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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