International Guidelines and Regulatory Agencies for Toxicity Studies

Supervised by:Dr. Ajay GaurH.O.D. Quality Assurance

Submitted by:Sunil SainiM.Pharm(P`ceutics) Sem-2nd

LACHOO MEMORIAL COLLEGE OF SCIENCE AND TECHNOLOGY (PHARMACY WING)

JODHPUR

JAI NARAYAN VYAS UNIVERSITY, JODHPUR

Contents:

Introduction

Regulatory Agencies for Toxicity Studies

International Guidelines

ICH/WHO

OECD

FDA

Introduction:

One of the most important milestones in product development is the decision to enter into

clinical trials with a candidate product. This important decision is based, in part, on data

produced during non-clinical safety testing of the candidate during the preclinical phases of

development.

The quality and reproducibility of safety data are hereby key components of their utility for

supporting the assumption of safety in humans.

Regulatory Agencies for Toxicity Studies:

For regulatory purposes, and derived from their scientific objectives, non-clinical studies are

divided into three parts:

Investigations of the pharmacodynamics actions of a compound (primary and secondary

pharmacodynamics and safety pharmacology);

Investigations of the compound’s behaviour and fate in the organism (pharmacokinetics;

absorption, distribution, metabolism, excretion [ADME]); and

Investigations to ensure that the substance does not pose any potential untoward safety risk

(toxicology) when it may finally be administered to humans.

Cont….

Regulatory Agencies:

ICH

OECD

FDA

WHO

International Guidelines:

ICH & WHO: International Conference on Harmonisation & World Health Organization

ICH & WHO 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(most important

reason now a days to withdraw drug from market).

CARCINOGENICITY STUDIES

S1A: 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.

Cont….

S1B: Testing for Carcinogenicity of Pharmaceuticals

This document provides guidance on the need to carry out carcinogenicity studies in both mice

and rats.

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.

Cont….

GENOTOXICITY STUDIES

S2(R1): Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals

Intended for Human Use 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.

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.

Cont….

TOXICOKINETICS AND PHARMACOKINETICS

S3A: Note for Guidance on Toxicokinetics: 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.

S3B: Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies

This document gives guidance on circumstances when repeated dose tissue distribution studies

should be considered (i.e., when appropriate data cannot be derived from other sources).

Cont….

TOXICITY TESTING

S4: Duration of Chronic Toxicity Testing in Animals (Rodent and Non Rodent

Toxicity Testing)

The text incorporates the guidance for repeat-dose toxicity tests that was agreed at the time

of ICH 1, in 1991 (reduction of the duration of repeat dose toxicity studies in the rat from 12 to

6 months).

Cont….

REPRODUCTIVE TOXICOLOGY

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

Toxicity to Male Fertility S5A,S5B(M)

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.

Cont….

BIOTECHNOLOGICAL PRODUCTS

S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals

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

products.

Cont….

PHARMACOLOGY STUDIES

S7A: Safety Pharmacology Studies for Human Pharmaceuticals

This document addresses the definition, objectives and scope of safety pharmacology studies.

S7B: The Non-Clinical Evaluation of the Potential for Delayed Ventricular

Repolarization (QT Interval Prolongation) by Human

This Guideline describes a non-clinical testing strategy for assessing the potential of a test

substance to delay ventricular repolarization.

Cont….

IMMUNOTOXICOLOGY STUDIES

S8: Immunotoxicity Studies for Human

This Guideline addresses the recommendations on nonclinical testing for immunosuppression

induced by low molecular weight drugs (non-biologicals).

Cont….

NONCLINICAL EVALUATION FOR ANTICANCER PHARMACEUTICALS

S9: Nonclinical Evaluation for Anticancer

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.

PHOTOSAFETY EVALUATION

S10: Photosafety Evaluation of Pharmaceuticals (Draft Document)

The S10 draft Guideline has been released for consultation under Step 2 of the ICH process in

November 2012.

OECD

OECD: Organisation for Economic Co-operation and Development

The mission of the OECD is to promote policies that will improve the economic and social well-

being of people around the world.

The OECD provides a forum in which governments can work together to share experiences and

seek solutions to common problems. 

GUIDELINES:

402 Acute Dermal Toxicity

403 Acute Inhalation Toxicity

404 Acute Dermal Irritation/Corrosion

405 Acute Eye Irritation/Corrosion

Cont….

406 Skin Sensitisation

407 Repeated Dose 28-day Oral Toxicity Study in Rodents

408 Repeated Dose 90-Day Oral Toxicity Study in Rodents

409 Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents

410 Repeated Dose Dermal Toxicity: 21/28-day Study

411 Subchronic Dermal Toxicity: 90-day Study

412 Repeated Dose Inhalation Toxicity: 28-day or 14-day Study

413 Subchronic Inhalation Toxicity: 90-day Study

414 Prenatal Developmental Toxicity Study

415 One-Generation Reproduction Toxicity Study

Cont….

416 Two-Generation Reproduction Toxicity Study

417 Toxicokinetics

420 Acute Oral Toxicity - Fixed Dose Method

421 Reproduction/Developmental Toxicity Screening Test

422 Combined Repeated Dose Toxicity Study with the Reproduction

423 Acute Oral toxicity - Acute Toxic Class Method

424 Neurotoxicity Study in Rodents

425 Acute Oral Toxicity: Up-and-Down Procedure

451 Carcinogenicity Studies

452 Chronic Toxicity Studies

453 Combined Chronic Toxicity/Carcinogenicity Studies

Cont….

471 Bacterial Reverse Mutation Test

473 In vitro Mammalian Chromosomal Aberration Test

474 Mammalian Erythrocyte Micronucleus Test

475 Mammalian Bone Marrow Chromosomal Aberration Test

476 In vitro Mammalian Cell Gene Mutation Test

477 Genetic Toxicology: Sex-Linked Recessive Lethal Test in Drosophila melanogaster

478 Genetic Toxicology: Rodent Dominant Lethal Test

479 Genetic Toxicology: In vitro Sister Chromatid Exchange Assay in Mammalian Cells

480 Genetic Toxicology: Saccharomyces cerevisiae, Gene Mutation Assay

481 Genetic Toxicology: Saccharomyces cerevisiae, Mitotic Recombination Assay

482 Genetic Toxicology: DNA Damage and Repair, Unscheduled DNA Synthesis in Mammalian Cells in vitro

Cont….

483 Mammalian Spermatogonial Chromosome Aberration Test

484 Genetic Toxicology: Mouse Spot Test

485 Genetic Toxicology: Mouse Heritable Translocation Assay

486 Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells in vivo

Cont….

DRAFT GUIDELINES

403 Acute Inhalation Toxicity

404 Acute Dermal Irritation/Corrosion

405 Acute Eye Irritation/Corrosion

426 Developmental Neurotoxicity Study

429 Skin Sensitisation: Local Lymph Node Assay

430 In Vitro Skin Corrosion: Transcutaneous Electrical Resistance Test (TER)

431 In Vitro Skin Corrosion: Human Skin Model Test

432 In Vitro 3T3 NRU Phototoxicity Test

FDA

FDA: Food and Drug Administration

FDA is responsible for protecting the public health by assuring the safety, efficacy and security

of human and veterinary drugs, biological products, medical devices, our nation’s food supply,

cosmetics, and products that emit radiation.

FDA is also responsible for advancing the public health by helping to speed innovations that

make medicines more effective, safer, and more affordable and by helping the public get the

accurate, science-based information they need to use medicines and foods to maintain and

improve their health. FDA also has responsibility for regulating the manufacturing, marketing

and distribution of tobacco products to protect the public health and to reduce tobacco use by

minors.

Cont….

Guidance Documents:

Content and Format of INDs(Investigational New Drugs) for Phase 1 Studies

Single Dose Acute Toxicity Testing for Pharmaceuticals

Product Specific guidance

anti-virals

vaginal contraceptives and STD preventatives

Special Protocol Assessment

Submission in Electronic Format

Cont….

Draft Guidances:

Carcinogenicity study protocols

Immunotoxicology

Photosafety testing

Statistical evaluation of carcinogenicity studies

Cont….

Types of Toxicology Studies Recommended

General Toxicology

acute and repeat dose toxicology studies

Special Toxicology Studies

local irritation studies, e.g., site specific, ocular

hypersensitivity studies for inhalation and dermal drug products

Reproductive and Developmental Toxicology Studies

male and female fertility

embryonic and fetal development

post-natal reproductive and developmental effects

Thank You