BOSTON – The Harvard-Partners Center for Genetics and Genomics is partnering with the US Food and Drug Administration to develop a pharmacogenomics-based dosing algorithm for the widely prescribed anticoagulant warfarin.
News of the collaboration follows on the heels of a highly publicized clinical trial on pharmacogenomics-guided warfarin dosing that did not reach its primary endpoint, which could place personalized medicine in a bad light, according to some observers.
HPCGG and FDA officials said that perfecting a dosing algorithm for PGx-guided warfarin dosing may help alleviate concerns raised by that clinical trial and ease some of the payor and physician reluctance to adopt the technique in mainstream practice.
Senior members of the HPCGG met with high-ranking FDA officials at a personalized medicine conference here last week to discuss the possibility of using the FDA’s pharmacodynamic and pharmacokinetic modeling tools to improve a warfarin dosing algorithm that the research center has been working on over the past year.
“In partnering with [the FDA], we’re using their pharmacokinetic and pharmacodynamic modeling, in order to improve the algorithm … and the output we hope will be a nomogram that will be used initially throughout the Partners system,” Mason Freeman, chief of the Lipids Metabolism Unit at Massachusetts General Hospital, Harvard Medical School, said during the conference hosted by HPCGG.
Freeman said that HPCGG discussed the details of the collaboration during the meeting with Lawrence Lesko and Felix Frueh, the director and associate director of genomics, respectively, at FDA’s Office of Clinical Pharmacology.
The goal of the project would be to develop a nomogram, or graphical calculating device, that physicians can use to more accurately dose warfarin for patients with polymorphisms in their CYP2C9 and VKORC1 genes.
The initial Partners study is slated for completion at the end of 2008. If the nomogram improves patient outcomes within the Partners system, then HPCGG hopes it will be used as part of a larger NIH study.
Freeman said NIH is funding a national multi-center trial for PGx-based warfarin dosing. “But I don’t think they know what nomogram they’re going to be using,” he added. “We’re hoping we’ll be able to provide that.”
The Partners study is part of a set of pharmacogenomic and pharmacoeconomic clinical trials that HPCGG announced last year [see PGx Reporter 11-15-06] According to Freeman, HPCGG has initiated both studies, and enrolled 100 patients in the CReating an Optimal Warfarin Nomogram, or CROWN, study.
Study investigators have already created a genetic test, Freeman said. “We can do the test in less than 36 hours, allowing us to make the dosing decision.”
The collaboration comes as a clinical trial on pharmacogenomics-guided warfarin dosing that did not reach its primary endpoint is being undeservedly trotted out by academia and press to give a bad name to personalized medicine, according to FDA’s Lesko.
“There is a sort of bias in the way we look at personalized medicine to kind of look for reasons why not, instead of the reasons why,” Lesko said at the conference, during a panel discussion between representatives from insurance companies.
, published in the Nov. 7 issue of Circulation
, enrolled more than 200 patients initiated on warfarin randomized to either PGx-guided or standard dosing. It found that “an algorithm guided by pharmacogenetic andclinical factors improved the accuracy and efficiency of warfarindose initiation.”
“The therapeutic problem with warfarin is a very real problem and I’m embarrassed as a physician in the 21st century to tell you how we actually treat people with this drug today.”
While the study did not reach its primary end point of a reductionin bleeding outcomes, as measured by out-of-range internationalnormalized ratio, subset analyses indicated that “pharmacogeneticguidance showed promise for wild-type and multiple variant genotypes.”
The study was conducted by researchers at the University of Utah School of Medicine and LDS Hospital, Intermountain Healthcare.
According to Lesko, the study’s negative findings received too much publicity, while the positive aspects – that PGx-guide dosing was more accurate over standard dosing methods – did not receive much attention.
“It’s odd in personalized medicine, when an article comes out and there are three press conferences on that article, and two webcasts,” Lesko said. “There was actually very positive news coming out in the article which people didn’t really focus on.”
In the study, PGx-guided dosing predicted doses moreaccurately and approximated stable doses, resultingin smaller and fewer dosing changes and INRs, the authors found.
However, out-of-range INRs occurred for 30.7 percent of patients with PGx dosing and 33.1 percent of patients with standard dosing. For this measure, while the primary end point “did not differ significantlybetween arms, … when restricted to wild-type patients and multiple variant carriersin exploratory analyses,results … achieved nominalsignificance,” according to the study authors.
Multiple variant allele carriers, meanwhile, wereat increased risk of an INR, the study found.
According to Lesko, while this study yielded negative and positive results, the greater proportion of clinical data about PGx-guided warfarin dosing speaks of the technique’s improved accuracy over standard methods.
“What the study results showed was a reduction in bleeding outcomes, by one-fourth over standard of care. That’s pretty convincing. That’s not INR measurements. I think you need to look at that,” Lesko told a panel of representatives from various insurance companies such as Aetna and WellPoint.
“You’re going to have studies that show both positive and negative results. If you look at the weight of evidence, most of it is positive and most of it coming out now is on clinical outcomes,” he said.
But diagnostic developers have said that reimbursement for warfarin testing remains unnecessarily spotty despite the availability of this clinical outcomes data, not to mention an FDA-approved genetic test for warfarin sensitivity and updated drug labels recommending genetic testing for warfarin labeling [see PGx Reporter 09-26-2007
Several participants at the conference suggested that by merely recommending genetic testing in its update to warfarin labeling, the FDA is not fully using its regulatory muscle to spur payor and physician adoption of genetic tests to guide warfarin dosing.
At the time of the FDA update to the anticoagulant’s label, however, the agency said that it would require more outcomes data before requiring doctors to perform genetic tests to dose warfarin [see PGx Reporter 09-05-2007
With the CROWN study, the HPCGG is hoping it can answer some of the murky areas surrounding PGx-guided warfarin dosing that have hindered physicians from adopting the technology and made payors reluctant to reimburse for tests.
“The therapeutic problem with warfarin is a very real problem and I’m embarrassed as a physician in the 21st century to tell you how we actually treat people with this drug today,” Freeman said.