REGULATORY AFFAIRS

1. ICH GUIDELINES
SUMEL ASHIQUE
M.PHARM
(PHARMACEUTICS)

2. 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.

3. 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

4. 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

5. 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

6. 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
6

7. 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

8. 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

9. 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 9

10. 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

11. 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.)
11

12. GUIDELINES
MULTIDISCIPLINARYMULTIDISCIPLINARY
EFFICACYEFFICACY
SAFETYSAFETY
QUALITYQUALITY

13. "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

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

15.  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

16. 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 for16

17.  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

18.  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

19. • 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

20.  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

21.  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

22.  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

23. • 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

24.  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

25. • 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

26.  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

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

28.  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.
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29.  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

30.  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 the30

31. • 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

32. • 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

33. • 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

34. Q6B: Specifications : Test Procedures and
Acceptance Criteria for
Biotechnological/Biological Products
• 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

35.  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

36.  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.
36

37.  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

38. 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

39. 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

40.  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

41.  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

42. • 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

43. 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

44. 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

45. 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

46. • 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

47. 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

48. 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

49.  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

50. 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

51. • 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

52. 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

53. 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

54. 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.

55. • 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

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

57.  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

58.  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

59.  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

60.  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

61.  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

62.  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

63.  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
63

64.  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

65. 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

66. • 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

67.  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

68.  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

69.  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

70.  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

71.  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

72. (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

73.  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

74.  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

75.  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

76. 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

77.  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

78. 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

79.  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

80.  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

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

82.  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

83.  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

84. • 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 use84

85. 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

86.  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 86

87.  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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