Safety assessments advantages

With the aim of developing animal models appropriate for safety assessment of allergenic potential a number of species has been considered, including swine [94,99] and dogs [94,100-102], Although these species have their advantages, discussion here... 

This approach appears somewhat irrational and without much scientific merit, since many of these new molecules are minimally toxic or nontoxic by this sort of acute evaluation. As in the case of interferons or monoclonal antibodies, the toxic effects observed in humans might not be predicted from safety assessments in rodents. An appropriate test species should be selected. Is the rat or mouse the appropriate species to evaluate a species-specific rDNA protein such as human growth hormone or interferons, or would nonhuman primates be more suitable Does the nonhuman primate really offer any advantages There is some consensus that the nonhuman primate may be a more appropriate species for testing some rDNA human proteins. 

In addition to rodent studies, regulatory guidelines for pharmaceuticals require that repeated dose safety studies of up to nine months (in the United States, six months elsewhere) in duration be conducted in a nonrodent species. The most commonly used nonrodent species is the dog, followed by the monkey and pig. Another nonrodent model used to a limited extent in systemic safety evaluation is the ferret. The major objectives of this chapter are (1) to discuss differences in rodent and nonrodent experimental design, (2) to examine the feasibility of using the dog, monkey, pig, and ferret in safety assessment testing, and (3) to identify the advantages and limitations associated with each species. 

This section is devoted to the definition and comparison of the three nonrodent animal models (dog, ferret, and monkey) in terms of experimental procedures, environmental and dietary requirements, as well as advantages and disadvantages of use in safety assessment testing. 

Advantages and Disadvantages. Advantages of using monkeys in safety assessment studies include their phylogenetic proximity, as well as their physiological, behavioral, and, often, metabolic similarities, to humans (Table 16.13). An example is the similarity between the ovarian cycle of female monkeys and women (Mazue and Richez, 1982), which makes the monkey the ideal animal model for reproductive studies. Another advantage associated with most species of monkeys used in safety assessment studies is that they are much smaller than nonrodents such as the dog and, thus like the ferret, require less test compound. 

While there are advantages and disadvantages associated with all three nonrodent species, the dog is probably the nonrodent species most frequently used in safety assessment studies. This is because dogs are relatively docile and even tempered,... 

Further, the imaging biomarkers identified in preclinical safety assessment studies can also be used in clinical drug safety studies, as MRI is widely available and safe to use in volunteer studies. This can be an advantage for the preclinical safety assessment function as it provides feedback on predictability of animal models to human disease using the same endpoint. Clearly, one would not run MRI on all clinical safety studies but in those cases where there is no cheaper, simpler safety biomarker available and there is doubt about the degree of risk posed in man, for example, because of species differences or because the effect size in the placebo group is expected to be very high. 

An exposure scenario can be as wide or specific as a company carrying out a risk assessment deems necessary. The advantage of a generic exposure scenario is that it covers a range of uses, but this may result in some over-protective risk-reduction measures being implemented. In comparison, a specific exposure scenario can clearly delineate how to control exposures from distinct uses or target potential high-exposure uses that require particular safety measures. A specific exposure scenario may therefore require a more in-depth safety assessment. 

In recognizing that many of these challenges can be difficult to tackle with traditional frequentist approaches, some key opinion leaders in the field commented "Safety assessment is one area where frequentist strategies have been less applicable. Perhaps Bayesian approaches in this area have more promise." [3]. Bayesian methods have many advantages and are suitable for safety assessment primarily in the following aspects ... 

As a safety assessment techniqne, the FHA has a nnmber of advantages which include ... 

Each of these tools has its own advantages and disadvantages and the extent to which these can be used during various phases of the product life cycle, and the degree to which it can be applied to safety assessments, vary. Listed in alphabetical order, the tools/techniques most frequently used by the author have been shaded. 

Appendix A supports Chapter 6 by summarising the advantages and limitations of some of the models used for causal or consequence analyses. Appendix B supports Chapters 4, 5, 8 and 9 by summarising useful safety criteria that can be used in safety assessments. Appendix C provides a brief introduction to goal structured notation, which is useful for defining safety arguments as referenced in Chapters 8 and 9. 

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