Abstract
More and more studies have shown that genetic determinants may mediate variability among persons in the response to a drug, and thus some therapeutics may benefit only a subset of patients. Genomic technologies, such as DNA sequencing, mRNA transcript profiling, and comparative genomic hybridization, are providing biomarkers to predict who are most likely to respond to a given drug, and thus brings opportunity to conduct targeted clinical trials with eligibility restricted to the subset of patients. In this paper, we evaluate the relative cost of a targeted design versus an untargeted design for a randomized phase III clinical trial comparing a new treatment to a control. Our investigation indicates that the effectiveness of the targeted design critically depends upon the difference of treatment effect between patient subsets, the proportion of targeted patients in the population, the diagnostic assay performance, and the relative cost of screening versus drug expenses.
Highlights
The evidence that genetic determinants may mediate variability among persons in the response to a drug is increasing
Several studies have classified some patients as having a “poor metabolism” for certain drugs due to lack of CYP2D6 activity [2,3]
We evaluate the relative cost of the untargeted randomized phase III clinical trial design versus the targeted design based on the is the positive predictive value (PPV) of the diagnostic assay, and ω− = 1− ω+
Summary
The evidence that genetic determinants may mediate variability among persons in the response to a drug is increasing. The striking differences in the frequency of EGFR mutation and response to Iressa between Japanese and U.S patients raise general questions regarding variations in the molecular pathogenesis of cancer among patients Genomic technologies such as DNA sequencing, mRNA transcript profiling, and comparative genomic hybridization [6] are providing evidence that many diseases are more molecularly heterogeneous than previously recognized. A traditional phase III randomized clinical trial is often conducted to evaluate a test regimen, comparing it with a control regimen for all patients in the disease category These traditional approaches may lack efficacy, since molecularly targeted drugs may only be effective for a subset set of the patients with a traditionally defined disease.
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