Exposure-response analysis

Newhook, R., Meek, M.E., and Walker, M., Carbon disulfide hazard characterization and exposure-response analysis, Environ. Carcinog. Ecotoxicol. Rev., C19, 125-160, 2001. 

Stayner L, Smith R, Bailer J, et al. 1997. Exposure-response analysis of risk of respiratory disease associated with occupational exposure to chrysotile asbestos. Occup Environ Med 54 646-652. 

FDA approval. Usually evidence of efficacy from two or more adequate and well-controlled clinical trials along with safety information is required for the regulatory approval of a new indication for a drug. The idea is that replication of the results of a single trial is needed to rule out the possibility that a finding of efficacy in a single trial is due to chance. This example describes the application of exposure-response analysis to establish an FDA-approvable claim of drug efficacy based on a dose-reponse relationship that was obtained from two pivotal clinical trials that used different final-treatment doses. 

Miller R, Frame B, Corrigan B, Burger P, Bockbrader H, Garofalo E, Lalonde R. Exposure-response analysis of pregabalin add-on treatment of patients with... 

Stayner L, Steenland K, Greife A, Hornung R, Hayes RB, Nowlin S, Morawetz J, Ringenburg V, Elliot L, Halperin W. Exposure-response analysis of cancer mortality in a cohort of workers exposed to ethylene oxide. Am J Epidemiol 1993 138(10) 787-98. 

Hughes K, Meek ME, Walker M, and Beauchamp R (2003) 1,3-Butadiene Exposure estimation, hazard characterization, and exposure-response analysis. Journal of Toxicology and Environmental Health. Part B, Critical Reviews 6(1) 55-83. 

Liteplo, R. G., and Meek, M. E. (2003). Inhaled formaldehyde Exposure estimation, hazard characterization, and exposure-response analysis. J Toxicol Environ Health B Crit Rev 6(1), 85-114. 

Madl, A. K., Unice, K. M., Brown, J. L., Kolanz, M. E., and Kent, M. S. (2007). Exposure-response analysis for beryllium sensitization and chronic beryllium disease among worka-s in a beryllium metal machining plant. J Occup Environ Hyg 4(6), 448-466. 

Steenland NK and Brown D (1995) Silicosis Among Gold Miners Exposure Response Analysis and Risk Assessment. Am J Public Health 85 1372-1377. 

If the results for the study drug me tunbiguous (e.g., QTc prolongation at lower dose but no prolongation at higher dose, or QTc prolongation at a single isolated time point), exposure-response analysis can help interpret the data. 

In 86 % of the cases where exposure-response analysis showed that the slope was not positive, i.e., there was no evidence of a relationship between drug concentration and QTc, the corresponding QT study had been designated as negative. This equates to a sensitivity of 86%. 

Chapel S, Hutmacher MM, Bockbtader H, de Greef R, Lalonde RL (2011) Comparison of QTc data analysis methods recommended by the ICH E14 guidance and exposure response analysis case study of a thorough QT study of asenapine. Clin Pharmacol Ther 89 75-80... 

Darpo B, Ferber G, Garnett G, liu J, Stockbridge N (2015) Topic of timely interest - decision criteria for negative QT assessment using exposure response analysis of data from early-phase clinical studies letter to the Editor Ther Innov Regul Sci 49 717-719... 

The Power of Exposure-Response Analysis Compared to the E14 Time-Matched Analyses... 

---