The development of standards for a warfarin dosing biomarker under a collaboration with the C-Path Institute could pave the regulatory pathway for markers involving other therapeutic agents.

One of the aims of the C-Path project - which is focused on cardiovascular biomarkers, initially for warfarin - is to develop standards for the validation of genomic/proteomic biomarker research, according to C-Path Institute CEO Raymond Woosley.

However, the outcomes of the warfarin project could inform broader regulatory policy.

In an interview with "The Pink Sheet," Woosley explained that although some research sites have conducted warfarin dosing studies based on genetic testing, the development and application of standards is necessary so FDA can make regulatory decisions based on study results.

C-Path expects such standards to be developed during the first year of the collaboration, which was announced in an April 7 Federal Register notice. The application for the cooperative agreement has been submitted and could be finalized as soon as June.

The specific goal of the program is to "help establish an infrastructure and support the direct and indirect costs associated with a program to develop and clinically validate a genotype-driven warfarin dosing algorithm and related studies," the notice states.

"Such a pharmacogenetic algorithm may improve the therapeutic efficacy and safety of warfarin dosing. Results may include improved patient outcomes, reduced resource use (costs of achieving safe and therapeutic anticoagulation), and reduced drug-related adverse events."

C-Path hopes that this work will help create a regulatory pathway for inclusion of genomic information in product labeling and assist in the development of an agency guidance on the subject, Woosley said.

Whatever test is ultimately validated for warfarin could serve as a model for personalized medicine, FDA Office of Counterterrorism & Pediatric Drug Development Office Acting Deputy Director Shirley Murphy suggested at the Keck Graduate Institute's Bioethics Symposium in Claremont, Calif. on April 13.

"This will be the first prospectively, genomicly informed study to see 'okay, if we identify, if we modulate the dose, are we actually getting the safer dose into the patient that's still effective?'" she said.

She also noted that physician utilization of warfarin dosing biomarkers "could be rapidly driven into the whole practice of medicine." However, she did indicate that physicians would need to be educated to properly utilize the results from genetic tests.

As part of its agreement with FDA, C-Path will also spearhead an educational effort to inform physicians, researchers and genomic testing equipment manufacturers on the findings of the studies as well as the regulatory standards developed.

The institute will communicate its findings to stakeholders and medical professionals in conjunction with the Arizona Center for Education & Research on Therapeutics and American College of Clinical Pharmacy.

FDA appears ready to move forward with the addition of genetic testing instructions to warfarin labeling.

Murphy noted that the agency has been discussing revisions to labeling for warfarin (Bristol-Myers Squibb's Coumadin and generics) to incorporate genomic diagnostic testing in dosing instructions.

"We're now working with [the] company around labeling and adding the test into the labeling," she said.

The topic of genomic-based dosing guidelines for warfarin is not new. In November 2005, FDA's Pharmaceutical Science Advisory Committee/Clinical Pharmacology Subcommittee considered the validity of including pharmacogenomic data related to dosing in warfarin labeling.

The committee voted 7-2 that the evidence for the influence of both VKORC1 and CYP2CP genotypes on warfarin dosing warrants the inclusion of genetic testing information in labeling.

In addition, FDA said at the meeting that it was considering developing a standardized format for inclusion of pharmacogenomic information in labeling (¹ [A#00670480014], p. 20).

Under the three year cooperative agreement with FDA, C-Path will assist the agency in obtaining and validating information from clinical studies, including a trial currently underway at the University of Utah, which will be used for the validation of genetic testing used to determine appropriate warfarin dosing.

The university has access to an extensive database of more than 13,000 DNA samples from cardiac patients in the Intermountain Heart Collaborative Study Research Registry DNA and Proteomic Bank.

The trial, which aims to enroll 200 patients and is expected to be completed by June, currently has 32 patients enrolled.

Investigators are utilizing a technology developed by Salt Lake City-based Idaho Technology. The genomic test being utilized in the study can deliver clinicians results in approximately one hour.

In addition to establishing a model for incorporating genome-based diagnostics in drug labeling, Woosley said a larger goal of the program is to help make the agency's drug-diagnostic co-development white paper more specific. FDA's combination products draft guidance is slated to come out in 2006 (² Also see "Biomarker Qualification Guidance To Require Fit For Use Validation" - Pink Sheet, 27 March, 2006., p. 25).

The cardiovascular biomarker project is the latest of several collaborations between the C-Path Institute and FDA under the namesake initiative. C-Path is also involved in the Predictive Safety Testing Consortium, an effort to bring pharmaceutical companies together to help development of safety testing methods that can be used in drug development (³ Also see "Critical Path Consortium To Allow Patents But Preserve Access For Partners" - Pink Sheet, 20 March, 2006., p. 8).

Under the cooperative agreement, the agency will provide $750,000 in funding to C-Path for the warfarin project, and an equal sum annually throughout the life of the program, pending availability of funds. The agreement expires following the third year.

Warfarin Dosing Biomarkers Could Be Model For Genetic Tests In Labeling

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