Regulatory guidelines for conducting toxicity studies by ich
- 1. REGULATORY GUIDELINES FOR CONDUCTING TOXICITY STUDIES BY ICH PRESENTED BY VIVEK SHARMAAND NAVEEN SINGH M.PHARM PHARMACOLOGY
- 2. INTRODUCTION ICH (Full form = International Council on Harmonization) is a committee that provides the pharmaceutical stability guidelines for industries and International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. QUALITY Relating to chemical and pharmaceutical Q.A. (Stability testing. Impurity testing, etc.) ICH GUIDELINES SAFETY Relating to invitro and in vivo clinical studies ( Toxicity testing's) EFFICACY Relating to clinical studies (dose response studies, GCP etc.) MULTIDICIPLINARY Relating to crosscutting guidelines which can be guidelines for MedDRA. ESTRI,M3,CTD,M5 etc.
- 3. REGULATORY GUIDELINES FOR CONDUCTING TOXICITY STUDIES OF ICH These are guidelines which are given under the guidelines of safety studies by ICH. 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. a) ICHS1A-1C Rodent Carcinogenicity b) ICHM7 Addendum Assessment & Control of Mutagenic Impurities c) ICHS9 Nonclinical oncology Q & A d) ICHS3A Q & A Note on Toxicokinetics: microdosing e) ICHE14/S7B Discussion Group f) ICHS5(R3) Reprotox g) ICHS11 Nonclincal Safety for Pediatric
- 4. EWG FOR ICHS1A-S1C –RODENT CARCINOGENICITY STUDIES FOR HUMAN PHARMACEUTICALS Expert Working Group gather data and assess that for further use. The main objective and goal is to ensure WOE (weight of evidence) approach of carcinogenicity is applicable to small molecule of pharmaceuticals. It also evaluate elements to predict 2yr rat study outcomes and values. 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 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
- 5. S2– GENOTOXICITY 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 provided 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. ICH Guidelines S2– Genotoxicity: S2B: A Standard Battery for Genotoxicity Testing for Pharmaceuticals : This document addresses 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 be to carry out a battery of in vitro and in vivo tests for genotoxicity The purpose of this guideline is to optimize the standard genetic toxicology battery for prediction of potential human risks, and for interpretation of results
- 6. S3A-S3B TOXICOKINETIC AND PHARMACOKINETICS 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. ICH Guidelines S3A-S3B Toxicokinetics and Pharmacokinetics: 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 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. ICH Guidelines 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
- 7. 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) Non-rodents (a study of nine months duration) • 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.
- 8. S6:PRECLINICAL SAFETY EVALUATION OF BIOTECHNOLOGY DERIVED PHARMACEUTICAL 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: Safety Pharmacology Studies for Human Pharmaceuticals 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. S7A The Nonclinical 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
- 9. S8 : IMMUNOTOXICITY STUDIES FOR HUMAN PHARMACEUTICALS This guideline addresses the recommendations on nonclinical testing for immunosuppressant and 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. 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.
- 10. S10 GUIDELINES-PHOTO SAFETY EVALUATION OF PHARMACEUTICALS 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.
- 11. S11-FOR NON CLINICAL SAFETY TESTING IN SUPPORT OF DEVELOPMENT OF PRDIATRIC 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 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
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