Drug development biomarker validation

Lesko, L.J. and Atkinson, A.J., Jr., Biomarkers and surrogate endpoints — Use in drug development and regulatory decision making criteria, validation, strategies, Ann. Rev. Pharmacol. Toxicol, 41, 347-366, 2001. 

Fig. 2. Dynamic steps in the drug development cycle. As explained in the text, multiple strategies can be used for initial drug target discovery, and at various steps in validating the drug target, mechanisms of action, or defining biomarkers of response, new drug targets can emerge.

A final caveat in the RPAIA field that limits biomarker discovery as well as other uses in drug development is the somewhat limited panel of antibodies that have been validated to date for the platform. Many antibodies that work on western blots have the potential to work with RPMAs as well, because in both platforms proteins are in a denatured state. However, because the molecular weight of analytes detected by RPMA cannot be known, it is imperative to demonstrate the specificity of antibodies, usually measured by the absence of nonspecific reactive bands on western blots developed under similar blocking conditions. A second requirement for antibody validation is proof of principle that an antibody detects quantitative changes in the expected target on an... 

Cummings J, Ward TH, Greystoke A, et al. Biomarker method validation in anticancer drug development. Br. J. Pharmacol. 2008 153 646-656. 

Recent advancements in genomics and proteomics have generated considerable interest in the discovery and validation of biomarkers in mechanism-based drug development [69-71], These advances have been welcomed to reduce the cost, increase success rates, and accelerate timelines in the drug discovery and development process. Herein, a brief overview of the application of biological markers in early discovery, development, toxicological assessments, and efficacy studies in humans is presented. 

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. 

Lesko LJ, Atkinson AJ Jr. Use of biomarkers and surrogate endpoints in drug development and decision making Criteria, validation, strategies. Annu Rev Pharmacol Toxicol 2001 41 347-66. 

Validation of a biomarker begins with the description of the pathogenesis of a disease and culminates when it is determined that the biomarker is applicable to clinical trials. This validation process follows a stepwise process depending on the stage of drug development. 

Lee, J.W., Nordblom, G.D., Smith, W.C., and Bowsher, R.R. (2003) Validation of bioanalytical assays for novel biomarkers practical recommendations for clinical investi gation of new drug entities. In Bloom J., and Dean R.A. (eds), Biomarkers in Clinical Drug Development. Marcel Dekker, New York, pp. 119 148. 

Many, if not all, of these procedures have evolved over many years and with continuous feedback within the scientific communities around the world. Much of this has been conducted within an organization called the Clinical Laboratory Standards Institute (CLSI) formerly known as the National Committee for Clinical Laboratory Standards (NCCLS). Many guidance documents are available from this organization s Web site (see below) that explain how some of the assay performance characteristics are established for the purposes of diagnostics. A number of these experiments are very similar to, or indeed the same as, experiments we conduct in validating biomarker assays for use in drug development and are listed in Table 7.1. 

---