Non-clinical pharmacology and toxicology

In the United States, the FDA has issued guidelines that make specific recommendations for the non-clinical pharmacology and toxicology sections of an Investigational New Drug application (IND). These guidelines are available on the FDA web site (http // www.fda.gov/cder/PharmTox/guidances.htm). 

Non-clinical pharmacology and toxicology section This section is to present data in addition to that included in the IND. Long-term toxicology data are required. The sponsor is also expected to provide study results of the drag on reproduction and effects on fetuses. 

A sponsor submits a clinical trial application to the Competent Authority in each Member State where the trials are to be conducted. The Competent Authority has 60 days to review and approve or reject the application. Application is in prescribed forms and covers the proposed clinical trial protocol, manufacturing and quality controls on the drug, and supporting data, such as (a) chemical, pharmaceutical and biological data, (b) non-clinical pharmacological and toxicological data and (c) clinical data and previous human experience. The supporting data are submitted in the Common Technical Document (CTD) format (Section 7.8). 

Non-Clinical Study Reports Toxicological and Pharmacological Tests 111... 

Hanson, L.A., Bass, A.S., Gintant, G., Mittelstadt, S., Rampe, D. and Thomas, K. (2006) ILSI-HESI cardiovascular safety subcommittee initiative evaluation of three non-clinical models of QT prolongation. Journal of Pharmacological and Toxicological Methods, 54, 116—129. 

Center for Drug Evaluation and Research (CDER). Guidance for Industry, Guidelines for the Eormat and Content of the Non-Clinical Pharmacology/Toxicology Section of an Application EDA Rockville, MD, 1987. 

Non-clinical Written and Tabulated Summary Pharmacology Pharmacokinetics Toxicology Clinical Summary Biopharmaceutics and Associated Analytical Methods Clinical Pharmacology Studies Clinical Efficacy Clinical Safety... 

A related problem concerns a scientifically defensible definition of the lower limit of quantitation (LLOQ). This is sometimes referred to simply as the LOQ but in fact the upper limit of quantitation (ULOQ) can also be an important parameter for validated analytical methods (see Chapter 9). A very important definition of LLOQ is that of the US FDA with regard to bioan-alytical data used in human clinical pharmacology and in bioavailabihty and bioequivalence studies requiring pharmacokinetic evaluation (FDA 2001) this guidance also applies to bioanalytical methods used for non-human pharmacology-toxicology studies and preclinical studies. According to this protocol, the LLOQ is accepted as the lowest standard on the cahbration curve provided that (a) the analyte response for this concentration (amount)... 

Note Conventional safety pharmacology studies can reasonably be expected to predict "Type A" ADRs. Functional toxicological measurements may predict "Type C" ADRs. Conventional toxicology studies address "Type D" ADRs. Prediction of "Type B" responses requires a more extensive non-clinical and clinical evaluation, often only addressing risk factors for the idiosyncratic response. "Type E" ADRs are rarely investigated non-clinically using functional measurements unless there is cause for concern. 

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. 

The design and the execution of safety pharmacology studies are focused upon the safety of human volunteers and patients in clinical trials. ICH S7A and may be soon S7B strive for effective integration of safety pharmacology results with those of the non-clinical (toxicology) and clinical safety databases. 

A description of the non-clinical studies concerning the drug s pharmacological actions - and toxicological effects. 

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