Nonclinical Study Design, Monitoring & Evaluation
Once a study has been designed and the protocol has been set, it is important to monitor the study as it progresses to ensure that once placed at an outside contract research organization (CRO), the study is being conducted correctly and according to protocol. This is of particular concern for more complex studies with lots of moving parts and a high price tag. Understanding of Good Laboratory Practices (GLP) and the experimental procedures to be conducted are particularly beneficial when monitoring a study. Finally, specific expertise may also be necessary to evaluate the results from studies – either those currently in progress or ones that were conducted in years past. Proper interpretation of findings is especially critical for regulatory approval and to ensure the safety of one’s product.
Exponent’s toxicologists have significant expertise in the design, monitoring, and evaluation of a diverse set of toxicology safety studies, including:
- Acute, subchronic, and chronic toxicity studies
- Dose range-finding and dose-escalation studies
- Toxicokinetic and mode-of-action evaluations
- Carcinogenicity bioassays
- In vivo and in vitro genotoxicity assays, including
- Ames assays
- Chromosomal aberration assays
- Micronucleus assays
- Neurotoxicity and neurodevelopmental studies
- Developmental and reproductive toxicity studies, including multi-generation studies
- Juvenile animal studies
- Biocompatibility and cytotoxicity assays
Exponent scientists have extensive experience in the pharmaceutical industries, academia, and government that can be brought to bear in ensuring that the studies done for our clients are the best they can be the first time around. In particular, our team of scientists has considerable regulatory experience as members of national and international expert committees on a diverse set of toxicology issues related to developmental and reproductive toxicity, endocrine disruption, genotoxicity, mode of action assessments and neurotoxicity testing. Further, our scientists have served on national and international committees involved in the generation and revision of testing guidelines for developmental neurotoxicity testing, and genotoxicity testing.
Bal-Price AK, Coecke S, Costa L, Crofton KM3, Fritsche E, Goldberg A, Grandjean P, Lein PL, Li A, Lucchini R, Mundy WR, Padilla S, Persico AM, Seiler AEM, Kreysa J. Advancing the Science of developmental neurotoxicity (DNT): Testing for better safety evaluation. ALTEX 2012; 29:202–215.
DeSesso, JM, Williams AL, Ahuja A, Bowman CJ, Hurtt ME. The placenta, transfer of immunoglobulins, and safety assessment of biopharmaceuticals in pregnancy. Crit Rev Toxicol 2012; 42:185–210.
DeSesso JM. Chapter 6: Comparative gestational milestones in vertebrate development. In Developmental and Reproductive Toxicology: A Practical Approach, 3rd Ed. Hood RD (Ed.). Informa
Healthcare, London, pp. 93‐138, 2012.
Garman RH, Li AA, Kaufmann W, Auer RN, Bolon B. Recommended methods for brain processing and quantitative analysis in rodent developmental neurotoxicity studies. Toxicol Pathol. 2015 Aug 21. pii: 0192623315596858. [Epub ahead of print].
Gollapudi BB, Johnson GE, Hernandez LG, Pottenger LH, Dearfield KL, Jeffrey AM, Julien E, Kim JH, Lovell DP, MacGregor JT, Moore MM, van Benthem J, White PA, Zeiger E, Thybaud V. Quantitative approaches for assessing dose‐response relationships in genetic toxicology. Environ MolecMutagen 2013; 54:8–18.
Gollapudi BB, Lynch AM, Heflich RH , Dertinger SD, Dobrovolsky VN, Froetschle R, Horibata K, Kenyon MO, Kimoto T, Lovell D, Stankowski Jr. LF, White PA, Witt KL, Tanir JY. The in vivo Pig‐a assay: A report of the International Workshop on Genotoxicity Testing (IWGT) Workgroup. Mutat Res (In Press).
Hentz KL. Safety assessment of pharmaceuticals. In Reference Module in Biomedical Sciences. Elsevier, 2014.
LeBaron MJ, Schisler MR, Torous DK, Dertinger SD, Gollapudi BB. Influence of counting methodology on erythrocyte ratios in the mouse micronucleus test. Environ Molec Mutagen 2013; 54:222–228.
Li AA, Baum MJ, McIntosh LJ, Day M, Liu F, Gray LE. Building a scientific framework for studying hormonal effects on behavior and on the development of the sexually dimorphic nervous system. Neurotoxicology 2008; 29:504–519.
Llorens J, Li A, Ceccatelli S, Sunol C. Strategies and tools for preventing neurotoxicity: to test, to predict and how to do it. Neurotoxicology 2012 Aug; 33(4):796–804.
Martus HJ, Hayashi M, Honma M, Kasper P, Gollapudi B, Mueller L, Schoeny R, Uno Y, Kirkland DJ. Summary of major conclusions from the 6th International Workshop on Genotoxicity Testing (IWGT), Foz do Iguaçu, Brazil. Mutat Res Genet Toxicol Environ Mutagen. 2015: 783:1-5.
Schisler MR, Moore MM, Gollapudi BB. In vitro mouse lymphoma (L5178Y Tk (+/‐) ‐3.7.2C) forward mutation assay. Methods in Molecular Biology 2013; 1044:27–50.
Sura R, Settivari RS, LeBaron MJ, Rowlands JC, Carney EW, Gollapudi BB. A critical assessment of the methodologies to investigate the role of inhibition of apoptosis in rodent hepatocarcinogenesis. Toxicol Mech Methods. 2015:25:192-200.
Zeiger E, Gollapudi B, Aardema MJ, Auerbach S, Boverhof D, Custer L, Dedon P, Honma M, Ishida S, Kasinski AL, Kim JH, Manjanatha MG, Marlowe J, Pfuhler S, Pogribny I, Slikker W, Stankowski LF Jr, Tanir JY, Tice R, van Benthem J, White P, Witt KL, Thybaud V. Opportunities to integrate new approaches in genetic toxicology: An ILSI-HESI workshop report. Environ Mol Mutagen. 2015:56:277-85.
John M. DeSesso, Ph.D., DABFM, DABFE, FACFEI, DABCHS, Fellow ATSHealth SciencesPrincipal ScientistAlexandria