-based biological assays, which measure
biochemical or physiological response at the cellular level;
 Biochemical assays, which measure biological activities
such as enzymatic reaction rates or biological responses
induced by immunological interactions.
34

 Q7: Good Manufacturing Practice Guide for
Active Pharmaceutical Ingredients
 The main objective of this guideline is that to
maintain the quality of the active pharmaceutical
ingredients
 Personnel:
 Buildings and Facilities:
 Process equipment:
 Documentation and Records:
35

 Q8(R2): Pharmaceutical Development
• This guideline is intended to provide guidance
on the contents of Pharmaceutical
Development of drug products
• The aim of pharmaceutical development is to
design a quality product and its manufacturing
process to consistently deliver the intended
performance of the product.
• The Pharmaceutical Development section also
describe the type of dosage form and the
formulation that are suitable for the intended
use.
• Q8 gives information about Drug Substance,
Excipients, Container Closure System. 36

 Q9: Quality Risk Management
• The purpose of this document is to offer a
systematic approach to quality risk management.
• This guideline provides principles and tools for
quality risk management that can be applied to all
aspects of pharmaceutical quality including
development, manufacturing, distribution; and the
inspection and submission/review processes
throughout the lifecycle of drug substances and
drug (medicinal) products, biological and
biotechnological products, including the use of raw
materials, solvents, excipients, packaging and
labeling materials.
37

 PRINCIPLES OF QUALITY RISK
MANAGEMENT
 Two primary principles of quality risk
management are:
 The evaluation of the risk to quality should be based
on scientific knowledge and ultimately link to the
protection of the patient; and
 The level of effort and documentation of the quality
risk management process should be commensurate
with the level of risk.
38

General Quality Risk Management Process:
Risk Review
RiskCommunication
Risk Assessment
Risk Evaluation
unacceptable
Risk Control
Risk Analysis
Risk Reduction
Risk Identification
Review Events
Risk Acceptance
Initiate
Quality Risk Management Process
Output / Result of the
Quality Risk Management Process
RiskManagementtools 39

 Q10: Pharmaceutical Quality System
• This document establishes a new ICH tripartite
guideline describing a model for an effective
quality management system for the
pharmaceutical industry, referred to as the
Pharmaceutical Quality System.
• comprehensive model for an effective
pharmaceutical quality system is based on
International Standards Organization (ISO)
quality concepts, includes applicable Good
Manufacturing Practice (GMP) regulations
40

 Status of Safety Topics Safety" Topics, i.e., those
relating to in vitro and in vivo pre-clinical studies
(Carcinogenicity Testing, Genotoxicity Testing, etc.)
 S1A-S1C---- Carcinogenicity studies:
 S1A: Guideline on the Need for Carcinogenicity
Studies of Pharmaceuticals
• Carcinogenicity studies should be performed for any
pharmaceutical whose expected clinical use is continuous
for at least 6 months.
• This document provides a consistent definition of the
circumstances under which it is necessary to undertake
carcinogenicity studies on new drugs. These
recommendations take into account the known risk
factors as well as the intended indications and duration
of exposure.
41

• The objectives of carcinogenicity studies are to identify a
tumorigenic potential in animals and to assess the
relevant risk in humans.
 S1B: Testing for Carcinogenicity of Pharmaceuticals
• This document provides guidance on the need to carry out
carcinogenicity studies in both mice and rats, and guidance
is also given on alternative testing procedures which may
be applied without jeopardizing safety.
 S1C(R2): Dose Selection for Carcinogenicity Studies of
Pharmaceuticals
• This document addresses the criteria for the selection of
the high dose to be used in carcinogenicity studies on
new therapeutic agents to harmonize current practices
and improve the design of studies.
42

o S2– Genotoxicity:
o S2(R1): Guidance on Genotoxicity Testing and Data
Interpretation for Pharmaceuticals Intended for Human
Use
• This guidance is a combination of ICH S2A and S2B
guidelines:
o S2A: Guidance on Specific Aspects of Regulatory
Genotoxicity Tests for Pharmaceuticals;
• This document provided specific guidance and
recommendations for in vitro and in vivo tests and on the
evaluation of test results. It includes terms related to
genotoxicity tests to improve consistency in applications.
43

 S2B: Genotoxicity: A Standard Battery for Genotoxicity
Testing for Pharmaceuticals :
 This document addresses two fundamental areas of
genotoxicity testing: the identification of a standard set of
assays to be conducted for registration, and the extent of
confirmatory experimentation in any particular
genotoxicity assay in the standard battery.
 Registration of pharmaceuticals requires a
comprehensive assessment of their genotoxic potential. It
is clear that no single test is capable of detecting all
relevant genotoxic agents. Therefore, the usual approach
should be to carry out a battery of in vitro and in vivo
tests for genotoxicity
44

 The purpose of this guideline is to optimize the
standard genetic toxicology battery for prediction of
potential human risks, and for interpretation of
results, with the ultimate goal of improving risk
characterization for carcinogenic effects that have
their basis in changes in the genetic material.
45

• S3A –S3B--- Toxicokinetics and Pharmacokinetics:
• S3A: Note for Guidance on Toxicokinetics: The
Assessment of Systemic Exposure in Toxicity
Studies
• ICH guidelines do not require toxicokinetic studies to be
conducted, except in pregnant, lactating animals, before
initiating reproductive studies.
• In this context, toxicokinetics is defined as the generation
of pharmacokinetic data, either as an integral component
in the conduct of non-clinical toxicity studies or in
specially designed supportive studies, in order to assess
systemic exposure.
• This document gives guidance on developing test
strategies in toxicokinetics and the need to integrate
these pharmacokinetics into toxicity testing, in order to
aid in the interpretation of the toxicology findings and
and their relevance to clinical safety issues
46

 The primary objective of toxicokinetics is: to describe
the systemic exposure achieved in animals and its
relationship to dose level and the time course of the
toxicity study.
47

 S3B: Pharmacokinetics: Guidance for Repeated
Dose Tissue Distribution Studies
• Tissue distribution studies are essential in providing
information on distribution and accumulation of the
compound and/or metabolites, especially in relation to
potential sites of action; this information may be useful for
designing toxicology and pharmacology studies and for
interpreting the results of these experiments.
• This document gives guidance, when the repeated dose
tissue distribution studies should be considered (i.e., when
appropriate data cannot be derived from other sources). It
also gives recommendations on the conduct of such studies
48

 S4: Duration of Chronic Toxicity Testing in
Animals (Rodent and Non-Rodent Toxicity
Testing)
The objective of this guidance is to set out the
considerations that apply to chronic toxicity testing in
rodents and non rodents as part of the safety evaluation
of a medicinal product
 Rodents(a study of 6 months duration)
 Non-rodents(a study of nine months duration).
49

 S5: Detection of Toxicity to Reproduction for
Medicinal Products & Toxicity to Male
Fertility
• This document provides guidance on tests for
reproductive toxicity.
• It defines the periods of treatment to be used in
animals to better reflect human exposure to
medical products and allow more specific
identification of stages at risk.
• It should encourage the full assessment on the
safety of chemicals on the development of the
offspring.
50

• S6: Preclinical Safety Evaluation of
Biotechnology-Derived Pharmaceuticals
This document covers the pre-clinical safety testing
requirements for biotechnological products. It
addresses the use of animal models of disease,
determination of when genotoxicity assays and
carcinogenicity studies should be performed, and the
impact of antibody formation on duration of
toxicology studies.
The primary goals of preclinical safety evaluation are:
1) to identify an initial safe dose and subsequent dose
in humans;
2) to identify potential target organs for toxicity and
for the study of whether such toxicity is reversible;
3) to identify safety parameters for clinical monitoring.
51

 S7A: Safety Pharmacology Studies for Human
Pharmaceuticals
 This guideline was developed to protect clinical trial
participants and patients receiving marketed products
from potential adverse effects of pharmaceuticals
 This document addresses the definition, objectives and
scope of safety pharmacology studies.
 It also addresses which studies are needed before
initiation of Phase 1 clinical studies as well as
information needed for marketing.
52

S7B : The Nonclinical Evaluation of the
Potential for Delayed Ventricular
Repolarization (QT Interval Prolongation)
By Human Pharmaceuticals
 This guideline describes a non-clinical testing strategy
for assessing the potential of a test substance to delay
ventricular repolarization.
 This guideline includes information concerning non-
clinical assays and integrated risk assessments.
53

 S8 : Immunotoxicity Studies for Human
Pharmaceuticals
 This guideline addresses the recommendations on
nonclinical testing for immunosuppressant.
 The guideline might also apply to drugs in which
clinical signs of immunosuppressant are observed
during clinical trials and following approval to market.
 The term immunotoxicity in this guideline will
primarily refer to immunosuppressant, i.e. a state of
increased susceptibility to infections or the
development of tumors.

• S9: Nonclinical Evaluation for Anticancer
Pharmaceuticals
• This guideline provides information for
pharmaceuticals that are only intended to treat
cancer in patients with late stage or advanced
disease regardless of the route of administration,
including both small molecule and biotechnology-
derived pharmaceuticals.
• It describes the type and timing of nonclinical
studies in relation to the development of anticancer
pharmaceuticals and references other guidance as
appropriate.
• This guideline aims to facilitate and accelerate the
development of anticancer pharmaceuticals and to
protect patients from unnecessary adverse effects,
while avoiding unnecessary use of animals and other
resources
55

 Efficacy Guidelines Efficacy" Topics, i.e., those
relating to clinical studies in human subject (Dose
Response Studies, Good Clinical Practices, etc.)
56

 Clinical safety:
 E1-E2F---CLINICAL SAFETY:
 E1: The Extent of Population Exposure to Assess
Clinical Safety for Drugs Intended for Long-
Term Treatment of Non-Life-Threatening
Conditions
• This document gives recommendations on the
number of patients and duration of exposure for
the safety evaluation of drugs intended for the
long-term treatment of non-life-threatening
conditions
• This guidelines gives information on duration of
drug exposure and its relationship to both time
and magnitude of occurrence of adverse events
57

 E2A: Clinical Safety Data Management :
Definitions and Standards
• This document gives standard definitions and
terminology for key aspects of clinical safety
reporting.
• It also gives guidance on mechanisms for
handling adverse drug reactions in the
investigational phase of drug development.
58

 E2B(R3): Clinical Safety Data Management
Data Elements for Transmission of Individual
Case Safety Reports
• The objectives of the working group is to identify, define
and standardize the data elements for the transmission
of individual case safety reports(adverse reactions,
adverse event reports).
• Following its submission to ISO for development as an
International Standard. Key parts of this updated
guideline will be incorporated into the Implementation
Guide for Electronic Transmission of Individual Case
Safety Reports Message Specification which is currently
available for public awareness.
59

 E2C(R1): Clinical Safety DataManagement:
Periodic Safety Update Reports for
Marketed Drugs
 This document gives guidance on the format
and content of safety updates, which need to be
provided at regular intervals to regulatory
authorities to ensure maximum efficacy and to
avoid duplication of marketed drugs .
60

 E2D: Post-Approval Safety Data Management:
Definitions and Standards
• This document provides a standardized procedure for
post-approval safety data management.
• The definitions of the terms specific to post-approval
phase are also provided.
• The practices of the data management were
standardized in such cases obtained from consumers,
literatures, internets which are all specific to post-
approval data management.
61

 E2E: Pharmacovigilance Planning
• This guideline is intended to aid in planning
pharmacovigilance activities, especially in preparation
for the early post marketing of a new drug (in this
guideline, the term "drug" denotes chemical entities,
biotechnology-derived products, and vaccines).
• The main focus of this guideline is on a Safety
Specification and Pharmacovigilance Plan that might
be submitted at the time of license application.
• The guideline describes a method for summarizing the
important identified risks of a drug, important
potential risks, and important missing information,
including the potentially at-risk populations and
situations where the product is likely to be used that
have not been studied.
62

 E2F: Development Safety Update Report
• The main focus of the DSUR is collection of data from clinical
trials of investigational drugs including biological’s, with or
without a marketing approval.
• The DSUR should provide safety information from all ongoing
clinical trials that the sponsor is conducting or has completed
during the review period including:
 clinical trials conducted using an investigational drug whether
with or without a marketing approval, i.e., human pharmacology,
therapeutic exploratory and therapeutic confirmatory trials
(Phase I – III)
 clinical trials conducted using marketed drugs in approved
indications, i.e., therapeutic use trials (Phase IV);
 other therapeutic use of an investigational drug;
 comparability trials conducted to support changes in the
manufacturing process of medicinal products 63

 E3: Structure and Content of Clinical Study
Reports
• This document describes the format and content of a
study report that will be acceptable in all three ICH
regions. It consists of a core report suitable for all
submissions and appendices.
• The clinical study report described in this guideline is
an integrated full report of an individual study of any
therapeutic, prophylactic or diagnostic agent (referred
to herein as drug or treatment) conducted in patients.
64

 The guideline is intended to assist sponsors for the
development of a report that is complete, free from
ambiguity, well organized and easy to review
 STRUCTURE AND CONTENT OF CLINICAL
STUDY REPORTS
• Title page
• Table of contents for the individual clinical study
report
• List of abbreviations and definition of terms
• Ethics (ethical conduct of the study, patient
information and consent )
65

• Investigators and study administrative
structure
• Introduction
• Study objectives
• Overall study design and plan - description
• Selection of study population
• Selection of doses in the study
• Efficacy and safety variables
• Efficacy results and tabulations of individual
patient data
• Safety evaluation
66

 E4: Dose-Response Information to Support
Drug Registration
 This document gives recommendations on the
design and conduct of studies to assess the
relationship between doses, blood levels and
clinical response throughout the clinical
development of a new drug.
 This information can help in identifying an
appropriate starting dose, to adjust dosage to the
needs of a particular patient, and a dose beyond
which unacceptable side effects are seen.
67

 E5(R1): Ethnic Factors in the Acceptability of
Foreign Clinical Data
• The purpose of this guidance is to facilitate the
registration of medicines among ICH regions.
• This document addresses the intrinsic
characteristics of the drug recipient and
extrinsic characteristics associated with
environment and culture that could affect the
results of clinical studies carried out in regions
• Describes the concept of the "bridging study"
that a new region may request to determine
whether data from another region are applicable
to its population.
68

 E6(R1): Good Clinical Practice : Consolidated
Guideline
• Good Clinical Practice (GCP) is an international
ethical and scientific quality standard for designing,
conducting, recording and reporting trials that involve
the participation of human subjects.
• This Good Clinical Practices document describes the
responsibilities and expectations of all participants in
the conduct of clinical trials, including investigators,
monitors, sponsors .
• GCPs cover aspects of monitoring, reporting and
achieving of clinical trials and incorporating these into
Essential Documents and on the Investigator's
Brochure.
69

 E7-E11----CLINICAL TRIALS:
 E7: Studies in Support of Special Populations :
Geriatrics
 This document provides recommendations on the special
considerations which apply in the design and conduct of
clinical trials of medicines that are likely to have
significant use in the elderly.
 E.g.: New Molecular Entities that are likely to have
significant use in the elderly, because the disease
intended to be treated is characteristically a disease of
ageing ( e.g., Alzheimer's disease)
70

 E8: General Considerations for Clinical Trials
 This document sets out the general scientific principles
for the conduct, performance and control of clinical
trials.
 The guideline addresses a wide range of subjects in the
design and execution of clinical trials.
 The ICH document "General Considerations for Clinical
Trials" is intended to:
(a)describe internationally accepted principles and
practices in the conduct of both individual clinical trials
and overall development strategy for new medicinal
products
71

(b) facilitate the evaluation and acceptance of foreign
clinical trial data by promoting common
understanding of general principles
c) present an overview of the ICH clinical safety and
efficacy documents and facilitate the user's access to
guidance
(d) provide a separate glossary of terms used in the ICH
clinical safety and efficacy related documents that
pertain to clinical trials
72

 E9: Statistical Principles for Clinical Trials
 This biostatistical guideline describes essential
considerations on the design and analysis of clinical
trials, especially the "confirmatory" (hypothesis-testing)
trials that are the basis for demonstrating effectiveness
73

 E10: Choice of Control Group and Related
Issues in Clinical Trials
• This document addresses the choice of control groups in
clinical trials.
• Control groups in clinical trials can be classified on the
basis of two critical attributes: (1) the type of treatment
used and (2) the method of determining who will be in
the control group.
• The type of control treatment may be any of the
following four: (1) placebo, (2) no treatment, (3) different
dose or regimen of the study treatment, or (4) a different
active treatment.
74

 E11: Clinical Investigation of Medicinal
Products in the Pediatric Population
• This document addresses the conduct of clinical
trials of medicines in pediatric populations.
• This document will facilitate the development of
safe and effective use of medicinal product in
pediatrics.
• Specific clinical study include:
• (1) timing of initiation of pediatric studies during
medicinal product development;
• (2) types of studies (pharmacokinetic,
pharmacokinetic/ pharmacodynamic (PK/PD),
efficacy, safety);
• (3) age categories;
• (4) ethics of pediatric clinical investigation.
75

 E12-Guidelines for Clinical Evaluation by
Therapeutic Category
 The ICH Efficacy Guidelines are applicable to all
therapeutic classes of drugs, but there are some
therapeutic classes which need individual drug
evaluation guidelines among the three regions.
76

 E12: Principles for Clinical Evaluation of New
Antihypertensive Drugs
 This document provides general principles for
the clinical evaluation of new anti-hypertensive
drugs.
 It describes core principles for the evaluation of
antihypertensives that are accepted in the three
ICH regions, but some region-specific
differences remain, therefore this document
should be considered an "ICH Principle
Document" rather than an "ICH Guideline".
77

 E14: The Clinical Evaluation of QT/QTc Interval
Prolongation and Pro-Arrhythmic Potential for
Non-Antiarrhythmic Drugs
• This document provides recommendations to sponsors
concerning the design, conduct, analysis, and
interpretation of clinical studies to assess the potential of
a drug to delay cardiac repolarization.
• This assessment should include testing the effects of new
agents on the QT/QTc interval as well as the collection of
cardiovascular adverse events.
• The investigational approach used for a particular drug
should be individualized, depending on the
pharmacodynamic, pharmacokinetic, and safety
characteristics of the product, as well as on its proposed
clinical use.
78

 E15: Definitions for Genomic Biomarkers,
Pharmacogenomics, Pharmacogenetics, Genomic
Data and Sample Coding Categories
• In order to develop harmonised approaches to drug
regulation, it is important to ensure that consistent
definitions of terminology are being applied across all
constituents of the International Conference on
Harmonisation (ICH).
• An agreement on definitions will facilitate the
harmonization in the discipline of pharmacogenomics
and pharmacogenetics for global drug development and
approval processes.
79

 E16: Genomic Biomarkers Related to Drug
Response: Context, Structure and Format of
Qualification Submissions
 The guideline describes recommendations regarding
context, structure, and format of regulatory submissions
for qualification of genomic biomarkers(E15).
 clinical and non-clinical genomic biomarkers related to
drug response including pharmacokinetics,
pharmacodynamics,efficacy and safety aspects.
80

• Multidisciplinary Guidelines
"Multidisciplinary" Topics, i.e., Topics which
do not fit uniquely into one of the above
categories (MedDRA, ESTRI, M3, CTD, M5)
81

 M1 Medical Terminology
• New Medical Dictionary for Regulatory Activities
Terminology (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.
• It provides an international medical dictionary
applicable to all phases of product development.
• Its goal is to provide a comprehensive and specific
terminology to help standardize, facilitate and simplify
regulatory processes.
82

 M2 Electronic Standards for Transmission of
Regulatory Information (ESTRI)

 Facilitate 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 Common
Technical Document developed by the ICH M4.
 ICH M2 has initiated the development of the Next Major
Version of the eCTD (eCTD NMV) to improve robustness,
flexibility and long term stability of the message.
83

• 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 or are
intended for a long duration of use
84

 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.
85

 M4:The Common Technical Document
• 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.
• 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
86

 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.
87

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