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While Wary of Genohyping, FDA s Lesko Offers Proof that Agency is Committed to PGx

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The concept of personalized medicine could fall prey to the same over-exuberance that has tripped up previous technology waves, according to a recent speech by a senior Food and Drug Administration official.

Larry Lesko, director of the Office of Clinical Pharmacology and Biopharmaceuticals at the FDA's Center for Drug Evaluation and Research, even has a name for his theory, which he dubbed "genohyping instead of genotyping." For example, Roche's much-publicized AmpliChip CYP450 genotyping test, approved this year in the US and late least year in Europe, has the potential to reduce adverse drug events by 20 percent, but that its ultimate utility is still an "open question."

Nevertheless, Lesko, speaking in a keynote address at the Bio-IT World Conference in Boston last week, said that the FDA is fully behind pharmacogenomics, and offered an overview of some of the agency's activities that extend well beyond the pharmacogenomics guidance document that it formally released in late March.

Most recently, he noted, the agency's oncology advisory committee voted on May 5 not to approve Johnson & Johnson's investigational leukemia drug Zarnestra due to the "heterogeneity of the trial population," which would make it difficult to identify patients who would benefit most from the drug. This decision, based on a core principle of pharmacogenomics, "indicates a change in FDA's thinking" in the drug-approval process, he said.

The agency has also begun "retrofitting" existing drugs using genomics methods, Lesko said. One recent example of this is Pfizer's colorectal cancer drug Camptosar, which is currently in the process of having its label updated to account for results from recent studies showing that a polymorphism in the UGT1A1 gene can be a good indicator for toxicity risk in patients taking the drug, Lesko said.

Pharmacogenomics-related studies underway at the FDA for existing drugs include the widely prescribed blood thinner warfarin, which has a high frequency of adverse events. Lesko said the agency is beginning its own genomics-based study of the drug using 400 patients. If the study leads to any conclusive results, "we'll re-label the drug," he said.

The agency is also reaching out to its counterparts in Europe and Japan in an effort to "harmonize" international regulatory issues surrounding pharmacogenomics. Lesko said that an International Conference on Harmonization is scheduled for November in Romewhere FDA and regulatory agencies from other nations will discuss, among other topics, an effort to develop pharmacogenomics policies for third-world countries.

Lesko also noted a number of challenges that pharmacogenomics still faces before it moves more broadly into clinical practice. Obstacles include the lack of a distribution network for new diagnostic tests; the uncertain threshold for sensitivity and specificity in genomics-based diagnostics; reimbursement issues; and the limited number of genomic biomarkers for disease diagnosis, prognosis, dose selection, and response.

Another challenge, he said, is data interpretation. Lesko said the approval of the AmpliChip test earlier this year has led to a quandary for some of its early adopters. Clinicians are running the test, and then asking what the data means, and whether they should adjust their dosage, Lesko said. While the AmpliChip has the potential to reduce adverse drug events by 20 percent, its ultimate utility is still an "open question," he said.

A final hurdle, he noted, will be overcoming industry doubts that a business model exists for pharmacogenomics. After all, with pharma still looking for the next big blockbuster, the idea of a smaller, segmented market for a new therapeutic is not very attractive.

Countering this, Lesko cited the example of Genentech's Herceptin as an argument in favor of targeted approaches. The drug was approved around eight years sooner than the average blockbuster, saving an estimated $35 million in clinical trial costs and generating an estimated $2.5 billion in revenue during that eight-year period, he said.

As a more recent example, he cited AstraZeneca's lung cancer drug Iressa, which the FDA failed for the general population. The drug has been shown to be effective in Asians, however, and AstraZeneca now plans to market it in Japan, China, and other Asian markets, he said.

According to Lesko, "That's not a failure — that's a success."

— Bernadette Toner ([email protected])

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