Standard toxicity studies

A more pedestrian, but important, consideration is the absolute quantity of food that is consumed in a study. Decreased food intake resulting from chemically induced toxicity may influence body weight and somatic development of offspring. It is often difficult to distinguish between such secondary effects on development and possible direct effects of a chemical on development. It is not possible to distinguish between these possibilities in standard toxicity studies unless a pair-fed control group is used. 

Since many biotechnology products are designed to modulate the immune system, basic immunotoxicity parameters have traditionally been evaluated as part of standard toxicity studies. Over time more and more immunotoxicity specific parameters have been validated in toxicology species, including primates. These parameters (humoral and cell-mediated) should be measured as appropriate. Other specific issues for biopharmaceuticals include immunogenicity, as previously discussed. 

Methods include standard toxicity studies and additional immunotoxicity studies conducted as appropriate. Whether additional immunotoxicity studies are appropriate should be determined by a weight of evidence review. 

Findings from standard toxicity studies (STS) pharmacological properties of the drug intended patient population structural similarities to known immunomodulators disposition of the drug clinical information. 

This new ICH guideline replaces all guidances from EU, USA and Japan. It represents a very pragmatic approach and uses studies, e.g standard toxicity studies, which are conducted anyhow (see Table 15). There is great confidence in the prediction of these assays for any potential of new compounds to induce immune suppression or immune stimulation. This guideline helps to reduce the number of animals and requires additional studies only in special cases for concern. 

The data base for GA consists of intraperitoneal and subcutaneous subchronic studies in rats, teratology studies in rats and rabbits, and delayed neuropathy studies in rats and chickens. Deficiencies in the data base include the lack of a multi-generation reproductive toxicity study, a standard toxicity study in a second species, and adequate toxicity studies by the oral exposure route. Although well-designed and well-conducted, the principal study involved a non-oral (intraperitoneal) exposure route. Consequently, overall confidence in the RfD is low. 

Conducting a stand-alone study in nonhuman primates is often not practical due to animal cost and availability. In these instances, incorporation of antigen immunization in the standard toxicity studies is justified and generally believed not to affect the interpretation of compound effects on standard toxicity end points. 

Incorporation of Immunophenotyping into Standard Toxicity Studies. Lymphocyte immunophenotyping can be performed as part of the standard toxicity... 

Incorporation of Immunophenotyping into Immunotoxicity Studies. In cases where the standard toxicity studies indicate there may be effects on the immune system, lymphocyte immunophenotyping can be incorporated into an immunotoxicity study (Roth et al., 2006). This approach has been studied in... 

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