Clinical endpoints applications

Finally, the ability of aprepitant to block emesis, a therapeutically relevant endpoint for the ultimate clinical application of the drug, as discussed below, was tested in the presence of several emetogens in the ferret. This species is believed to be a valid animal model for cancer chemotherapy-induced emesis in humans. Aprepitant (1) effectively blocked retching and vomiting due to cisplatin, apomorphine, and morphine at a dose of 3.0 mg/kg p.o. and 0.3 mg/kg i.v. (in the case of cisplatin).8... 

NIH Definitions Working Group. Biomarkers and surrogate endpoints in clinical research Definitions and conceptual model. In Downing GL, ed. Biomarkers and surrogate endpoints Clinical research and applications. Amsterdam Elsevier 2000. p. 1-9. 

The application of NIR for predicting the endpoint of clinical or production scale batches based on the NIR calibration models developed in the laboratory may prove to be very important to the pharmaceutical manufacturer. When drugloading or polymer-coating efficiencies vary, as they do, from lab scale equipment to the larger equipment used for manufacturing, the availability of a rapid on-line or at-line measurement for prediction of process endpoint may save many millions of dollars in time and materials. Although the standard error of prediction may not match the values obtained when... 

Few biomarkers will become surrogate endpoints. However, characteristics supporting a biomarker maturing into a surrogate endpoint are (a) biologic plausibility, (b) successful application in prior clinical trials, and (c) presence of significant risk-benefit considerations. Table 17.1 presents a summary of these considerations... 

One of the most potent applications of pharmacometrics is the informative construction of clinical trials by using clinical trial simulation (CTS). Population PM models are of great value when used in CTS because estimates of typical parameters along with parameter variability can be incorporated. There are three basic types of models needed to execute a CTS an input-output model, a covariate model, and an execution model. These are described in detail in Chapter 34 of this book. Clinical trial simulation can improve pediatric study structure by examining the impact of many important factors such as dropouts, choosing varying endpoints, and deviations from protocol. Pediatric PM models find great utility when applied to CTS. 

Regardless of the type of marketing application, the clinical data must be based on sound scientific principles to demonstrate the endpoint of substantial equivalence or safety and effectiveness. These principles consist of a proper study design, including controls and the adequate number of patients, monitoring of the study to assure the protocol is followed by the investigators, and proper analysis of results. 

J.F. Niblack. In G.J. Downing (Ed.), Biomarkers and Surrogate Endpoints Clinical Research and Applications. Elsevier Science, 2000. 

---