Ich guidelines seminar

By
Md gayasuddin
M.Pharm (pharmacology)
MNR college of pharmacy

Contents

 introduction
 ICH objectives
 ICH Organizational structure
 ICH Harmonisation process
 ICH Work Product
 ICH Guidelines

What does ICH stands for?
 The complete name of ICH is the "International
Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for
Human Use".

What is ICH ?
 ICH is a joint initiative involving both regulators and
research-based industry representatives of the
European Union, Japan and the USA in scientific and
technical discussions of the testing procedures
required to assess and ensure the safety, quality and
efficacy of medicines.

What is the goal of ICH ?
 The goal of ICH is to promote international harmonization
by bringing together representatives from the three ICH
regions (EU, Japan and USA) to discuss and establish
common guidelines.
 Another goal of ICH is to make information available on
ICH, ICH activities and ICH guidelines to any country or
company that requests the information, and to promote a
mutual understanding of regional initiatives in order to
facilitate harmonisation processes related to ICH
guidelines regionally and globally, and to strengthen the
capacity of drug regulatory authorities and industry to
utilise them.
 The ICH Global Cooperation Group (GCG) was formed in
1999 and is charged with this task.

ICH objectives
 The objective of ICH is to increase international
harmonisation of technical requirements to ensure
that safe, effective, and high quality medicines are
developed and registered in the most efficient and
cost-effective manner. These activities have been
undertaken to promote public health, prevent
unnecessary duplication of clinical trials in humans,
and minimize the use of animal testing without
compromising safety and effectiveness.

ICH Organisational Structure

The ICH structure consists of the
 ICH Steering Committee,
 ICH Coordinators,
 ICH Secretariat and
 ICH Working Groups.
 The ICH Global Cooperation Group (GCG) and the
ICH MedDRA Management Board are sub-committees
of the ICH Steering Committee.

Steering committee
 The Steering Committee is the body that governs the
ICH, determines the policies and procedures for ICH,
selects topics for harmonisation and monitors the
progress of harmonisation initiatives. Each of the six
ICH parties has two seats on the ICH Steering
Committee. Each of the Observers nominates non-
voting participants to attend the ICH Steering
Committee Meetings. IFPMA also participates as a
non-voting member.

The 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. Due to structural differences
within the EU and MHLW,
 ICH Technical Coordinators are also designated from
the EMA and PMDA respectively.

The ICH Secretariat
The Secretariat operates from the IFPMA offices, in Geneva, and is
primarily concerned with preparations for, and documentation of,
meetings of the Steering Committee.

At the time of ICH Conferences, the Secretariat is responsible for the
technical documentation and for liaison with the speakers for the
Conference.

Working Groups
SAFETY EFFICACY

QUALITY MULTIDISCIPLINARY

STEERING COMMITTEE
Endorses topics, guidelines and monitors
progress

Global Cooperation Group (GCG)
 The ICH Global Cooperation Group (GCG) was formed
on March 11, 1999, as a subcommittee of the ICH
Steering Committee.
 It is made up of one representative from each of the six
parties on the ICH Steering Committee, plus the
IFPMA.
 The ICH Observers, WHO, Canada and EFTA are also
part of the GCG.

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. This important group of non-voting members represent non-ICH
countries and regions.
 The International Federation of Pharmaceutical Manufacturers &
Associations (IFPMA) has been closely involved with ICH since its
inception and participates as a non-voting member.

ICH parties
 The ICH Parties are the founding members of ICH and
represent the regulatory bodies and research-based
industry in the EU, US and Japan.

ICH parties
6 parties
 EU
 EFPIA (European federation of pharmaceutical industries’ associations)
 MHLW (Ministry of health, Labor and welfare, Japan)
 JPMA (Japan Pharmaceuticals manufacturers Association)
 US FDA
 PhRMA
 Observers : WHO, TPP(canada)
 International federation of Pharmaceutical manufacturer’s
association

The Observers
The ICH Observers include
 the European Free Trade Association (EFTA) -
currently represented by Swiss medic (Swiss Agency
for Therapeutic Products),
 Health Canada and World Health Organization
(WHO).
 The Observers have been associated with the ICH
process from the beginning to act as a link with non-
ICH countries and regions.

ICH Harmonisation Process
 The ICH Steering Committee is responsible for the governance
of ICH. This includes deciding on the adoption of every ICH
project, whether a new topic, maintenance of an existing
Guideline, or a specific implementation work.
 Each harmonisation activity is initiated by a Concept Paper
which is a short summary of the proposal. Depending on the
category of harmonisation activity a Business Plan may also be
required.
 Any ICH Party or Observer is welcomed to submit a proposal for
a new ICH activity.
 The ICH Steering Committee decides on the adoption of every
ICH project and then endorses the creation of an EWG/IWG.
 ICH harmonisation activities fall into 4 categories: Formal ICH
Procedure, Q&A Procedure, Revision Procedure and
Maintenance Procedure.

5 Steps in the ICH process
 Consensus building
Rapporteur prepares initial draft of a guideline/rcommendation for comment
with fixed deadline for comment (fax, e-mail). Interim report made to SC
meeting, if consensus is reached, sign-off - all members
 Start of regulatory action
 Wide ranging regulatory consultation
EU: published as a draft CPMP guideline; US: published as a draft guidance in
the Federal Register; Japan: translated & issued by MHLW for internal and
external consultation. A Regulatory Rapporteur is dessignated to draw up the
final document and sign-off
 Adoption of a tripartite harmonised text
Both regulatory and industry parties of SC must be satisfied. Adoption takes
place on the signatures from the 3 regulatory parties to ICH, affirming that the
Guideline is recommended for adoption by the 3 regulatory bodies
 Implementation

ICH Products
 ICH has developed over 50 harmonised Guidelines aimed at
eliminating duplication in the development and registration process,
so that a single set of studies can be generated to demonstrate the
quality, safety and efficacy of a new medicinal product.
 Quality-21 Guidelines
 Safety -14 Guidelines
 Efficacy -20 Guidelines
 Multidisciplinary -5 Guidelines

 Electronic Standards for the Transfer of Regulatory Information (ESTRI,
E2B)
 Common Technical Document (CTD & eCTD)
 Medical dictionary for adverse event reporting and coding of clinical
trial data (MedDRA)
 Considerationdocuments

ICH Guidelines
The ICH Topics are divided into four major categories and ICH Topic
Codes are assigned according to these categories.

Q S E M
"Quality" Topics, "Safety" Topics, "Efficacy" Topics, "Multidisciplinary"
i.e., those relating i.e., those relating i.e., those relating Topics, i.e., cross-
to chemical and to in vitro and in to clinical studies cutting Topics
pharmaceutical vivo pre-clinical in human subject which do not fit
Quality studies (Dose Response uniquely into one
Assurance (Carcinogenicity Studies, Good of the above
(Stability Testing, Testing, Clinical Practices, categories
Impurity Testing, Genotoxicity etc.) (MedDRA,
etc.) Testing, etc.) ESTRI, M3, CTD,
M5)

Safety Guidelines
 ICH has produced a comprehensive set of safety
guidelines to uncover potential risks like
carcinogenicity, genotoxicity and reprotoxicity. A
recent breakthrough has been a non-clinical testing
strategy for assessing the QT interval prolongation
liability: the single most important cause of drug
withdrawals in recent years.

ICH GUIDELINES ON SAFETY OF ANIMALS
 S1A Guideline on the Need for Carcinogenicity Studies of
Pharmaceuticals Nov. 1995
 S1B Testing for Carcinogenicity of Pharmaceuticals July 1997
 S1C(R2) Dose Selection for Carcinogenicity Studies of
Pharmaceuticals Mar. 2008
 S2(R1) Guidance on Genotoxicity Testing and Data
Interpretation for Pharmaceuticals Intended for
 Human Use Nov. 2011
 S3A Note for Guidance on Toxicokinetics: The Assessment of
Systemic Exposure in Toxicity Studies Oct. 1994
 S3B Pharmacokinetics: Guidance for Repeated Dose Tissue
Distribution Studies Oct. 1994
 S4 Duration of Chronic Toxicity Testing in Animals (Rodent
and Non Rodent Toxicity Testing) Sept. 1998

 S5(R2) Detection of Toxicity to Reproduction for
Medicinal Products and Toxicity to Male Fertility June
1993
 S6(R1) Preclinical Safety Evaluation of Biotechnology-
Derived Pharmaceuticals June 2011
 S7A Safety Pharmacology Studies for Human
Pharmaceuticals Nov. 2000
 S7B The Non-clinical Evaluation of the Potential for
Delayed Ventricular Repolarization (QT Interval
Prolongation) by Human Pharmaceuticals May 2005
 S8 Immunotoxicity Studies for Human Pharmaceuticals
Sept. 2005
 S9 Nonclinical Evaluation for Anticancer
Pharmaceuticals Oct. 2009
 S10 Photo safety Evaluation Nov. 2012

S1A (Nov. 1995)
 Need for Carcinogenicity Studies of Pharmaceuticals

 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.

 Results from genotoxicity studies, toxicokinetics, and
mechanistic studies can now be routinely applied in
preclinical safety assessment.

S1B (July 1997)
 Testing for Carcinogenicity of Pharmaceuticals

 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 (March 2008)
 Dose Selection for Carcinogenicity Studies of
Pharmaceuticals

 addresses the criteria for the selection of the high dose to be
used in carcinogenicity studies on new therapeutic agents to
harmonise current practices and improve the design of studies.

 the pharmacokinetic endpoint of 25 is declared to be applicable
also for pharmaceuticals with positive genotoxicity signals.

 This change has implications on reducing the pain or discomfort
of the animals at the maximally tolerated dose (MTD).

S2-R1 (March 2008)
 Guidance On Genotoxicity Testing And Data Interpretation For
Pharmaceuticals Intended For Human Use

 S2A: Guidance on Specific Aspects of Regulatory Genotoxicity
Tests for Pharmaceuticals :specific guidance and recommendations
for in vitro and in vivo tests and on the evaluation of test results. It
includes a glossary of terms related to genotoxicity tests to improve
consistency in applications.

 S2B: Genotoxicity: A Standard Battery for Genotoxicity Testing
for Pharmaceuticals; 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.

S3A (Oct. 1994)
 Note For Guidance On Toxicokinetics:
The Assessment Of Systemic Exposure In Toxicity
Studies

 gives guidance on developing test strategies in
toxicokinetics and the need to integrate pharmacokinetics
into toxicity testing, in order to aid in the interpretation of
the toxicology findings and promote rational study design
development.

S3B (Oct. 1994)
 Pharmacokinetics: Guidance For Repeated Dose
Tissue Distribution Studies

 This study is required when appropriate data cannot be
derived from other sources

 A comprehensive knowledge of the absorption,
distribution, metabolism and elimination of a compound is
important for the interpretation of pharmacology and
toxicology studies.

 useful for designing toxicology and pharmacology studies

S4 (Sep. 1998)
 Duration Of Chronic Toxicity Testing In Animals
(Rodent And Non Rodent Toxicity Testing)

 safety evaluation of a medicinal product

 for the development of medicinal products with the
exception of those already covered by the ICH Guideline on
Safety Studies for Biotechnological Products, e.g.,
Monoclonal antibodies, recombinant DNA proteins.

S5-R2 (Nov. 2000)
 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

S6 (Oct. 2009)
 Addendum To Ich S6: Preclinical Safety Evaluation Of
Biotechnology-derived Pharmaceuticals

 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

 Clarification on species selection, study design,
immunogenicity, reproductive and developmental toxicity
and assessment of carcinogenic potential.

S7A (Nov. 2000)
 Safety Pharmacology Studies for Human
Pharmaceuticals

 addresses the definition, objectives and scope of safety
pharmacology studies

 also addresses which studies are needed before initiation of
Phase 1 clinical studies as well as information needed for
marketing.

S7B (May 2005)
 The Non-clinical 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.

 Includes non-clinical assays and integrated risk
assessments

S8 (Sep. 2005)
 Immunotoxicity Studies for Human Pharmaceuticals
 addresses the recommendations on nonclinical testing for
immunosuppression induced by low molecular weight
drugs (non-biologicals and how each immunotoxicity
study should be performed
 It applies to new pharmaceuticals intended for use in
humans, as well as to marketed drug products proposed for
different indications or other variations on the current
product label in which the change could result in
unaddressed and relevant toxicologic issues
 Also applicable during CT and following approval to
market.

S9 (Oct. 2009)
 Nonclinical Evaluation for Anticancer
Pharmaceuticals

 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.

S10 (June 2010)
 Photosafety Evaluation of Pharmaceuticals

 This new Guideline on photosafety testing will be a
valuable adjunct to the guidance provided in the M3(R2)
Guideline.

Efficacy Guidelines
 The work carried out by ICH under the Efficacy
heading is concerned with the design, conduct, safety
and reporting of clinical trials. It also covers novel
types of medicines derived from biotechnological
processes and the use of pharmacogenetics/
pharmacogenomics techniques to produce better
targeted medicines.

Efficacy Guidelines
 Clinical Safety E1-E2F
 Clinical Study Reports E3
 Dose Response Studies E4
 Ethnic Factors E5
 Good Clinical Practice E6
 Clinical Trials E7-E11
 Guidelines for Clinical Evaluation by Therapeutic Category
E12
 Clinical Evaluation E14
 Pharmacogenomics E15-E16
 Joint Safety / Efficacy Topic M3

E1 (Oct. 1994)
 E1 – The Extent Of Population Exposure To Assess Clinical Safety
For Drugs Intended For Long-term Treatment Of Non-life-
threatening Conditions

 The tripartite harmonized ICH Guideline was finalised under Step 4 in
October 1994. This document gives recommendations on the numbers
of patients and duration of exposure for the safety evaluation of drugs
intended for the long-term treatment of non-life-threatening
conditions.
 Events where the rate of occurrence changes over a longer period of
time may need to be characterized depending on their severity and
importance to the risk-benefit assessment of the drug.
 The safety evaluation during clinical drug development is not expected
to characterise rare adverse events, for example, those occurring in less
than 1 in 1000 patients.

E2A (Oct. 1994)
 Clinical Safety Data Management: Definitions And
Standards For Expedited Reporting E2A

 There are two issues within the broad subject of clinical safety data
management that are appropriate for harmonization at this time:

 (1) the development of standard definitions and terminology for key
aspects of clinical safety reporting, and

 (2) the appropriate mechanism for handling expedited (rapid)
reporting, in the investigational (i.e., pre-approval) phase.

E2B-R2 (Feb. 2001)
 Maintenance Of The ICH Guideline On Clinical Safety
Data Management :
Data Elements For Transmission Of Individual Case
Safety Reports E2B(R2)

 to standardize the data elements for transmission of
individual case safety reports by identifying, and where
necessary or advisable, by defining the data elements for
the transmission of all types of individual case safety
reports, regardless of source and destination.

E2C-R1(Nov. 1996)
 Clinical Safety Data Management: Periodic Safety Update
Reports for Marketed Drugs E2C (R1)

 guidance on the format and content of safety updates, which need to
be provided at intervals to regulatory authorities after products have
been marketed. The Guideline is intended to ensure that the worldwide
safety experience is provided to authorities at defined times after
marketing with maximum efficiency and avoiding duplication of effort.

 E2C(R2) This Revision was endorsed by Steering Committee in
Dec.2010. It will Evaluate the ICH Pharmacovigilance documentation,
conduct a gap and potential improvement analysis of ECH E2C, E2E
and E2F and draft a new ICH E2C R2 covering periodic benefic risk
evaluation reporting.

E2D (Nov. 2003)
 Post Approval Safety Data Management: Definitions
and Standards for Expedited Reporting

 provides a standardized procedure for post-approval safety
data management including expedited reporting to
relevant authority.

 The definitions of the terms and concept specific to post-
approval phase are also provided.

E2E (Nov. 2004)
 Pharmacovigilance Planning
 planning of pharmacovigilance activities, especially in
preparation for the early post marketing period of a new
drug (chemical entities, biotech-derived products,
vaccines)
 Main focus: Safety specification and PV plan that mighty
be submitted at the time of license application

E2F (Aug. 2010)
 Development Safety Update Report
 The main focus of the DSUR is data from interventional
clinical trials (referred to in this document as "clinical
trials") of investigational drugs including biologicals, with
or without a marketing approval, whether conducted by
commercial or non-commercial sponsors.
 Intended for periodic reporting on drugs under
development (including marketed drugs that are under
further study) among the ICH regions.

E3 (Nov. 1995)
 Structure and Content of Clinical Study Reports

 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, in which the clinical and statistical
description, presentations, and analyses are integrated into a single
report, incorporating tables and figures into the main text of the
report, or at the end of the text, and with appendices containing the
protocol, sample case report forms, investigator related information,
information related to the test drugs/investigational products
including active control/comparators, technical statistical
documentation, related publications, patient data listings, and
technical statistical details such as derivations, computations, analyses,
and computer output etc.

E4 (March, 1994)
 Dose-response Information To Support Drug
Registration

 Knowledge of the relationships among dose, drug-
concentration in blood, and clinical response (effectiveness
and undesirable effects) is important for the safe and
effective use of drugs in individual patients.
 concepts of minimum effective dose and maximum useful
dose do not adequately account for individual differences
and do not allow a comparison, at various doses, of both
beneficial and undesirable effects.
 Any given dose provides a mixture of desirable and
undesirable effects, with no single dose necessarily optimal
for all patients.

E5 R1 (Feb. 1998)
 Ethnic Factors In The Acceptability Of Foreign Clinical
Data

 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 and 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.

E6-R1 (May 1996)
 Good Clinical Practice

 describes the responsibilities and expectations of all
participants in the conduct of clinical trials, including
investigators, monitors, sponsors and IRBs.
 GCPs cover aspects of monitoring, reporting and archiving
of clinical trials and incorporating addenda on the
Essential Documents and on the Investigator's Brochure
which had been agreed earlier through the ICH process.

E7 (June 1993)
 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.
 It requires special consideration due to the frequent
occurrence of underlying diseases, concomitant drug
therapy and the consequent risk of drug interaction.

E8 (July 1997)
 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.

E9 (Feb. 1998)
 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.
 The document will also assist scientific experts charged
with preparing application summaries or assessing
evidence of efficacy and safety, principally from clinical
trials in later phases of development.

E10 (July 2000)
 Choice of Control Group and Related Issues in
Clinical Trials

 This document addresses the choice of control groups in
clinical trials considering the ethical and inferential
properties and limitations of different kinds of control
groups. It points out the assay sensitivity problem in active
control equivalence / non-inferiority trials that limits the
usefulness of trial design in many circumstances.

E11 (July 2000)
 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.

E12 (March 2000)
 Principles for Clinical Evaluation of New
antihypertensive Drugs

 It provides a set of "Principles" on which there is general
agreement among all three ICH regions covering endpoints
and trial designs.
 It will not be subject to the usual procedures leading to a
fully harmonized document.

E14 (May 2005)
 The Clinical Evaluation of QT/QTc Interval Prolongation and
Proarrhythmic 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 repolarisation.
 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 individualised, depending on the pharmacodynamic,
pharmacokinetic, and safety characteristics of the product, as well as
on its proposed clinical use.
 The assessment of the effects of drugs on cardiac repolarisation is the
subject of active investigation.
 When additional data (non-clinical and clinical) are accumulated in
the future, this document may be reevaluated and revised.

E15 (Nov. 2007)
 Definitions For Genomic Biomarkers, Pharmaco-
genomics, Pharmacogenetics, Genomic Data And
Sample Coding Categories

 Pharmacogenomics and pharmacogenetics have the
potential to improve the discovery, development and use of
medicines.

E16 (Aug. 2010)
 Biomarkers Related To Drug Or Biotechnology
Product Development:
Context, Structure And Format Of Qualification
Submissions

 The Guideline describes recommendations regarding
context, structure, and format of regulatory submissions
for qualification of genomic biomarkers, as defined in ICH
E15.

M3 R2 (June 2009)
 Guidance On Non-clinical Safety Studies For The
Conduct Of Human Clinical Trials And Marketing
Authorization For Pharmaceuticals

 Harmonisation of the guidance for non-clinical safety
studies will help to define the current recommendations
and reduce the likelihood that substantial differences will
exist among regions.

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