Genotyping Of Warfarin Patients Will Be Discussed By FDA's Clinical Pharmacology Subcommittee
This article was originally published in The Pink Sheet Daily
Executive Summary
The subcommittee will consider whether warfarin labeling should be changed to recommend lower starting doses for patients with certain genotypes at Nov. 14-15 meeting.
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Whether to require genotyping of warfarin patients for genetic variations will be discussed by FDA's Clinical Pharmacology Subcommittee of the Advisory Committee on Pharmaceutical Science at its Nov. 14-15 meeting. In 1 briefing materials for the first day of the meeting, FDA asks the subcommittee, "Does the committee believe that genotyping some or all patients prior to beginning warfarin therapy would reduce adverse events and improve achievement of stable" international normalized ratios (INR)? [Editor's Note: To 2 watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.] The subcommittee will also consider whether "sufficient evidence exists to support the recommendation to use lower starting doses of warfarin for patients with genetic variations" in the liver cytochrome CYP2C9 and vitamin K epoxide reductase complex 1(VKORC1) "that lead to reduced activities?" If the subcommittee answers that the genotyping and lower dosing are warranted, FDA will ask the committee how that information can be conveyed in labeling for warfarin (Dupont's Coumadin and generics). The meeting will also tackle more general issues of how pharmacogenetic information is presented in labeling. FDA is proposing language for labeling if a drug is indicated only for a population with a certain genetic makeup. An example provided by the agency for language in the indications section states that the drug "is indicated for the treatment of patients with _______ genotypes. (See Clinical Studies: Clinically beneficial effects are limited to patients with ______ genotypes). [Drug] should be used only in patients with ______ genotypes." In the case of receptor-targeting agents, proposed language states that the drug "is indicated for patients with ___ receptor positive or ___ receptor unknown locally confined _____ cancer….Patients with ____ receptor negative disease…rarely responded to [Drug]. (See Clinical Studies: ______ protein expression for information regarding protein testing)." FDA also provides examples of language for other sections of drug labeling. The proposed language for the Clinical Pharmacology section of labeling includes a discussion of the enzymes that metabolize the drug and variations among racial groups with regard to their abilities to metabolize the enzyme. FDA wants to know if the subcommittee agrees with its labeling recommendations, "in particular, those related to metabolizing enzymes." The subcommittee will also discuss whether results of a genotype test should be reported when the clinical significance of the genotype is uncertain or incomplete. "Do we rely solely on evidence of clinical genotype response association data to report out certain genotypes or would in vitro data be sufficient in certain cases where alleles are rare and clinical data are difficult to obtain?" FDA asks. Also on Nov. 14, the subcommittee will be asked to comment on a case study that applies quantitative methods to assess genomic enrichment and biomarker titration design for a Phase III trial. On Nov. 15, the subcommittee will discuss the inclusion of biomarker information in drug labeling to individualize pharmacotherapy and receive an update on the Critical Path biomarker-surrogate endpoint project. - Danielle Foullon |