Carcinogenicity studies design

No information on the carcinogenic potential of polyalphaolefin hydraulic fluids was located. Studies designed to assess carcinogenicity in animals exposed via inhalation, oral, and dermal routes or a well-controlled cohort retrospective or prospective study would be useful for determining the carcinogenic potential of polyalphaolefin hydraulic fluids. 

Additionally, there are specialized studies designed to address endpoints of concern for almost all drugs (carcinogenicity, reproductive or developmental toxicity) or concerns specific to a compound or family of compounds (local irritation, neurotoxicity, or immunotoxicity, for example). When these are done, timing also requires careful consideration. It must always be kept in mind that the intention is to ensure the safety of people in whom the drug is to be evaluated (clinical trials) or used therapeutically. An understanding of special concerns for both populations should be considered essential. 

In the experimental evaluation of substances for carcinogenesis based on experimental results of studies in a nonhuman species at some relatively high dose or exposure level, an attempt is made to predict the occurrence and level of tumorogenesis in humans at much lower levels. In this chapter we will examine the assumptions involved in this undertaking and review the aspects of design and interpretation of traditional long-term (lifetime) animal carcinogenicity studies as well as some alternative short-term models. 

In this chapter, we consider the major factors involved in the design, conduct, analysis, and interpretation of carcinogenicity studies as they are performed in the pharmaceutical industry. 

The Europeans, meanwhile, have focused on the need for better care in study design, conduct and interpretation (Spindler et. al., 2000), aiming to incorporate these in the revision of the CPMP (Center for Proprietary Medicinal Products) carcinogenicity guidelines. 

Dose selection is one of the most important activities in the design of a toxicology study. It is especially critical in carcinogenicity studies because of their long duration. Whereas faulty dose selection in an acute or subchronic toxicity study can easily be corrected by repeating the study, this situation is much less desirable in... 

The information used for dose selection usually comes from subchronic toxicity studies, but other information about the pharmacological effects of a drug and its metabolism and pharmacokinetics may also be considered. The maximum recommended human dose (MRHD) of the drug may be an additional criterion, if this is known when the carcinogenicity studies are being designed. 

Food and Drug Administration (FDA) (2001). Guidance for Industry Statistical Aspects of the Design, Analysis and Interpretation of Chronic Rodent Carcinogenicity Studies of Pharmaceuticals. USDHEW, Washington, D.C. 

Pharmaceutical Manufacturers Association (PMA). (1988). Results of a Questionnaire Involving the Design of and Experience with Carcinogenicity Studies. This document has not been published in the open literature but is widely available within the pharmaceutical industry. It may be obtained by writing to the Pharmaceutical Manufacturers Association, Washington, DC. 

Weaver, R.J. and Brunden, M.N. (1998). The design of long-term carcinogenicity studies. In Design and Analysis of Animal Studies in Pharmaceutical Development (Chow, S. and Liu, J., Eds.), Marcel Dekker New York. 

Endrin was found not to be carcinogenic in Osbome-Mendel rats and B6C3F, mice under the conditions of a National Cancer Institute bioassay (NCI 1978). This conclusion is consistent with previously reported studies concerning endrin carcinogenicity in rats and mice. All reported studies, however, have study design limitations that make them inadequate for assessing the potential carcinogenicity of endrin in humans. 

The current label for PTH(l-34), the first approved PTH analogue, reports dose-related increase in osteosarcomas, osteoblastomas, and osteomas in two-rat carcinogenicity studies as well as results from a second two-year study in rats designed to determine the effect of treatment duration and animal... 

Carcinogenicity study in mice and rats These studies are designed to identify a tumorigenic potential and to assess the relevant risk in humans. These studies are conducted for pharmaceuticals that are generally administered over the life of a human and are generally not conducted for biopharmaceuticals (see Chapters 19 and 27). 

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