This document provides an overview of the ICH S11 guideline for non-clinical safety testing to support development of pediatric medicines. The guideline recommends standards for determining when juvenile animal testing provides informative data to support pediatric clinical trials. It advises that such testing should be considered when previous animal and human safety data, including from other drugs in the same class, are deemed sufficient to back pediatric studies. The expert working group developing the guideline will include representatives from regulatory bodies and the pharmaceutical industry across key regions.

1. TOXICITY STUDIES
AS PER ICH SAFETY
GUIDELINES
SOU R A BH KOSEY

2. INTRODUCTION
• Toxicology classically has been defined as the study of poisons &
concerned with the adverse effects of xenobiotics.
• Casarett 1996 defined it as a science that defines the limits of safety of
chemical agents for human & animal populations.
• Toxicological screening is very important for the development of new
drugs and for the extension of the therapeutic potential of existing
molecules.
• The US-FDA states that it is essential to screen new molecules for
pharmacological activity and toxicity potential in animals (21CFR Part
314).
• Toxicity tests are mostly used to examine specific adverse events or
specific end points such as cancer, cardiotoxicity, and skin/eye
irritation.
• Toxicity testing also helps calculate the No Observed Adverse Effect
Level (NOAEL) dose and is helpful for clinical trails.

3. 8/23/2019

4.  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 European Union, Japan and the United States
in scientific and technical discussions of the testing procedures required to
assess and ensure the safety, quality and efficacy of medicines
WHAT IS ICH

5. 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.
ICH LOCATION

6. 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.
OBJECTIVES OF ICH

7.  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.
GOALS OF ICH

8.  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.
MEMBERS OF ICH

9.  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.

10. 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.

11. 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.
ICH OPERATION

12. Step-1: Drafts are prepared and circulated through many revisions until
a "final harmonized 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.
Steps in the ICH process

13. • 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.)

14. ICH SAFETY GUIDELINES
• S1A: GUIDELINE ON THE NEED FOR CARCINOGENICITY STUDIES OF
PHARMACEUTICALS
• S1B: TESTING FOR CARCINOGENICITY OF PHARMACEUTICALS
• S1C(R2): DOSE SELECTION FOR CARCINOGENICITY STUDIES OF
PHARMACEUTICALS
• S2(R1): GUIDANCE ON GENOTOXICITY TESTING AND DATA
INTERPRETATION FOR PHARMACEUTICALS INTENDED FOR HUMAN USE
• S3A: NOTE FOR GUIDANCE ON TOXICOKINETICS: THE ASSESSMENT OF
SYSTEMIC EXPOSURE IN TOXICITY STUDIES
• S3B: PHARMACOKINETICS:GUIDANCE FOR REPEATED DOSE TISSUE
DISTRIBUTION STUDIES

15. CONTINUE..
• S4: DURATION OF CHRONIC TOXICITY TESTING IN ANIMALS
(RODENT AND NON RODENT TOXICITY TESTING)
• S5(R2): DETECTION OF TOXICITY TO REPRODUCTION FOR
MEDICINAL PRODUCTS & TOXICITY TO MALE FERTILITY
• S6: PRECLINICAL SAFETY EVALUATION OF BIOTECHNOLOGY-
DERIVED PHARMACEUTICALS
• S7A: SAFETY PHARMACOLOGY STUDIES FOR HUMAN
PHARMACEUTICALS

16. CONTINUE..
•S7B: THE NON-CLINICAL EVALUATION OF THE POTENTIAL FOR
DELAYED VENTRICULAR REPOLARIZATION (QT INTERVAL
PROLONGATION) BY HUMAN PHARMACEUTICALS
•S8: IMMUNOTOXICITY STUDIES FOR HUMAN PHARMACEUTICALS
•S9: NONCLINICAL EVALUATION FOR ANTICANCER
PHARMACEUTICALS
•S10 : PHOTOSAFETY EVALUATION OF PHARMACEUTICALS
•S11 : for NON CLINICAL SAFETY TESTING IN SUPPORT OF
DEVELOPMENT OF PRDIATRIC MEDICINES

18. 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.
 The objectives of carcinogenicity studies are to identify a tumorigenic
potential in animals and to assess the relevant risk in humans.
Carcinogenicity studies(S1A-
S1C)

19. 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.

20. 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:
S2A: Guidance on Specific Aspects of Regulatory
Genotoxicity Tests for Pharmaceuticals;
• This document provides 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.
S2– Genotoxicity:

21. • S2B: A Standard Battery for Genotoxicity Testing for
Pharmaceuticals :
 This document addresses two fundamental areas of genotoxicity testing:
1.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.
2.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

22. 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.

23. • 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.
S3A-S3B Toxicokinetics and
Pharmacokinetics:

24. 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 their
relevance to clinical safety issues
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.

25. 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

26. 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) - these are the gnawing animals of
the order rodentia, characterized by a single pair continuously growing
incisors in each of the upper and lower jaws.
Non-rodents (a study of nine months duration)

27. •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.

28. 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.

29. • 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.
29
S7A: Safety Pharmacology Studies for
Human Pharmaceuticals

30. • 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.
S7B : The Nonclinical Evaluation of the
Potential for Delayed Ventricular
Repolarization (QT Interval
Prolongation) By Human Pharmaceuticals

31. • 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.
S8 : Immunotoxicity Studies for
Human Pharmaceuticals

32. 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

33. These guideline applies to new APIs . New excipients clinical formulations
for dermal application and photodynamic therapy products.
It is an integrated process that can involve an evaluation of photochemical
characteristics, data from non clinical studies and human safety information.
The photo safety assessment aims to determine weather risk minimization
measures are warranted to prevent adverse events in humans.
In-vitro assay for photo-toxicity is the 3T3 neutral red uptake assay.
 in vivo for species selection irradiation sensitivity, heat tolerance,
performance of reference substance should be considered.
S10 Guidelines-Photo safety evaluation
of pharmaceuticals

34. S11-FOR NON CLINICAL SAFETY
TESTING IN SUPPORT OF
DEVELOPMENT OF PEDIATRIC
MEDICINES
 This guideline is needed to recommended standards for the conditions under
which non clinical juvenile animal testing is considered informative and
support pediatric clinical trails .
 The expert working group (EWG) Will consist of two nonclinical experts
nominated by EU,EFPIA,FDA, PhRMA, MHLW, JPMA, HEALTH Canada
and Swiss medic. One member can also be nominated by WHO Observer,
as well as RHIs, DRAs/doH

35. • The ICH M3 (R2) Guideline state, the conduct of any juvenile animal
toxicity studies should be considered when pervious animal data and human
safety data ,including effects from other drugs of pharmacological class, are
judged to be sufficient to support pediatric studies