Exploratory development biomarkers

To further characterize the toxicity and investigate its possible mechanism, a 14-day time-course study in the rat was conducted to allow for the observation of the lesion development and progression (Brenneman et al., 2014). Light microscopic (i.e., histochemical and IHC with quantification) and ultrastructural (i.e., TEM) examination showed that the injury appeared to originate as degeneration and loss of endothelial cells in the capillaries at the exocrine-endocrine interface. This injury was not associated with any increases in traditional or exploratory serum biomarkers of exocrine injury nor any evidence of endocrine dysfunction as assessed via an OGTT however, it was associated with an increase in EMPs that was not pancreas specific. 

So far we have considered biomarkers whose validity has been either somewhat established or discredited by their use in clinical practice or in clinical trials. However, the utility of biomarkers in aiding both drug development and the diagnosis and management of patients has resulted in the introduction of many new biomarkers, many of which are less well characterized. Innovative but incompletely evaluated biomarkers are particularly likely to play an important role in exploratory studies of a new drug candidate. Unfortunately, the degree of innovation represented by a biomarker is likely to vary inversely with the extent of its validation (53). This is a consequence of the fact that prior use in clinical trials is an important component of biomarker evaluation. 

FIGURE 6.1 Conceptual diagram of fit for purpose biomarkers method validation. The method validation processes include four activity circles prevalidation (preanalytical consid eration and method development), exploratory method validation, in study method validation and advanced method validation. The processes are continuous and iterative, dictated by the purpose of the biomarker application. The solid arrows depict the normal flow of biomarker development (prevalidation), method validation (exploratory or advanced), and application (in study method validation). The process could include moving the chosen biomarkers from exploratory mechanistic pilot studies to advanced validation and confirmatory studies, or from exploratory validation to advanced validation after changes in critical business decision. The broken arrows represent scenarios where validation data do not satisfy study requirements, necessitating assay refinement or modification. 

Documentation on assumptions should address those assumptions implicit in the pharmacokinetic or pharmacodynamic model and the statistical methodology chosen to evaluate the data. It should also state the assumed sensitivity of the parameters required to define the model relative to the data space being evaluated as well as any preconceived notions regarding biomarkers or surrogate markers evaluated as responses or covariates in the analysis. Hypotheses should be defined based on what was held a priori as true before the study or analysis, what was developed from preliminary or exploratory data analysis, and what would constitute a difference or equivalence in an effect or outcome, hi some instances the criteria for difference as opposed to equivalence can be defined from a statistical viewpoint independent of the actual study design. This approach does not always confer regulatory acceptance, however. 

It is currently well known that there is a lack of sensitive and specific pancreatic biomarkers available for use in drug development research. This is especially true in the preclin-ical setting, because these biomarkers are not routinely evaluated and prechnical pancreatic toxicity occurs infrequently. While exploratory biomarkers such as TLI, PLI, and TAP have been sporadically tested, there is great value in investing in the development of rehable reagents across... 

In order to help drug development sponsors understand the value of including exploratory biomarkers in nonclinical studies and clinical trials, the PSTC has posted summary data packages on each of the biomarkers that have received a Letter of Support on the C-Path website (Critical Path Institute s Predictive Safety Testing Consortium, 2015a). 

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