Toxicology preclinical studies

The adverse reaction potential of an investigational new drug, to some extent, may be indicated by its molecular structural similarities to other drugs of known actions and by pharmacologic and toxicologic preclinical studies in appropriate species of laboratory animals. The full adverse reaction profile of a drug, how-... 

Preclinical studies should address the potential toxicity due to inappropriate release of the conjugated toxin. Preclinical toxicology of monoclonal antibodies may not require extensive animal studies but should be examined for cross-reactivity with antigenic epitopes present on normal cells in vitro and for the presence of human or rodent vimses. Early clinical trial should involve biodistribution studies with radiolabelled material. 

Use data from preclinical pharmacology toxicology ( safety ) studies to support the safety of clinical trials. 

All INDS include an extensive review of outside (generally published) literature, with particular focus on any administration of the proposed drug to human subjects or on any published toxicology or preclinical studies that may indicate any possible adverse reactions. An eventual 505(b)(2) NDA will rely on some of these studies, in combination with IND-proposed pivotal new clinical studies, to support the application. This plan will be outlined in the IND study proposal and/or discussed at the pre-IND FDA conference. 

No adjuvant is licensed as a medicinal product in its own right, but only as a component of a particular vaccine. Therefore preclinical and toxicology studies need to be designed on a case-by-case basis to evaluate the safety profile of the adjuvant and adjuvant/ vaccine combination [60], Evaluation in preclinical studies is important for identifying the optimum composition and formulation process and also for allowing development of tests for quality control [61]. Data from these studies also helps plan protocols for subsequent clinical trials from which safety and efficacy in humans can be evaluated. 

When preclinical studies are conducted in house or are reported in peer-reviewed journals and intended to support clinical trials, they should be well-controlled and designed to answer specific toxicological questions. The data should also be available in sufficient detail to allow an independent review of the studies. Ideally study designs include not only efficacy but toxicological endpoints such as defined clinical laboratory parameters, macroscopic, and microscopic evaluation of tissues. 

This chapter provides a survey of US marketed biopharmaceuticals approved over the past 20 years. It is a simply a profile of the species and types of toxicology studies done for each drug for marketing approval. For a complete list of all preclinical studies for a biopharmaceutical, the reader is directed to the Web sites of the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). 

Once the phase 1 has been completed, next steps include the comparison of observed human exposure data (maximum concentration, Cmax and area under the concentration-time curve, AUC) to the exposures observed in the supportive preclinical studies, prediction of the human exposure in future clinical trials (based on dose level and frequency) and the calculation of the actual safety margins provided by the repeat-dose preclinical toxicology studies. The need for safety margins (based on preclinical safety and single-dose human data) to support phase lb or phase 2 dosing is usually considered on a case-by-case basis. 

There must be considerable overlap here between the basic pharmacodynamic and pharmacological experimentation, which has shown why the intended product may be of therapeutic value and the mechanisms of that desired activity, and the range of investigations that it is necessary and worthwhile to apply in the types of preclinical studies usually labeled as toxicology, here including pharmacokinetics. 

In addition, for preclinical studies to be useful in assuring the safety of human studies, sponsors should be able to relate the drug product being proposed for use in a clinical study to the drug product used in the animal toxicology studies that support the safety of the proposed human study. 

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