ICH Safety Guidelines

ICH SAFETY
GUIDELINES
Presented by- SIDDHI NIGHOT (07)
TANVI PARDHI (08)
What is ICH?
ICH - "International Council for Harmonization".
Mission: Unique in bringing together the regulatory authorities and

pharmaceutical industries to discuss scientific and technical aspects
of drug registration.
ICH Guidelines
Q-QUALITY GUIDELINES
S-SAFETY GUIDELINES
E-EFFICACY GUIDELINES
M-MULTIDISCIPLINARY GUIDELINES
SAFETY GUIDELINES
Those relating to invitro and invivo pre-clinical studies.

ICH has produced a comprehensive set of SAFETY GUIDELINES to
uncover potential risks.
S1 - CARCINOGENICITY STUDIES (S1A-S1C)
● S1A-Need for Carcinogenicity Studies Of Pharmaceuticals.
● Carcinogenicity Studies are to identify a tumorigenic potential in animals

and to assess the relevant risk in humans.
● These studies were needed if the clinical use was expected to be

continuously for 6 months or longer.
● Whereas, According to the US Food and Drug Administration,

Pharmaceuticals generally used for 3 months or more, require this studies.
▪ 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 as well as the
intended indications and duration of exposure.
S1B - Testing for Carcinogenicity of Pharmaceuticals.
● This document provides the guidance on the need to carry out

carcinogenicity studies in both mice and rats.
● This document also provides the guidance is also given on alternative testing
procedures which may be applied without jeopardizing safety.
● This guidelines include the data of mechanistic studies which has cellular
changes, biochemical measurements, considerations for additional
genotoxicity testing an modified protocols.
● This guideline also helps in the choosing of an appropriate species for long
term carcinogenicity testing based on general considerations and also
provides the information about the evaluation of carcinogenic potential.
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.
▪ This guidelines provides data for the conducting of dose-ranging studies,

Toxicity endpoints, Maximum feasible dose, limit dose, additional endpoints
in high dose and selection of middle & low doses in this studies.
S2- GENOTOXICITY STUDIES (S2A-S2B)
▪ 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 a glossary of terms related to genotoxicity tests to improve

consistency in applications.
S2B: Genotoxicity: A Standard Battery for Genotoxicity Testing for
Pharmaceuticals.
● This document addressed 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 carryout a battery of invitro &
invivo tests for genotoxicity.
S3-TOXICOKINETICS AND PHARMACOKINETICS (S3A-S3B)
● S3A: Note for the assessment of systemic exposure in toxicity studies.
● This document 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.
● 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.
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 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.
▪ It also gives recommendations on the conduct of such studies.
S4-TOXICITY GUIDELINES (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.
1. Rodents(a study of 6 months duration)
2. Non-rodents(a study of nine months duration)

S5 Reproductive Toxicology
▪ S5(R2) 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.
▪ S5(R3) Revision of S5 Guideline on Detection of Toxicity to Reproduction for
Medicinal Products & Toxicity to Male Fertility.
▪ Since the adoption of the S5(R2) Guideline experience has been gained with
the testing of pharmaceuticals using the current and novel testing paradigms.
Additionally, scientific, technological and regulatory knowledge has evolved
significantly.
▪ Consequently, there are now opportunities for modernising testing paradigms
to enhance human risk assessment, while also potentially reducing animal
use.
▪ There are also areas where the guideline could be revised or amended for
greater clarity as well as to align more fully with other more recent ICH
Guidelines, such as ICH M3(R2), ICH as well as ICH S9.
S6 Biotechnological Products
▪ S6(R1) 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.
S7A-S7B Pharmacology Studies
▪ S7A Safety Pharmacology Studies for Human 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.
▪ S7B 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.
▪ This Guideline includes information concerning non-clinical assays and

integrated risk assessments.
S8 Immunotoxicology Studies for Human Pharmaceuticals
▪ This Guideline addresses the recommendations on non clinical testing for

immunosuppression induced by low molecular weight drugs (non-biologicals).
▪ 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.
▪ In addition, the Guideline might also apply to drugs in which clinical signs of
immunosuppression are observed during clinical trials and following approval
to market.
▪ The term immunotoxicity in this guideline will primarily refer to

immunosuppression, i.e. a state of increased susceptibility to 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.
S10 Photosafety Evaluation of Pharmaceuticals
▪ This Guideline provides international standards for photosafety assessment

and harmonises such assessments supporting human clinical trials and
marketing authorizations for pharmaceuticals.
▪ It includes factors for initiation of and triggers for additional photosafety

assessment and should be in conjunction with ICH M3(R2), Section 14 on
Photosafety Testing.
S11 Nonclinical Safety Testing in Support of Development of Paediatric
Medicines
▪ The S11 Guideline is proposed to provide direction on the nonclinical studies

important to support a pediatric development program.
▪ It will recommend standards for the conditions under which nonclinical

juvenile animal testing is considered informative and necessary to support
paediatric clinical trials, and also provide guidance on the design of the
studies.
▪ A streamlined drug development and higher scientific rigor while minimizing
the unnecessary use of animals will be with the implementation of this new
harmonised ICH Guideline.
THANK YOU

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ICH SAFETY

ICH - "International Council for Harmonization".

Mission: Unique in bringing together the regulatory authorities and

Those relating to invitro and invivo pre-clinical studies.

● S1A-Need for Carcinogenicity Studies Of Pharmaceuticals.

● Carcinogenicity Studies are to identify a tumorigenic potential in animals

● These studies were needed if the clinical use was expected to be

● Whereas, According to the US Food and Drug Administration,

● This document provides the guidance on the need to carry out

▪ This guidelines provides data for the conducting of dose-ranging studies,

▪ S2A: Guidance on Specific Aspects of Regulatory Genotoxicity Tests for

▪ This document provided specific guidance and recommendations for in vitro

▪ It includes a glossary of terms related to genotoxicity tests to improve

● This document addressed two fundamental areas of genotoxicity testing.

● The identification of a standard set of assays to be conducted for registration,

● Registration of pharmaceuticals requires a comprehensive assessment of their

● It is clear that no single test is capable of detecting all relevant genotoxic

● S3A: Note for the assessment of systemic exposure in toxicity studies.

● This document gives guidance on developing test strategies in toxicokinetics

● The primary objective of toxicokinetics is to describe the systemic exposure

▪ Tissue distribution studies are essential in providing information on

1. Rodents(a study of 6 months duration)

2. Non-rodents(a study of nine months duration)

▪ S5(R2) Detection of Toxicity to Reproduction for Medicinal Products & Toxicity

▪ This document provides guidance on tests for reproductive toxicity. It defines

▪ S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived

▪ This document covers the pre-clinical safety testing requirements for

▪ It addresses the use of animal models of disease, determination of when

▪ S7A Safety Pharmacology Studies for Human Pharmaceuticals.

▪ This document addresses the definition, objectives and scope of safety

▪ It also addresses which studies are needed before initiation of Phase 1

▪ This Guideline describes a non-clinical testing strategy for assessing the

▪ This Guideline includes information concerning non-clinical assays and

▪ This Guideline addresses the recommendations on non clinical testing for

▪ It applies to new pharmaceuticals intended for use in humans, as well as to

▪ The term immunotoxicity in this guideline will primarily refer to

▪ This Guideline provides information for pharmaceuticals that are only

▪ It describes the type and timing of nonclinical studies in relation to the

▪ This Guideline provides international standards for photosafety assessment

▪ It includes factors for initiation of and triggers for additional photosafety

▪ The S11 Guideline is proposed to provide direction on the nonclinical studies

▪ It will recommend standards for the conditions under which nonclinical

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