Just within the past few months, we have seen Food & Drug Administration warnings issued for both warfarin and codeine, describing how a patient's genetic makeup directly affects the way a drug is metabolized, the potential for adverse effects, and the dose required. The agency stopped just short of recommending that patients undergo genetic testing prior to initiating therapy in both cases. But as we gain more knowledge about biomarkers and how they aid in monitoring disease and medication use, we are likely to see big changes in the way drugs are developed, with a concept known as drug-test codevelopment gaining momentum.

Parallel development of a drug and diagnostic test from the preclinical stage through to submission of a New Drug Application or Biologic License Application (NDA or BLA) is a hot topic. It calls for careful coordination, according to the FDA, but it also holds the promise of great improvements to public health. Currently, the agency is working on a strategy to give manufacturers better advice and guidance on the issue. Although examples of dual approvals are lacking, many experts believe that codevelopment may soon be the prevailing model as gene-based diagnostics continue to emerge and become increasingly important to both drug development and clinical practice.

Two in the hand

"This is a sea change in how medicine is performed," said David Flockhart, M.D., Ph.D., chief of clinical pharmacology at Indiana University School of Medicine. He explained how treatments are given only to patients with certain characteristics and no longer are we using a one-size-fits-all approach for everyone with a particular disease. "We'd much more carefully stratify people by using drug-test combinations."

The best understood and widely appreciated example of RxDx is trastuzumab (Herceptin, Genentech), according to Flockhart, where the overexpression of the HER2/neu gene is both predictive of response to treatment with the monoclonal antibody and prognostic of a poor outcome in women with breast cancer. During development, Genentech realized that treatment would require a test that could identify this subset of patients. The company went ahead and devised the diagnostic in order to select patients for clinical trials. Genentech originally partnered with Dako Corp. to develop a test that would also be suitable for commercial use and could gain FDA approval. The combination was approved in 1998 after both companies filed applications for coordinated use of the drug and test. Beyond trastuzumab, however, there are few examples of successful RxDx from beginning to end of development, although numerous projects are currently in the works.

For one, Vanda Pharmaceuticals, located in Rockville, Md., has a promising RxDx candidate in its antipsychotic iloperidone. The drug originally belonged to Novartis, but after discovering the drug's potential to cause QT prolongation—an adverse effect seen with atypical antipsychotics—Vanda decided to drop iloperidone. But that was after the firm had identified a couple of genetic markers linked to the metabolism and response of the drug. At the time, Vanda's CEO, Mihael Polymeropoulos, headed up Novartis' global pharmacogenetics department. When he left to form Vanda, he acquired the rights to iloperidone and has since done additional work to prospectively confirm the markers in a phase III trial.