Biomarkers


diagnostic on the label for a marketed therapy then typically samples from Phase III trials are used to demonstrate the value of the biomarker5.


Clinical utility: The term ‘clinical utility’, while widely used, is ill-defined. It is commonly used as a synonym for studies of clinical effectiveness and/or economic evaluations. The most basic definition of clinical utility refers to an estimation of the respec- tive benefits and risks resulting from test use. Risks and benefits are, at this higher level perspective, to be seen as encompassing both medical and eco- nomic connotations and considerations, even though the discussion of benefits and risks is often restricted to the former.


As healthcare payers are becoming increasingly cost-conscious, and reimbursement decisions are being more commonly influenced by medical-eco- nomic considerations, clinical utility is quickly becoming the overriding consideration with regard to the introduction of a companion or other diag- nostic. This adds significantly to the burden of research and development expenses for diagnostic companies since reliable estimates of clinical utility will usually require prospective, controlled studies


in which clinical end-points are reached and where interventions are/are not guided by testing for the biomarker of interest.


On the level of medical considerations, in the narrowest sense of the term, clinical utility refers to the ability of a screening or diagnostic test to pre- vent or ameliorate adverse health outcomes such as mortality, morbidity or disability through the adoption of efficacious treatments conditioned on test results. A screening or diagnostic test in isola- tion does not have inherent utility; because it is the adoption of therapeutic or preventive interventions that influence health outcomes, the clinical utility of a test depends on effective access to appropriate interventions, or to the way it beneficially can affect the choice of an intervention. This use of the term ‘utility’ is consistent with standard practice in evidence-based medicine, which focuses on objec- tive measures of health status to evaluate interven- tions. Clinical utility can more broadly refer to any use of test results to inform clinical decision-mak- ing. Finally, in its broadest sense, the medical inter- pretation of clinical utility can refer to any out- come considered important to individuals, their families, as well as to other societal strata.


Table 2: Summary of characteristics for various parameters used in describing clinical test performance METRIC


DEFINITION Accuracy Sensitivity Specificity Positive predictive value Negative predictive value Positive likelihood ratio Negative likelihood ratio Odds ratio (TP+ TN)/N TP/(TP + FN) TN/(TN + FP) TP/ (TP + FP) TN/ (TN + FN)


(TP/(TP + FN))/(FP/ (TN + FP))


(FN/(TP + FN))/(TN/ (TN + FP))


TP X TN/FN X FP STRENGTHS Intuitive


Does not depend on prevalence


Does not depend on prevalence


Clinical relevance Clinical relevance


Does not depend on prevalence


Does not depend on prevalence


Does not depend on prevalence; combines sensitivity and specificity


Area under curve Area under ROC curve


Does not depend on prevalence; combines sensitivity and specificity


WEAKNESSES Depends on prevalence


Applies only to diseased persons


Applies only to non- diseased persons


Depends on prevalence Depends on prevalence


Applies only to positive tests


Applies only to negative tests


Values FP and FN errors equally; not intuitive


Lack of clinical interpretation


FN = false-negative; FP = false-positive; N = sample size; ROC = characteristic; TN = true-negative; TP = true-positive 26 Drug Discovery World Winter 2010/11


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