At a time when the Food and Drug Administration is on the brink of incorporating gene-based information on the risk of adverse events in warfarin’s label, the Harvard Partners Center for Genetics and Genomics has launched a study to measure patient outcomes and cost when such information is used to make clinical decisions about warfarin.
The aim of the two-part trial, begun Oct. 1, is to investigate whether “there is something that could be done that would facilitate the right dose of warfarin for the patients,” and analyze the cost/benefit of incorporating genetic information to make better clinical decision for using warfarin, HPCGG Scientific Director Raju Kucherlapati told Pharmacogenomics Reporter this week.
“If you say that you need to do the test and its going to add to the overall care of the patients that’s not very attractive,” Kucherlapati told Pharmacogenomics Reporter this week. ”If we can show that by bringing genetics into the clinic it will change the cost-benefit ratio then that would be attractive.”
According to Kucherlapati, most warfarin dose-finding studies in the past have not looked at outcomes data. HPCGG’s trial is unique in that it will incorporate patients’ medical history and genetics to create an algorithm for determining an appropriate dose for patients.
The first component of the trial aims to improve the accuracy of warfarin dosing, currently estimated to be between 55 to 60 percent. This portion of the study is divided into two parts. The first is a prospective trial of 500 patients that aims to incorporate medical and genetic information from the patients into a nomogram, or algorithm, to determine the right warfarin dose for patients.
The second arm, which is still in the planning stages, will be a prospective randomized study of approximately 1,200 patients, one half of whom will receive the standard care without genetic information and the other half who will have their clinical decisions made based on their genetic information.
“Then we can test and see if incorporating the genetic information to make the decisions would indeed have better outcomes for those patients,” Kucherlapati said.
Five sites under the aegis of the Partners HealthCare System will be involved in the study, including Massachusetts General Hospital, Brigham and Women’s Hospital, Faulkner Hospital, North Shore Medical Center, and Newton-Wellesley Hospital. Between the five hospitals investigators hope to accrue approximately 100 patients per month. The dosing studies will be managed by Samuel Goldhaber and Christine Seidman of Brigham and Women’s Hospital, and Daniel Singer of Massachusetts General Hospital.
The dosing study is expected to conclude in September 2007. Each patient will receive warfarin for three months. Initial data from the trial are slated to be released at the end of 2007 or the beginning of 2008. The clinical trial will be officially unveiled at the HPCGG personalized medicine conference on Nov. 28-29 in Boston, HPCGG said.
The second portion of the trial will examine pharmacoeconomic factors by analyzing the costs and benefits of incorporating genetic information into patient care. Jerome Avorn of Brigham and Women’s Hospital will manage the pharmacoeconomic portion of the study. He could not be reached for comment.
Where is FDA on Warfarin’s New Label?
HPCGG’s trial comes at a time when the FDA is in the process of incorporating genetic information to warfarin’s label, which has made industry keen on developing CYP2C9 and VKORC1 genetic tests.
The FDA Clinical Pharmacology Subcommittee of Pharmaceutical Science Advisory Committee recommended testing for variations in the CYP2C9 and VKORC1 genes in patients requiring warfarin therapy November 2005.
During the most recent meeting of the Clinical Pharmacology Subcommittee on incorporating genetic information in tamoxifen’s label (see related story), Office of Clinical Pharmacology and Biopharmaceutics Director Lawrence Lesko provided an update on warfarin.), Office of Clinical Pharmacology and Biopharmaceutics Director Lawrence Lesko provided an update on warfarin.
“If you say that you need to do the test and its going to add to the overall care of the patients that’s not very attractive. If we can show that by bringing genetics into the clinic it will change the cost-benefit ratio then that would be attractive.”
According to Lesko, the agency is in the final stages of negotiating the language to include genetic information in warfarin’s label. Although no FDA-approved CYP2C9 and VKORC1 genetic tests are available at the time, he noted that numerous clinical trials are being planned or have already launched to “validate dosing algorithms and study clinical outcomes” based on these SNPs.
This week, for example, Kimball Genetics launched its warfarin sensitivity DNA test for research/investigational purposes along with the “Pharmacogenetics for Coumadin” study, already underway in collaboration with St. Luke’s Episcopal Hospitalis in Houston.
The warfarin sensitivity DNA test determines the presence of variations in CYP2C9 and VKORC1 genes, the company explained in a release. Kimball Genetics expects to offer the DNA test for routine clinical use in early 2007.
In addition, Nanogen is planning a test for resistance to warfarin based on mutations in the CYP2C9 gene. Potential competitors in this area include Genelex and Clinical Data, which both recently launched tests in this area, as well as the AmpliChip, which identifies CYP2D6 and CYP2C19 genotypes [PGx Reporter 10-18-06]