Toxicology clinical trials

Division of Clinical Trial Design and Analysis Preclinical pharmacology and toxicology Clinical trial design, safety and efficacy 20% of CBER clinical protocols are now for gene therapy. 

All preparations of enzymes intended for parenteral use are tested for safety in lower animals under the conditions anticipated in clinical trials ie, their use must be nonpyrogenic in the USP rabbit assay (255), and must be sterile. Such toxicologic studies are usually a prerequisite for approval by the FDA for the sale of such pharmaceuticals. 

Szarfman A, Talarico L, Levine JG. Analysis and risk assessment of hematological data from clinical trials toxicology of the hematopoietic system. In Sipes IG, McQueen CA, Gandolfi AJ, editors. Comprehensive toxicology. Vol. 4. New York Elsevier Science, 1997, p. 363-79. 

Buhles, W.C., Application of immunologic methods in clinical trials, Toxicology, 129,73, 1998. 

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. 

Dixit, R., What non-clinical toxicology and safety pharmacology data are needed to accelerate phase I—II clinical trials , Am. Pharm. Outsourcing, 5, 30-37, 2004. 

Data from 6 months of administration in nonrodents should be available before initiation of clinical trials longer than 3 months. Alternatively, if applicable, data from a 9-month nonrodent study should be available before clinical treatment duration exceeds that which is supported by the available toxicology studies. 

The use of animals for pharmacological and toxicological studies has yielded invaluable information for drug development. However, many drug candidates failed in Phase I and II clinical trials because the animal models were insufficient to represent human systems and functions for some drugs. Efficacy and acceptable toxicities derived from animal models were not replicated in humans (Exhibit 5.8). In recent years, the direction in development of drugs has shifted toward the use of ex vivo, in vitro assays and even in silico methods. Nevertheless, some tests must stiU be confirmed in animals. 

The clinical trial should be conducted methodically with clear objectives and outcomes that are statistically verifiable. The precUnical and toxicological data should have been carefully analyzed and should confirm the scientific finding. The trial should not be biased and should be able to be executed without unreasonable caveats and conditions. 

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