ABSTRACT
Biomarkers, as compared to a true endpoint such as survival, can often be measured earlier, easier, and more frequently; are less subject to competing risks, and less confounded. The utilization of biomarker will lead to a better target population with a larger e¤ect size, a smaller sample-size required, and faster decision-making. With the advancement of proteomic, genomic and genetic technologies, personalized medicine with the right drug for the right patient becomes possible. Conley and Taube (2004) described the future of biomarker/genomic
markers in cancer therapy: "The elucidation of the human genome and …fty years of biological studies have laid the groundwork for a more informed method for treating cancer with the prospect of realizing improved survival. Advanced in knowledge about the molecular abnormalities, signaling pathways, in‡uence the local tissue milieu and the relevance of genetic polymorphism o¤er hope of designing e¤ective therapies tailored for a given cancer in particular individual, as well as the possibility of avoiding unnecessary toxicity." Wang, Hung, and O’Neill (2006) from FDA have pointed out: "Gener-
ally, when the primary clinical e¢ cacy outcome in a phase III trial requires much longer time to observe, a surrogate endpoint thought to be strongly associated with the clinical endpoint may be chosen as the primary e¢ - cacy variable in phase II trials. The results of the phase II studies then provide an estimated e¤ect size on the surrogate endpoint, which is supposedly able to help size the phase III trial for the primary clinical e¢ cacy endpoint, where often it is thought to have a smaller e¤ect size." What exactly is a biomarker? National Institutes of Health Workshop
(Gruttola, 2001) gave the following de…nitions. Biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal
therapeutic intervention. Clinical endpoint (or outcome) is a characteristic or variable that re‡ects how a patient feels or functions, or how long a patient survives. Surrogate endpoint is a biomarker intended to substitute for a clinical endpoint. Biomarkers can also be classi…ed as classi…er, prognostic, and predictive biomarkers. A classi…er biomarker is a marker, e.g., a DNA marker, that usually
does not change over the course of study. A classi…er biomarker can be used to select the most appropriate target population or even for personalized treatment. For example, a study drug is expected to have e¤ects on a population with a biomarker, which is only 20% of the overall patient population. Because the sponsor suspects that the drug may not work for the overall patient population, it may be e¢ cient and ethical to run a trial only for the subpopulations with the biomarker rather than the general patient population. On the other hand, some biomarkers such as RNA markers are expected to change over the course of the study. This type of markers can be either a prognostic or predictive marker. A prognostic biomarker informs the clinical outcomes, independent
of treatment. It provides information about natural course of the disease in individual with or without treatment under study. A prognostic marker does not inform the e¤ect of the treatment. For example, NSCLC patients receiving either EGFR inhibitors or chemotherapy have better outcomes with a mutation than without a mutation. Prognostic markers can be used to separate good and poor prognosis patients at the time of diagnosis. If expression of the marker clearly separates patients with an excellent prognosis from those with a poor prognosis, then the marker can be used to aid the decision about how aggressive the therapy needs to be. The poor prognosis patients might be considered for clinical trials of novel therapies that will, hopefully, be more e¤ective (Conley and Taube, 2004). Prognostic markers may also inform the possible mechanisms responsible for the poor prognosis, thus leading to the identi…cation of new targets for treatment and new e¤ective therapeutics. A predictive biomarker informs the treatment e¤ect on the clinical
endpoint. A predictive marker can be population-speci…c: a marker can be predictive for population A but not population B. A predictive biomarker, as compared to true endpoints like survival, can often be measured earlier, easier, and more frequently and is less subject to competing risks. For example, in a trial of a cholesterol-lowering drug, the ideal endpoint may be death or development of coronary artery disease (CAD). However, such a study usually requires thousands of patients and many years to conduct.
