Revision of the current ICH S1 guidance on rodent carcinogenicity testing: Where do we stand?

Revision of the current ICH S1 guidance on rodent carcinogenicity testing: Where do we stand?

Abstracts / Toxicology Letters 258S (2016) S39–S53 W05-2 Revision of the current ICH S1 guidance on rodent carcinogenicity testing: Where do we stand...

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Abstracts / Toxicology Letters 258S (2016) S39–S53

W05-2 Revision of the current ICH S1 guidance on rodent carcinogenicity testing: Where do we stand? Peter Kasper Federal Institute for Drugs and Medical Devices (BfArM), Germany The two-species, two-year rodent bioassay has been the gold standard for carcinogenicity testing for nearly half a century. According to International Council for Harmonisation guidance documents (ICH S1) such studies need to be conducted to support marketing application for most small molecule pharmaceuticals. Although bioassays are among the most expensive and protracted studies during non-clinical drug development and use large numbers of animals they are long known as poor predictors of human risk, mainly due to oversensitivity. In August 2013 an ICH Regulatory Notice Document announced the evaluation of an alternative approach to the 2-year rat carcinogenicity test. This approach is based on the hypothesis that knowledge of pharmacological targets and pathways together with toxicological and other data can provide sufficient information to anticipate the outcome of a 2-year rat carcinogenicity study and their potential value in predicting the risk of human carcinogenicity of a given pharmaceutical. In order to investigate the accuracy of this hypothesis a prospective evaluation is currently in progress. Sponsors are encouraged to submit a Carcinogenicity Assessment Document (CAD) to Drug Regulatory Authorities (DRA) in the ICH regions for all investigational pharmaceuticals with ongoing or planned 2-year rat carcinogenicity studies with a prediction of the carcinogenic potential prior to knowing the outcome of the carcinogenicity testing. DRAs from each region will independently review the submitted assessments to evaluate the degree of concordance with Sponsors and between regulatory regions. Predictions in the submitted CADs are then checked against the actual outcome of the 2-yr rat studies as they are completed and reported to the DRAs. Results on the accuracy of predictions and the degree of concordance among all parties are anticipated to help define the conditions under which a weight-of-evidence evaluation is an appropriate alternative to a 2-yr rat carcinogenicity study. If this is the case then after revising the ICH S1 guideline, a waiver of a rat 2-year study might be granted by the DRA’s. This presentation will provide an overview of the current status of the evaluation process from a regulatory perspective of a CAD review committee member. http://dx.doi.org/10.1016/j.toxlet.2016.06.1262 W05-3 Carcinogenicity assessment documents and the added value of “weight-of-evidence” factors – An industry perspective Lutz Mueller Rodent 2 year carcinogenicity tests are standard practice for evaluation of risk/benefit for new pharmaceuticals. Their conduct is regulated under a series of ICH guidelines. The need to conduct these tests are undergoing a prospective review period within the ICH guideline revision process. In this process, a so-called “carcinogenicity assessment document” (CAD) has to be submitted to the agencies before knowing the outcome of a rat 2 year carcinogenicity study. This document foresees a number of “weight of evidence” criteria deemed important to predict outcome of the animal experiment to prospectively judge its value. Eventually, when

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the results of the animal experiment are known, the prediction will be checked against the actual outcome from all parties involved. The ultimate goal will be to achieve a reduction in the number of these very time-consuming and animal-costly experiments. This presentation will encompass a review of these evidence factors. With some examples, the use of these factors will be illustrated and how they would impact on the prediction of carcinogenic potency in animals and humans. The presentation will also elaborate on how these judgements could be interpreted in a different way between the concerned industry and health authority parties. http://dx.doi.org/10.1016/j.toxlet.2016.06.1263 W05-4 Future Directions in Carcinogenicity Testing for Pharmaceuticals Michael Graziano http://dx.doi.org/10.1016/j.toxlet.2016.06.1264 Workshop W06: Use and Misuse of the TTC Concept in Risk Assessment W06-1 Twelve years of TTC (of genotoxc carcinogens) – A success story? Dieter Schrenk Food Chemistry and Toxicology, University of Kaiserslautern, Germany After a paper by Munro in 1990 the threshold of toxicological concern (TTC) method gradually developed from Threshold of Regulation based on a one in a million calculated lifetime cancer risk. Later, the concept was extended to non-cancer endpoints using the distributions of NOAELs according to the Cramer classification. As a next step, the concept was extended to the issue of developmental toxicity and neurotoxicity. As the most recent major hallmark in this development, Kroes et al. published a TTC approach for genotoxic carcinogens in 2004. The method is based on a grouping of chemicals according to their major functional moieties such as azo compounds, benzidines, hydrazines, etc. It was the aim of the concept to provide a rational basis for risk assessment solely based on the chemical structure making use of the similarity with other chemicals. From the knowledge of the risk parameter distribution of those chemicals (mainly form animal experiments) estimates are made on the dose bearing a certain numeric risk (e.g. the theoretical additional cancer incidence of 10−6 ). There is wide consensus, that TTC should be applied only, if the amount of ‘real toxicological data’ on the chemical of interest is clearly insufficient for a quantitative risk assessment. Meanwhile, the concept has been further developed and adapted. A variety of authors and institutions have made suggestions and published concepts how TTC could be modified in order to provide a low concern estimate for e.g., defined and undefined chemical mixtures, genotoxic impurities in drugs, contaminants in phytomedicines, homeopathic mixtures, pesticide residues, contaminants in food etc. These concepts were published independently and in an un-coordinated manner. A less-thanlifetime procedure was suggested for limited exposures, a ‘benefit’ factor was introduced for pharmaceuticals in order to allow higher TTC levels and the standardization to body weight is discussed. Furthermore, there is uncertainty on which databases should be used for the grouping of chemicals and if the concept can be applied to