Title: Pitfalls In Nonclinical Safety Data Evaluation

Abstract:

Regulatory safety assessment is based on validated methods and standard procedures within the frame of quality (Good Laboratory Practices). However, when applying the standard methods to obtain and evaluate results in toxicology and safety pharmacology, a thorough critical approach should be applied, as misleading conclusions can result from pitfalls in data collection and subsequent analyses. In fact, nonclinical safety reports should refer data and relevant evaluation in a non-ambiguous manner, to allow go/no-go decision by the sponsor, and finally a positive acceptance by the authorities. Review of dozens of reports revealed a general good appraisal to safety evaluation under different type of studies and in different animal species, however in some cases statements had to be corrected to be consistent with the meaning of the results collected. Statistics is not the only criterion for data evaluation and redundancy of observations (for example daily body weight / food consumption) are often confounding factors owing to a number of significant findings which are meaningless, and sometimes related to changes/errors in procedures. Also, comparison to a control group makes sense in rodent studies, when for many parameters no pre-dose data are available, as is the case in non-rodents. Intra-individual variations (pre- vs post-dose effects) are in fact to be considered in principle, as this comparison more closely reflects the clinical situation. This holds true for both toxicological and pharmacological investigations, the latter being possibly more affected by the complexity of techniques and the amount of data to be evaluated, for example in continuous 24-h ECG telemetry determinations. In conclusion, the present investigation techniques in preclinical studies provide huge amount of data and the automated evaluation tools help the scientists to assess the toxicological profile of the drug under test. A critical evaluation of the applicability of conditions for data analysis coupled with the full knowledge of experimental phases is recommended for a better reliability of the results and to avoid uncertainties and misunderstandings.

Biography:

Alberto Morisetti has graduated in 1980 in Biological Sciences in Milan, Italy and is European Registered Toxicologist. Up to 2009 he worked as Study Director, Study Monitor, Head of Test Facilities for PharmaTox research and development. He is author/co-author of more than 30 scientific publications in the field of regulatory toxicology and pharmacology, mainly related to contrast media, imaging by different techniques, and regulatory issues, anticancer drugs. From 2010 he started the activity of consultancy in R&D for different Italian and foreign pharma companies, working on regulatory as well as industrial toxicology. His activity consists of drawing the nonclinical development plan, CRO selection, study monitoring and reviewing study reports, CTD and participating to meetings with regulatory authorities for anticancer, antibiotic, corticosteroid, medical device projects. Recent activities include EU Commission participation as nonclinical expert.