An integrative paradigm to impart quality to correlative science
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REVIEW
Open Access
An integrative paradigm to impart quality to correlative science Michael Kalos
Abstract Correlative studies are a primary mechanism through which insights can be obtained about the bioactivity and potential efficacy of candidate therapeutics evaluated in early-stage clinical trials. Accordingly, well designed and performed early-stage correlative studies have the potential to strongly influence further clinical development of candidate therapeutic agents, and correlative data obtained from early stage trials has the potential to provide important guidance on the design and ultimate successful evaluation of products in later stage trials, particularly in the context of emerging clinical trial paradigms such as adaptive trial design. Historically the majority of early stage trials have not generated meaningful correlative data sets that could guide further clinical development of the products under evaluation. In this review article we will discuss some of the potential limitations with the historical approach to performing correlative studies that might explain at least in part the to-date overall failure of such studies to adequately support clinical trial development, and present emerging thought and approaches related to comprehensiveness and quality that hold the promise to support the development of correlative plans which will provide meaningful correlative data that can effectively guide and support the clinical development path for candidate therapeutic agents. Introduction The primary objective of early stage clinical trials is to evaluate the safety of experimental therapeutic products. As a consequence, early stage trials have typically focused on the evaluation of novel experimental products on small cohorts of patients at late stages of disease, who have progressed through a series of prior treatments and are physiologically compromised in significant ways as a result of both disease status and prior treatment. Additionally, to minimize the potential for unanticipated toxicity issues, early stage trials typically evaluate novel therapeutic products at doses that are significantly lower than those predicted to have biological activity. Correlative studies, which are common secondary objectives in clinical trials, can be described as covering two broad and related aspects of clinical trial research: the evaluation of markers associated with (i) positive
Correspondence: [email protected] Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, 422 Curie Boulevard, BRBII/III, Philadelphia, PA 19104-4283, USA
clinical activity and (ii) product bioactivity and mechanism of action. Since critical variables such as patient status, cohort size, and product dose are by intent sub-optimal, positive clinical activity is not commonly observed in early stage trials there is an inherent consequent inability to effectively identify and evaluate potential correlates of positive cl
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