Preclinical Safety Assessment

It may seem that the course of preclinical safety assessment (and of other aspects of development) of a pharmaceutical is a relatively linear and well-marked route, within some limits. This is generally the case, but not always. There are a number of special cases where the pattern and phasing of development (and of what is required for safety assessment) do not fit the usual pattern. Four of these cases are... 

TABLE 12.5. Points to Consider in the Preclinical Safety Assessment of Biologies... 

LeBel, C.P and Foss, J.A., Use of a rodent neurotoxicity screening battery in the preclinical safety assessment of recombinant-methionyl human brain-derived neurotrophic factor,... 

Bass R, Kleeburg U, Schroder H, et al. Current Guidelines for the Preclinical Safety Assessment of Therapeutic Proteins. Toxicol Letts 1992 64/65 339 47. 

Cavagnaro JA. Preclinical safety assessment of biological products. In Mathieu M, ed. Biologies Development A Regulatory Overview. Waltham, MA Parexel International, 1993 23 i0. 

Verdier F. Preclinical safety assessment of vaccines in biotechnology and safety assessment. In Thomas JA, Fuchs RL, eds. Biotechnology and Safety Assessment. 3rd ed. Academic Press, San Diego, 2002 397-412. 

Types of Biopharmaceuticals Survey data on preclinical safety assessment programs were analyzed for 34 biopharmaceuticals cases. The numbers of antibodies, human proteins, and human protein analogues either in the development or marketed as of 2001 in Japan were 13,12, and 6, respectively. The remainder were bioconjugates, DNA-derived vaccines, and human T cell epitopes. Thus antibodies and human proteins are the two major biopharmaceuticals. 

Immunogenicity is a substantial complication for preclinical safety assessment studies. Antibodies can invalidate the animal model species. Antibody production alone, however, should not necessarily prohibit the conduct of these studies. The effect on pharmacokinetics and pharmcodynamics needs to be measured and evaluated. The potential consequences of the antibodies on endogenous molecules also needs to be evaluated. Secondary effects, such as antibody deposition, should be measured. The lack of ability to predict absolute human immunogenicity does not preclude the use of animals to assess the relative potential for an immune response. 

Robison RL, Myers LA. Preclinical safety assessment of recombinant human GM-CSF in rhesus monkeys. Int Rev Exp Pathol 1993 34A 149,172. 

Green J, Black, L. Overview of preclinical safety assessment for immunomodulatory biopharmaceuticals. Hum Exp Toxicol 200 19(4) 208-12. 

Considerations for Preclinical Safety Assessment of Oncology Products 578... 

CONSIDERATIONS FOR PRECLINICAL SAFETY ASSESSMENT OF ONCOLOGY PRODUCTS... 

The impact of the drug attributes of biopharmaceuticals on preclinical safety assessment programs for oncology products is not unique to this therapeutic area. As is true for all biopharmaceuticals, species cross-reactivity must be determined prior to selection of an appropriate animal model for safety evaluation. The nature of cross-reactivity can be based on a combination of phar-... 

The strategies to develop the preclinical safety assessment programs for biotechnology-derived therapeutics have often been characterized as case by... 

Bussiere JL, McCormick GC, Green JD. Preclinical safety assessment considerations in vaccine development. Pharm Biotechnol 1995 6 61-79. 

Practical Considerations in the Design of Preclinical Safety Assessments for Biopharmaceuticals... 

PRACTICAL CONSIDERATIONS IN DESIGN OF PRECLINICAL SAFETY ASSESSMENTS... 

PRACTICAL CONSIDERATIONS IN DESIGN OF PRECLINICAL SAFETY ASSESSMENTS TABLE 38.15 Comparative weights of various organs... 

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