Use Of Pharmacogenomic Classifiers In New Drug Development

With a pharmacogenomic classifier for predicting which patients are likely to benefit from an available treatment regimen, the emphasis should be on validation of the clinical utility of using the classifier. With an experimental therapy, however, the emphasis should be on demonstrating effectiveness of the drug in a population identified by the classifier. Simon and Maitournam (15,16) demonstrated that use of a genomic classifier for focusing a clinical trial in this manner can result in a dramatic reduction in required sample size, depending on the sensitivity and specificity of the classifier for identifying such patients. Not only can such targeting provide a huge improvement in efficiency in phase III development, it also provides an increased therapeutic ratio of benefit to toxicity and results in a greater proportion of treated patients who benefit.

Simon and Maitournam consider use of the targeted design shown in Fig. 1. During pre-clinical and phase I/II clinical development one identifies a fully specified classifier of which patients have a high probability of responding to the experimental drug. That classifier is then used to select patients for phase III trial. This is a form of enrichment design. Table 1 shows the approximate number of events required in order to have 80% statistical power for comparing exponential survival times using the design of Fig. 1.

The 196 events shown in Table 1 is compared to the number of events required in a standard clinical trial if the classifier is not used to select patients for randomization (Table 2). The table assumes that the treatment is not effective for the classifier negative patients. More extensive results on relative efficiency of the targeted and untargeted designs are described by Simon and Maitournam (15,17).

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