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FDA Panel Leans Toward Including CYP2D6 Dx in Tamoxifen Label, But is Split on Language

A majority of an FDA advisory panel believes the agency should update the label for the breast cancer drug tamoxifen to include information about CYP2D6 genotype testing, but the panelists have not reached a consensus on certain details of the issue.
Specifically, the FDA’s Pharmaceutical Science Clinical Pharmacology Subcommittee, which met Oct. 18, was split over whether the label should “recommend” the genetic test or make it an “option” for health care providers and patients to discuss.
The regulatory impact of recommending that physicians prescribe a CYP2D6 test as opposed to making the test an option is not immediately clear.
Within the panel’s language there is “indeed a very subtle difference,” Felix Frueh, the head of the FDA’s Interdisciplinary Pharmacogenomics Research Group, told Pharmacogenomics Reporter in an e-mail this week. “We have labels … that do not ‘recommend’ a test, yet put the reason for testing in fairly plain language.” He was referring to Lilly’s attention-deficit/hyperactivity disorder drug Strattera, whose label states under a section titled “Laboratory Tests”:
“Routine laboratory tests are not required. CYP2D6 metabolism — Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of Strattera compared with extensive metabolizers. Approximately 7% of the Caucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs. The blood levels in PMs are similar to those attained by taking strong inhibitors of CYP2D6. The higher blood levels in PMs lead to a higher rate of some adverse effects of Strattera.”
“How a label will read … is a product of the negotiation between FDA and sponsor, and, of course, the scientific evidence that we believe needs to be addressed,” Frueh wrote in his e-mail. “The interpretation of such can be, perhaps, less clear. I would argue, however, that it makes little sense to go through all this effort and at the end not recommend that a test would, in fact, be a good idea.”
Although the recommendations of FDA’s expert panels are non-binding, the agency has generally taken their advice. Advisory subcommittee members do not vote on the questions posed to them. Panelists are only required to indicate whether they are in consensus or not regarding any given issue. 
The panel’s findings can be found here.
Panel Results Buoy Dx Shops’ Outlook
Despite a lack of consensus from the FDA panel, makers of CYP2D6 tests saw the results as good news. Atiqur Rahman, director of the FDA’s Division of Clinical Pharmacology V, presented a list of CYP2D6 test makers to the panel (see sidebar).
Eager to cash in on the pending relabeling, Autogenomics, a Carlsbad, Calif.-based array company, told Pharmacogenomics Reporter sister publication BioArray News of its intentions to submit a CYP450 2D6 panel with its BioFilmChip platform to the FDA for 510(k) clearance by year-end. 
According to Ram Vairavan, Autogenomics’ vice president of sales and marketing, the company is interested in submitting the assay “because of the FDA subcommittee ruling that 2D6 is an important subparameter to assess in tamoxifen therapy.”
Touting its comprehensive panel of alleles in its cytochrome P450 2D6 tests which would be “ideal for use if such a re-labeling were to occur for tamoxifen,” Vairavan added that Autogenomics is “confident that that re-labeling will occur.”
“We are staying tuned the same way [as when] the subcommittee recommended the re-labeling of 2C9 and VKORC1 for warfarin sensitivity” earlier this year, Vairavan said. “We believe this is a great revenue opportunity for Autogenomics.”
Similarly, Gentris, a Research Triangle Park, NC-based pharmacogenomics firm announced last month that it has submitted six human genomic DNA reference controls for the cytochrome P450 2D6 assay to the FDA for 510(k) clearance, and expects it will receive approval within 90 days. The controls are intended for use with tests like Roche’s AmpliChip as well as non-array-based 2D6 tests like those sold by Tm Bioscience and Third Wave Technologies.
“It’s obvious that these controls have a direct usage with an FDA-approved 2D6 test, which is the Roche AmpliChip,” Gentris CEO Michael Murphy told BioArray News this week. Murphy added that the possible re-labeling of tamoxifen could reinforce the position of pharmacogenomics companies in the market place.

“I would argue that it makes little sense to go through all this effort and at the end not recommend that a test would, in fact, be a good idea”

“The industry now is very much in a situation where we have to follow what the FDA does,” Murphy said. “Without an FDA mandate for testing there is no assurance of a marketplace for pharmacogenomic testing. It’s still not being offered by doctors voluntarily even though there are significant adverse drug reactions occurring that can be prevented,” he said.
The AmpliChip, which Affymetrix makes for Roche, is the only FDA-approved test that detects 29 variant alleles of CYP2D6 and CYP2C19. Affy CEO Steve Fodor recently said during the company’s third-quarter conference call that Affy’s clinical lab business can profit if the FDA advisory panel recommends re-labeling tamoxifen to include genetic-specific information for women who carry a variant of the CYP2D6 gene. Additionally, a possible update to tamoxifen’s label will likely foment demand from physicians who had been reluctant to adopt the AmpliChip, Affy said [PGx Reporter 11-08-06].
FDA Outlines Regulatory Need for CYP2D6 Tests
Presenting before the subcommittee, FDA Office of Oncology Products Director Richard Pazdur said that genetic tests like those for CYP2D6 are particularly needed in oncology.
In a slide titled, “How can [pharmacogenomics] help to optimize benefit/risk in Oncology?” Pazdur explained how cancer patients suffer from the serious adverse events, inadequate tumor responses and minimum survival benefit associated with most cancer drugs. Genetic tests could help optimize risk/benefit profiles of oncologics by targeting those patients who will experience less toxicity or yield a higher response to the drug.
“While it is true that particularly in oncology we would hope to see higher degrees of efficacy, it is also true that in oncology we find a more ‘binary’ response, i.e. the drug clearly works or does not work, whereas in other areas (just consider pain as an example) there is a bigger grey area,” Frueh wrote in his e-mail.
“This makes such a label update significant, because if we can predict that there is no efficacy in one group and have alternative means to treat, we can make that decision based on a more precise yes/no evaluation,” Frueh said. “Related to this, if we can predict that it is very unlikely that a patient will benefit from a drug, it is of course not acceptable to expose this patient to the potential of experiencing an adverse event — this, again, particularly important in oncology where toxicity is common (and sometimes used to determine that there is efficacy).”
The FDA has so far relied on genotypic data to modify doses for patients using the acute lymphatic leukemia drug 6-mercaptopurine and Pfizer’s colorectal cancer agent Camptosar (irinotecan).
The agency approved Third Wave Technologies’ Invader UGT1A1 molecular assay last year and mandated that the drug’s label be changed to recommend treatment alterations for those with the relevant allele, making it the first relabeling instance in which the agency included information about a gene's influence on the risk of adverse events. A test based on interrogating CYP2D6 genes would be the first time the FDA has looked at efficacy as the primary goal [Pharmacogenomics Reporter 06-14-06].
— Justin Petrone, editor of BioArray News, contributed to this article.

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