CEO SUMMARY: Since 2011, the University of Florida Health System has used pharmacogenetic test (PGx) results to guide physicians when they prescribe certain drugs. This initiative has improved patient outcomes, reduced the overall cost per episode of care, and gained partial reimbursement from health insurers for PGx test claims. As this testing becomes more widespread, clinical pathologists and laboratory scientists have an opportunity to add value because primary care physicians often struggle to master this new clinical discipline.
PRECISION MEDICINE IS DEMONSTRATING HOW ITS EFFECTIVE USE can improve patient outcomes. That’s been the experience at the University of Florida Health (UFH), which initiated a precision medicine program in 2011 that uses pharmacogenetic testing (PGx) provided by the health system’s laboratory division.
With seven years of experience and data, the pharmacogenetics testing program and precision medicine initiative at UFH can be a useful road map that other pathologists and clinical lab administrators can follow as they develop similar, added-value activities in collaboration with physicians and pharmacists within their own health networks.
The lessons learned and experience at initiating and sustaining this precision medicine program at the University of Florida, was presented by Julie A. Johnson, PharmD, the Dean and Distinguished Professor in the College of Pharmacy, during her presentation at The Dark Report’s Precision Medicine for Health Network CEOs conference in Nashville, in September.
Johnson showed that at the University of Florida Health, providers use pharmacogenetics testing to identify and use the most effective medications. Doing so can prevent major adverse cardiac events, such as heart attack, stroke, and death, for patients who have a percutaneous coronary intervention (PCI), a non-surgical procedure to address a narrowing of the coronary arteries.
Pharmacogenetics testing is among the most action able elements of precision medicine today, said Johnson, the founding Director of the UF Health Precision Medicine Program. Started in 2011, this program involves genotyping patients, then having physicians, pharmacists, and clinical pathologists collaborate to use genomic data to improve care.
The results of a multi year effort to use pharmacogenetic test results to guide physicians when they prescribe drugs has generated multiple benefits:
- improved patient outcomes;
- reductions in the overall cost per episode of care; and,
- at least partial reimbursement from health insurers for test claims for pharmacogenetic testing.
For this article, the word ‘pharmacogenetics’ is used in relation to genes determining drug metabolism, while ‘pharmacogenomics’ (or PGx) has a broader definition that encompasses all genes in the genome that may determine drug response.
As pharmacogenetics testing becomes more widespread, clinical pathologists and laboratory scientists have an opportunity to add value because, by definition, an effective clinical program that incorporates such testing requires collaboration involving the patient’s care team, the clinical laboratory, and the pharmacy. What’s more, the nation’s primary care physicians have struggled to master this new clinical discipline, meaning they need extensive training in a field where new knowledge is added almost monthly.
“The problem in many clinical settings is that physicians treating patients often do not understand pharmacogenetics testing and so may not order these tests for their patients,” stated Petr Starostik, MD, the Director of Molecular Pathology for the Pathology Laboratories at UF Health.
“The whole field of pharmacogenetics testing is driven by the need for education, meaning we need to make sure that physicians ordering PGx tests are educated properly,” Starostik explained.
Need to Educate Doctors
Recognizing this need to educate physicians and encourage more appropriate use of pharmacogenomics testing, the National Human Genome Research Institute issued grants under its Implementing Genomics in Practice (IGNITE) program. UF Health was one of the six medical centers to win such grants.
“Under the IGNITE grant at UF Health, pharmacists use pathology testing results to educate physicians at the point of care,” noted Starostik. “At the same time, pathologists have a critical role in developing these programs and producing the test results in support of the pharmacogenetic program.”
In 2012, UF Health’s Department of Pharmacy started a precision medicine program using pharmacogenetic testing to identify how well individual patients needing percutaneous cardiac intervention (PCI) will metabolize the medications they need. PCI is a non-surgical procedure used to treat a narrowing of the coronary arteries. For these patients, cardiologists prescribe clopidogrel, a blood thinner.
In 2016, the FDA updated the label for clopidogrel to warn that patients who are CYP2C19 poor metabolizers may have diminished effectiveness of the drug as compared to patients with normal CYP2C19 function. The drug label suggests that a different platelet P2Y12 inhibitor be used in patients identified as CYP2C19 poor metabolizers, note guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC).
Health Insurers Pay Some Amount for Lab
IN 2011, THE UNIVERSITY OF FLORIDA HEALTH SYSTEM started the UF Health Precision Medicine Program to genotype patients and then have physicians, pharmacists, and clinical pathologists collaborate in an effort to use genomic data to improve care.
One of the first initiatives in this program involved using pharmacogenetic testing to identify how well patients needing percutaneous cardiac intervention (PCI) would metabolize the blood thinner clopidogrel. Since then, UF Health has developed tests to assess patients for metabolizing drugs for hepatitis C and opioids, among other tests. “For all of these implementations we have focused on developing the clinical evidence,” Johnson explained in her presentation at The Dark Report’s Precision Medicine for Health Network CEOs conference in Nashville.
After the first year, UF Health began billing for this pharmacogenetic testing and had a payment rate of about 85%, Johnson explained. Seven different third-party payers, including Medicare, reimbursed for such testing.
“This means that, of the 85% of bills that we submitted to payers, we got paid something,” Johnson said. “The range of what we received was a bit wide. Having health insurers reimburse some amount for this testing was significant.” Going forward, accountable care organizations may be inclined to pay for such testing too, she added.
The CPIC guidelines require testing for CPY2C19. They recommend an alternative therapy for poor metabolizers, meaning those patients who carry one or two loss-of-function alleles, Johnson said.
At UFH, patients are tested for genotype and phenotype, Starostik said. When the pharmacists developed the PGx program, they asked pathologists to run the tests and incorporate the clinical test results into each patient’s electronic medical record.
“It was great that the pharmacists were so active in implementing this program,” Starostik said. “If I had to pull this together without the engagement of the pharmacists, then the Pathology Department would have to answer questions from physicians as they look at these results and don’t know what they mean.”
When UF Health named Starostik the director of molecular pathology in 2014, the program had been in place for two years. “Since then, it has been a great collaboration between the College of Pharmacy and the College of Medicine,” he said. “For those of us here in molecular pathology, our role was established under the IGNITE grant to collaborate with the College of Pharmacy here in Gainesville.”
To enhance its role in the program, the pathology department invested heavily in new technology to be able to run the tests for CYP2C19. “The department purchased the QuantStudio Real-Time PCR systems from ThermoFisher Scientific and ran a whole panel of tests of some 200 SNPs (single nucleotide polymorphisms),” added Starostik. “Then we reported those clinical results directly into UF Health’s Epic electronic medical record system. Using those results, the Pharmacy Department recommends the appropriate medication based on each patient’s clinical test result.
“We also collaborated with the College of Pharmacy in putting together the clinical result,” he explained. “The clinical result for a patient shows two elements. One is the genotype and the second is the phenotype, which shows what type of metabolizer the patient is. By that, I mean the clinical test results that would show how the patient will react to the drug. Each patient can be either a normal metabolizer, a low metabolizer, or a high metabolizer.”
Researchers and Clinicians Are Developing Clinical Evidence to Support Pharmacogenetic Testing
AS MOST CLINICIANS AND LABORATORY SCIENTISTS KNOW, much of the pharmacogenetics data being developed focuses on the drug metabolizing enzymes that have very common genetic variations,” Julie Johnson, PharmD, said. “By most estimates, these variations are present in more than 95% of the population. This means almost everyone has some genetic variation in one or more genes that lead people to metabolize drugs differently.
“In clinical terms, people are either normal metabolizers or fall into one of three categories,” she explained. “One: they may have no functional protein. Two: they may have reduced function or intermediate enhanced function, meaning they have either a duplication of the allele or increased expression of the protein. Or, three: they are rapid or ultra-rapid metabolizers.
“For this discussion, I’ll focus on CYP2C19, which has this whole range, meaning patients have genetic variations that cause both increased metabolism and reduced or no metabolism,” she added. “Patients were tested for how they would metabolize clopidogrel, an antiplatelet drug used to prevent heart attacks and strokes in persons with heart disease or peripheral vascular disease.
“We know that clopidogrel has to be bioactivated in a two-step process and the most important enzyme in that activation is CYP2C19,” she explained.
“We also know that CYP2C19 has a common loss-of-function variation and the *2 allele is the most common of these variations. When we say ‘common’ we mean 30% of people of European ancestry, 30% to 35% of people of African ancestry, and as much as 70% of Asians carry at least one loss-of-function allele.
“As a clinical pharmacologist, this is the type of evidence I need,” Johnson said. “Such evidence tells me that if you carry a reduced-function allele, you are less likely to activate to the active metabolite. There’s very clear evidence supporting that hypothesis.
“If you have less of the pharmacological activity (meaning less anti-platelet reactivity), then you have an increased risk of death due to a stroke or heart attack,” she added.
At UF Health, clinicians follow the guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC), an international consortium of clinicians dedicated to facilitating the use of pharmacogenetic tests for patient care.
“The CPIC guidelines for CPY2C19 and clopidogrel were published in 2011 and updated in 2013 when new drugs became available as alternatives,” Johnson said. “The guidelines said that ultra-metabolizers or normal metabolizers using clopidogrel are fine, but for those who carry one or two loss-of-function alleles, CPIC guidelines recommend an alternative therapy.”
Patients Ask for PGx Tests
UF Health’s pharmacogenetics program is important not only for improving patient outcomes but also because many patients today may be more knowledgeable about pharmacogenetic testing than physicians, Starostik added. “Frequently, a patient will ask the physician to run a genetic test before the physician prescribes the medication,” he said.
“But if the physician doesn’t understand the specific test needed for this patient’s prescription drug, then what happens?” Starostik asked. “For these reasons, the whole field of pharmacogenetics testing requires continuous education of the providers.
“Most providers don’t know anything about PGx testing, which means they won’t order these tests for their patients,” he noted. “And, if the providers don’t order this testing, then they can cause patient harm. If the patient experiences harm, however, that adverse event will not be obvious right away.
“Should a physician not order the right PGx test, it won’t cause problems such as myocardial infarction or strokes or anything acute like that,” Starostik explained. “Nothing will happen in the next five or ten minutes because the consequences of not ordering the test are delayed. They are under the surface where we don’t see them. But there is an adverse effect to that patient over time.”
Pain management is another opportunity. “Especially now with the opioid crisis, PGx testing could help identify people who do not respond well to pain management with opioids,” Starostik explained. “If they don’t respond well to opioids, they could overdose because they are hyper-metabolizers and cannot get rid of the pain.”
To identify patients who may be poor metabolizers for opioids, the pathologists run the cytochrome P450 2D6 test. “Without this testing, these patients could be harmed,” he said.
One problem UF Health encountered when it started the program was how to incorporate genomic data into the health system’s electronic medical record system, said Johnson. Physicians wanted to be able to store the genetic information from pharmacogenetic testing so that it could be accessed when needed by the clinicians.
“Was there room for it in the electronic health records? Does that data sit behind a wall versus inside the wall?” she asked. “At the same time, we needed to develop clinical evidence for pharmacogenetics. There was lots of data and much of it was retrospective analyses from clinical trials.
Focus on Therapeutic Drugs
“As a clinical pharmacologist, the data made it obvious to me that A plus B equals C,” she said. “However, the average physician doesn’t have the same focus on therapeutic drugs that I have and so may need to be convinced that A plus B does, in fact, equal C.
“For these reasons, as we proceeded to implement pharmacogenomics into clinical settings, we’ve tried to marry that implementation with ongoing evidence development,” added Johnson. “Early on, we had three big goals: One, to improve treatment outcomes. Two, to improve safety, and, three—potentially—to reduce the cost of medical care,” she stated.
Contact Julie A. Johnson, PharmD, at 352-273-6309 or firstname.lastname@example.org., Petr Starostik, MD, at 352-265-9900 or email@example.com.
Researchers with IGNITE Consortium Demonstrate How Pharmacogenetics Testing Boosts Outcomes, Reduces Cost
PHARMACOGENTICS TESTING enables clinicians to identify patients who metabolize medications more quickly or more slowly than normal. This knowledge is particularly important for drugs such as clopidogrel, an antiplatelet therapy that cardiologists use to prevent stroke, heart attack, and other heart problems.
Once researchers recognized the clinical differences between normal metabolizers and slow metabolizers, their next step was to incorporate this information into clinical practice. To do so, they needed to answer the question about how PGx testing would affect patient outcomes and costs.
Last year, researchers from nine sites in the Implementing Genomics in Practice (IGNITE) consortium reported that genotype-guided antiplatelet therapy reduced the risk of adverse cardiovascular outcomes.
Building on this effort, researchers presented a poster, “Real World Cost-Effectiveness of CYP2C19 Guided Antiplatelet Therapy in Patients with Acute Coronary Syndrome and Percutaneous Coronary Intervention,” at the 39th Annual North American Meeting of the Shared Medical Decision Making conference in Pittsburgh.
Josh Peterson, MD, MPH, Associate Professor of Medicine and Biomedical Informatics at Vanderbilt University, and Nita A. Limdi, PharmD, PhD, a professor in the Department of Neurology in the University of Alabama at Birmingham, are IGNITE researchers who are involved in the study on the effectiveness of using antiplatelet therapy based on CYP2C19 testing.
To evaluate the effectiveness of using PGx testing for 1,815 patients with percutaneous coronary intervention (PCI), the researchers compared patient outcomes and the cost effectiveness of four treatment strategies against a base case.
The four strategies involved using clopidogrel for some patients, using ticagrelor (a second blood thinner) for some patients, and switching medications based on PGx test results.
Four Alternative Approaches
For the base case (or reference strategy), researchers used clopidogrel antiplatelet therapy for all patients and then compared those results with results from the four alternative approaches:
• In strategy 1, the researchers used ticagrelor for all patients.
• In strategy 2, the researchers treated all patients with ticagrelor therapy for 30 days and then switched those patients to clopidogrel.
• In strategy 3, the researchers did genotype testing at the time of the PCI, then treated all patients who did not have a loss-of-function (LOF) allele with clopidogrel and treated all patients who had an LOF allele with ticagrelor.
• In strategy 4, the researchers did genotype testing after 30 days of treatment with ticagrelor for all patients and then switched non-LOF patients to clopidogrel and maintained those with an LOF allele on ticagrelor.
For the study, researchers used a measure of clinical outcomes called quality-adjusted life years (QALY).
“In the study, we demonstrate that genotype-guided escalation was cost effective at the widely-referenced willingness-to-pay threshold of $50,000 per quality-adjusted life-year gained,” they wrote. The study, with updated results, is currently being considered for publication.