To assess the present and future prospects for the use of co-developed companion diagnostics in drug use and development, speakers representing groups involved with test development as well as speakers representing pharmaceutical manufacturing were invited to share their perspectives. A theme that emerged was the importance of obtaining analytical validity, clinical validity, and clinical utility evidence for tests, regardless of how the tests are specifically developed, distributed, or conducted.


A number of important shortcomings currently affect clinicians’ use of IVDs. One important issue is that IVDs vary in performance and have many sources of potential error, said Walter Koch, vice president of global research at Roche Molecular Systems. No fewer than a dozen different methods are currently used for mutation detection, he said. Furthermore, tumors are heterogeneous, which raises the possibility that variability in tissue sampling may lead to results based on just a few cells that may not accurately reflect the cellular makeup of the tumor. In addition, reagents used in tests can be variable because of considerable lot-to-lot variation, and in manual analyses data interpretations may vary. Koch noted that two studies performed in Europe support the notion that procedural steps are not well controlled in some laboratories. In fact, for KRAS testing, only 70 percent of the laboratories accurately reported all of the mutations (Beau-Faller et al., 2011; Bellon et al., 2011; Dequeker et al., 2011).

In addition to the KRAS example above, Koch cited an example from Roche’s clinical trials for Zelboraf, where the cobas® 4800 BRAF V600 Mutation Test was used to identify patients with melanoma tumors harboring the V600E BRAF mutation (Cheng et al., 2012). While Koch noted that FDA recognizes Sanger sequencing as the “gold standard” for variant detection in the absence of an FDA-approved test, he pointed out that it may be poorly suited for cancer tissue mutation analysis because of known poor sensitivity for samples containing less than 25 percent mutant alleles, which is frequently the case in cancer (Anderson et al., 2012; Halait et al., 2012). Other potential consequences of relying on Sanger sequencing include invalid results (no results), false negatives (incorrectly identified as wild-type), and false positives (incorrectly identified as BRAF V600E) that may occur more often, as reported by Anderson et al. (2012). The downstream clinical implications of these errors could include inappropriate denial or delayed access to Zelboraf or patients inappropriately receiving the drug, which may lead to preventable toxicity in addition to poor efficacy. “Today, a lot of laboratories are using [Sanger] technology to do these kinds of mutation analyses,” Koch said. “They are perhaps inappropriate for this use.”

The National Academies of Sciences, Engineering, and Medicine
500 Fifth St. N.W. | Washington, D.C. 20001

Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement