Preclinical safety evaluation

S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals... 

ICH Topic S 6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (CPMP/ICH/302/95). March 1998. 

Basic Principles for Preclinical Safety Evaluation of Cellular and Gene Therapies. For biotechnology-derived products in general... 

The principle purposes of preclinical safety evaluation in this context remain... 

Some biotechnologically derived pharmaceuticals will cross-react with species that can be evaluated toxicologically, while others cross-react only with nonhuman primates such as the chimpanzee, a protected species. In this case, a well-designed safety, or Phase 0 study at doses higher than the proposed clinical dose may provide valuable safety information. However, a lack of cross-reactivity with any nonhuman species does not necessarily make preclinical safety evaluation impossible, not does it limit toxicity testing to species in which the protein lacks relevant pharmacological activity. Some alternative possibilities are summarized in Table 12.9. 

Zbinden, G. (1966). The significance of pharmacologic screening tests in the preclinical safety evaluation of new drugs. J. New Drugs 6 1-7. 

Anon., ICH S6 Preclinical safety evaluation of biotechnology-derived pharmaceuticals, CPMP/ICH/302/95, London, July 16,1997. 

US Pharmacopeia 29/NationaI Formulary 24,1086, Rockville, MD, 2006, p. 2921. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH S6 Preclinical Safety Evaluation of Biotechnology-derived Pharmaceuticals, 1997. 

Ryan AM, Eppler DB, Hagler KE, Bruner RH, Thomford PJ, Hall RL, et al. Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic humanized monoclonal antibody. Toxicol Pathol 1999 27 78-86. 

ICH (2011) ICH guideKne S6 (Rl)— preclinical safety evaluation of biotechnology-derived pharmaceuticals, http //www.ema. europa.eu/docs/en GB / document library/ Scientific guideline / 2 0 09 / 09 / WC500002828.pdf Accessed 24 Aug 2011... 

Cavagnaro JA (2008) Preclinical safety evaluation of biopharmaceuticals. Wiley, Hoboken... 

Weinbauer GF et al (2008) Reproductive/ developmental toxicity assessment of biopharmaceuticals in nonhiunan primates. In Cavagnaro JA (ed) Preclinical safety evaluation of biopharmaceuticals. A science-based approach to facilitating clinical trials. Wiley, New Jersey, pp 379-397... 

Haworth R, Pilling AM. The PCR assay in the preclinical safety evaluation of nucleic acid medicines. Human Experi Toxicol 19.5 (200) 267-276. 

The preclinical safety evaluation of a new excipient generally commences after initial in vitro pharmacy work to demonstrate the material s proposed role. Additionally, some in vivo investigations (often a short exposure study in the rodent) may occur, for example, comparing the new proposed material in a drug formulation versus a marketed drug formulation. Enhanced drug exposure and/or a reduced toxicity profile (through the use of lower-dose levels or excipient protection) may be a study end point. 

Many drugs are now known to cause this adverse effect, which often becomes apparent during the preclinical safety evaluation. 

Committee for Proprietary Medicinal Products Note for Guidance on Preclinical Safety Evaluation of Biotechnology-derived Pharmaceuticals. Human Medicines Evaluation Unit, The European Agency for the Evaluation of Medicinal Products, London (1997). 

To date, no studies on the metabolism of cetuximab have been performed in humans or in animals. Indeed, metabolism studies are not generally performed for mAbs. Several pathways have been described that may contribute to antibody metabolism, all of which involve biodegradation of the antibody to smaller molecules (i. e., small peptides or amino acids). This fact has been recognized in the International Conference on Harmonization (ICH) guidance document Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals [22], where it is stated in Section 4.2.3 that "... the expected consequence of metabolism of biotechnology-derived pharmaceuticals is the degradation to small peptides and individual amino acids. .. and that therefore classical biotransformation studies as performed for traditional small molecule pharmaceuticals are not needed. 

ICH (1998b), CPMP. Note for Guidance on Preclinical Safety Evaluation of Biotechnology- Derived Pharmaceuticals, Geneva. Available at http //www.ich.org/ LOB/media/MEDIA503.pdf (accessed October 2006). 

Preclinical Safety Evaluation of Biopharmaceuticals A Science-Based Approach to Facilitating Clinical Trials, edited by Joy A. Cavagnaro Copyright 2008 by John Wiley Sons, Inc. 

Preclinical Safety Evaluation of Biopharmaceuticals A Science-Based, Approach to Facilitating... 

The conduct of toxicology studies in laboratory animals has been driven by experience, historical precedence, and governmental requirements, and the results of these studies usually, and reasonably, have led to restrictions on the use, or method of use, of the chemicals concerned [1], The primary objective of pharmaceutical preclinical safety evaluation is to provide information essential for the initiation of clinical trials. Scientific rationale and controlled reproducible data are used to show that the initial human risk is so low as to be ethically and practically acceptable in relation to the medical value of the information to be obtained from humans. Preclinical safety studies performed throughout the course of product development facilitate and may guide work... 

TABLE 3.3 Case-by-case approach to preclinical safety evaluation... 

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