nal antibodies do not work very well overall, with 5, 10, maybe 15 percent of patients who have tumors with wild-type KRAS showing a response. Taking all the observations into account, it is generally agreed that a randomized controlled trial (RCT) to test the clinical utility of a KRAS gene test would not be appropriate.

There are also good basic science data on genetic variation in the response to tamoxifen or warfarin, but there is much more confusion about whether the genetics are clinically relevant. In warfarin management, for example, there are many additional considerations, such as height, weight, concomitant medications, diet, and compliance. In this case, RCTs would seem to be very important.

The way an Institutional Review Board (IRB) views a trial impacts whether an RCT is conducted. A study of the published literature found that RCTs that have gone through IRB review have a 40 to 60 percent success rate for the hypothesis being tested in the trial (Djulbegovic and Bercu, 2002). If there was a 10 percent chance of success, no one would fund the trial and an IRB would not approve it. Similarly, if there was 90 percent chance of success, the same thing would occur. A trial needs to fall somewhere in this 40–50–60 percent range to garner IRB approval.

Something that happens fairly often with diagnostic tests is that the 40 to 60 percent success range is already exceeded based on known information. For a genetic test, retrospective data may suggest an 80 or 90 percent likelihood of a particular result. Already, the predicted success rate of the hypothesis is outside of that 40–60 percent range where, based on documentation, an IRB will tend to approve it. An insurer, or another decision maker, may want to see data from an RCT, but the type of trials they are asking for would not likely be approved by an IRB.

It is important for companies bringing a diagnostic test into the marketplace, or facing insurer decisions, to remember that a product faces very different value propositions across its life cycle, Quinn said. In the early investment phase, intellectual property, barriers to competition, and development risk are important considerations. When seeking regulatory approval, meeting Food and Drug Administration (FDA) standards for safety and efficacy are paramount. After approval, the focus is on demonstration of clinical utility and comparative effectiveness. Quinn recalled the studies described by Ginsburg (see Chapter 4) where patients whose gene expression profile predicted low risk were in a control (observation) group; however, if the gene profile predicted high risk, there was a control group as well as a therapy group. One problem with this approach, Quinn said, is that the genetic test is not being compared to something else. True, the results of the genetic test can help assign therapy, he said, but if the gene panel costs $400, and a $50 antibody to do the same thing exists but was

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