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Clinical trial designs incorporating predictive biomarkers.

ABSTRACT: Development of oncologic therapies has traditionally been performed in a sequence of clinical trials intended to assess safety (phase I), preliminary efficacy (phase II), and improvement over the standard of care (phase III) in homogeneous (in terms of tumor type and disease stage) patient populations. As cancer has become increasingly understood on the molecular level, newer "targeted" drugs that inhibit specific cancer cell growth and survival mechanisms have increased the need for new clinical trial designs, wherein pertinent questions on the relationship between patient biomarkers and response to treatment can be answered. Herein, we review the clinical trial design literature from initial to more recently proposed designs for targeted agents or those treatments hypothesized to have enhanced effectiveness within patient subgroups (e.g., those with a certain biomarker value or who harbor a certain genetic tumor mutation). We also describe a number of real clinical trials where biomarker-based designs have been utilized, including a discussion of their respective advantages and challenges. As cancers become further categorized and/or reclassified according to individual patient and tumor features, we anticipate a continued need for novel trial designs to keep pace with the changing frontier of clinical cancer research.

SUBMITTER: Renfro LA

PROVIDER: S-EPMC4737867 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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Clinical trial designs incorporating predictive biomarkers.

Renfro Lindsay A LA Mallick Himel H An Ming-Wen MW Sargent Daniel J DJ Mandrekar Sumithra J SJ

Cancer treatment reviews 20160105

Development of oncologic therapies has traditionally been performed in a sequence of clinical trials intended to assess safety (phase I), preliminary efficacy (phase II), and improvement over the standard of care (phase III) in homogeneous (in terms of tumor type and disease stage) patient populations. As cancer has become increasingly understood on the molecular level, newer "targeted" drugs that inhibit specific cancer cell growth and survival mechanisms have increased the need for new clinica ...[more]

PMID: 26827695

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Project description:The regression discontinuity (RD) design is a quasi-experimental design that estimates the causal effects of a treatment by exploiting naturally occurring treatment rules. It can be applied in any context where a particular treatment or intervention is administered according to a pre-specified rule linked to a continuous variable. Such thresholds are common in primary care drug prescription where the RD design can be used to estimate the causal effect of medication in the general population. Such results can then be contrasted to those obtained from randomised controlled trials (RCTs) and inform prescription policy and guidelines based on a more realistic and less expensive context. In this paper, we focus on statins, a class of cholesterol-lowering drugs, however, the methodology can be applied to many other drugs provided these are prescribed in accordance to pre-determined guidelines. Current guidelines in the UK state that statins should be prescribed to patients with 10-year cardiovascular disease risk scores in excess of 20%. If we consider patients whose risk scores are close to the 20% risk score threshold, we find that there is an element of random variation in both the risk score itself and its measurement. We can therefore consider the threshold as a randomising device that assigns statin prescription to individuals just above the threshold and withholds it from those just below. Thus, we are effectively replicating the conditions of an RCT in the area around the threshold, removing or at least mitigating confounding. We frame the RD design in the language of conditional independence, which clarifies the assumptions necessary to apply an RD design to data, and which makes the links with instrumental variables clear. We also have context-specific knowledge about the expected sizes of the effects of statin prescription and are thus able to incorporate this into Bayesian models by formulating informative priors on our causal parameters.

Dataset Information

Clinical trial designs incorporating predictive biomarkers.

Publications

Clinical trial designs incorporating predictive biomarkers.

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