By Turna Ray
The US Food and Drug Administration is planning to respond to a meta-analysis published last year in the Journal of the American Medical Association that raised questions about whether the agency had prematurely updated the label of the anti-platelet drug Plavix with genetic testing information.
Researchers led by Michael Holmes of University College London analyzed data from 32 studies involving more than 42,000 patients who experienced cardiovascular events, stent thrombosis, or bleeding events. When the researchers analyzed data from 26 of those studies where patients were exposed to Plavix (clopidogrel) in a treatment-only trial design, those with one or more loss-of-function CYP2C19 alleles experienced lower metabolite levels and less platelet inhibition, signaling reduced response to the drug.
However, noting that there was "evidence of small-study bias" in this data since most of these studies included fewer than 200 CVD events, Holmes and colleagues restricted their analysis to the four studies with 200 or more events and found that Plavix metabolizers did not have a worse outcome than normal metabolizers. Furthermore, in six randomized trials the study investigators did not identify any significant associations between CYP2C19 genotypes and Plavix efficacy in terms of cardiovascular events and bleeding.
This meta-analysis in JAMA was accompanied by an editorial from Cleveland Clinic cardiologist Steven Nissen, who lauded Holmes et al. for their analysis and asserted that by updating Plavix's label with a boxed warning about CYP2C19 testing, the agency displayed "irrational exuberance."
Although the FDA doesn't feel the need to respond to Nissen's criticisms, a spokesperson told PGx Reporter that the agency is planning to publish a response to Holmes et al., which will "conclude that the meta-analysis entirely supports the current Plavix labeling."
Plavix is converted into its active metabolite by the CYP2C19 enzyme. The FDA first updated the label for Plavix in 2009 to inform doctors that CYP2C19 poor metabolizers experienced diminished response to the drug and that PGx tests could be used to identify genotypes linked to variable treatment response. Then, in 2010, the FDA added a "black box" warning to Plavix's label to highlight that poor metabolizers, or patients with the CYP2C19*2/*2 genotype, "exhibit higher cardiovascular event rates following acute coronary syndrome or percutaneous coronary intervention than patients with normal CYP2C19 function." (PGx Reporter 3/17/2010)
The warning also noted that CYP2C19 genotyping tests could help guide therapeutic strategies and advised doctors to "consider alternative treatment strategies" in poor metabolizers.
However, the controversy around Plavix testing sparked after the American College of Cardiology and the American Heart Association issued a consensus document at odds with FDA's view, stating that there wasn't sufficient evidence to support routine use of genetic testing or platelet function testing in medical practice.
"Amid this uncertainty, FDA-cleared direct-to-consumer tests are available and demand is escalating," Holmes et al. wrote, but this claim is not accurate. The FDA has not yet cleared any test validated to perform PGx testing for Plavix, let alone a DTC test. The agency did approve in 2010 AutoGenomics' CYP2C19 test for aiding "therapeutic strategy" with drugs metabolized by the enzyme but did not name any specific drugs. Meanwhile, a number of laboratory-developed tests exist for gauging the CYP2C19 genotypes associated with Plavix response.
The struggle to discern when investigational interventions are ready for real-world implementation exists in all disciplines of medicine, not just personalized medicine. Acknowledging that the rapid pace of genomic discoveries presents an enormous data challenge in terms of validating significant genotype-phenotype associations, the FDA has taken a proactive role in encouraging collaborative biomarker validation programs and in updating drug labels with pharmacogenetic information based on literature reviews.
Despite these efforts, industry players have accused the agency of hindering personalized medicine by failing to keep regulations on par with technological advances. In light of this, the debate around Plavix's labeling update is a rare instance where FDA has been accused of acting too quickly. "No matter how promising, pharmacogenomic approaches to treatment must withstand the same scrutiny required of all therapeutic advances – careful evaluation through well-designed randomized clinical trials," Nissen wrote in his editorial.
In his view, the FDA erred by recommending genetic testing based on studies that measured surrogate markers – such as platelet reactivity and blood metabolite levels – to gauge the association between CYP2C19 alleles and Plavix response. Noting that drugs that improve biochemical or physiological measures of disease may not necessarily impact patient outcomes, Nissen asserted that "when examining the pharmacogenetic factors influencing the efficacy of a drug such as clopidogrel, the effects of CYP2C19 loss-of-function alleles on antiplatelet efficacy cannot be equated to increases in cardiovascular morbidity and mortality."
However, FDA officials have noted that they don't always have the luxury of making decisions based on perfect data. In updating the Plavix label with PGx information, the FDA considered retrospective genetic analysis from the CHARISMA trial involving more than 2,400 patients; TRITON-TIMI 38, which included more than 1,400 patients; and other smaller studies. In TRITON-TIMI 38, poor and intermediate CYP2C19 metabolizers treated with Plavix experienced higher cardiovascular events, such as myocardial infarction and stent thrombosis, than did extensive metabolizers. In CHARISMA, meanwhile, only poor metabolizers saw high cardiac event rates, compared to the other genotypes.
"Unfortunately, what wasn't available [at the time of the labeling change] was a single study showing how CYP2C19 genotypes impacted [Plavix-treated] patients' pharmacokinetics, or their blood levels of the metabolites; their platelet reactivity, which is the pharmacodynamics; and their clinical outcomes," said Lawrence Lesko, former director of the Office of Clinical Pharmacology at FDA's Center for Drug Evaluation and Research, who played a leadership role in adding PGx information to Plavix's label. "So, you had to rely on integration of studies. Some of which looked at the blood [metabolite] levels and the pharmacodynamics, and others looked at [platelet reactivity] and the outcomes."
There were other unknowns, according to Lesko, that kept the agency from providing more definitive guidance on how physicians should use CYP2C19 testing to inform treatment decisions regarding Plavix. For example, there was little data distinguishing how intermediate metabolizers – for example patients with CYP2C19*1/*2 or CYP2C19*1/*3 genotypes – responded to Plavix compared to poor metabolizers. And although the data at the time suggested that CYP2C19 genotypes influenced Plavix response mainly in acute coronary syndrome patients with high ST segment elevation or those who had undergone a percutaneous coronary intervention, the agency didn't specify in the label those disease states (such as atrial fibrillation) in which genotype didn't influence drug response.
Several months after FDA added the black-box warning to Plavix's label in March 2010, the New England Journal of Medicine published a study in which Pare et al. genotyped patients from two previously conducted randomized trials: the Clopidogrel in Unstable Angina to Prevent Recurrent Events trial, known as CURE, and the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events, called ACTIVE A. In this study, researchers found that in atrial fibrillation and acute coronary syndrome patients treated with Plavix, CYP2C19 genotypes didn't impact the rate of cardiovascular events (PGx Reporter 9/1/2010).
Critics of this analysis asserted at the time that the lack of a PGx association seen in CURE and ACTIVE A was due to the fact that patients at high risk of cardiac events weren't enrolled in these trials.
"In retrospect, … if that black box had said, '[H]igh-risk patients are those with ST segment elevation who are at risk for myocardial infarction, [so] don't worry about patients with unstable angina or patients with atrial fibrillation with no other problems,' … it would have helped," said Lesko, who currently heads the University of Florida's Center for Pharmacometrics and Systems Pharmacology. "But what the agency said [in the label] was accurate," he added.
Furthermore, Lesko defended the FDA's use of gene-association studies that focused on surrogate markers, such as platelet aggregation, since platelet reactivity testing is commonly used by doctors to quickly assess whether patients are responding to Plavix.
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"You rely on platelet reactivity because when you're managing patients, you need a fast read … on what their baseline is and what their change is after a loading dose of the drug. So, it's a surrogate endpoint in that there is a fairly good, not perfect, but a fairly good correlation between platelet reactivity and outcome," he reflected. "And that's why in fact physicians do bedside platelet reactivity to assess the status of their patient."
At the time of the Plavix PGx labeling change, the "feeling was that platelet reactivity was a fairly good surrogate for outcomes," Lesko continued. "And because the outcomes in these patient subsets were relatively low in terms of event rates, it didn't make sense to wait for the outcome data in light of the mechanistic understanding of how the drug worked."
The Totality of Evidence
The emerging data to date has shown that the FDA "was right on" in updating the Plavix label, according to Lesko. "You're never going to have studies that all point in the same direction," he reflected.
He noted that two other meta-analyses were published before the Holmes et al. study that found that CYP2C19*2 homozygous patients were at heightened risk for cardiac events. "You have a totality of evidence, and this is true in almost every phase of medicine, whether it's personalized or not, and people bring in a judgment and a value based on their own interpretation of the data and their own biases," Lesko said.
Countering naysayers such as Nissen, Scripps Health Chief Academic Officer Eric Topol has repeatedly argued that the primary utility of CYP2C19 PGx testing will be in patients who have undergone PCI and are at risk of stent thrombosis. Topol and early adopters of CYP2C19 Plavix testing have pointed out that meta-analyses that have failed to find a significant link between CYP2C19 loss-of-function alleles and poor response included diverse cardiac patient populations and didn't separate poor metabolizers from intermediate metabolizers.
Holmes et al. included studies involving patients with one or more copies of CYP2C19 loss-of-function alleles, which would include intermediate metabolizers. Additionally, the researchers considered studies where patients experienced a variety of cardiac events, such as death, coronary heart disease, stroke, stent thrombosis, target vessel revascularization, and hospitalization for ACS.
"The inclusion of studies with both stable CHD and ACS might dilute an association if the magnitude of effect of clopidogrel was greater in ACS than in stable CHD," Holmes and his colleagues wrote in the paper. "However, when we stratified studies according to recruitment at the time of ACS, we found no heterogeneity in the association between CYP2C19 genotype and risk of CVD events."
Jessica Mega, a cardiologist at Brigham and Women's Hospital, commended Holmes and his colleagues for conducting a "very comprehensive meta-analysis," but she believes that the researchers' conclusions may be hampered by heterogeneity in the study population.
"Some of the outcomes, such as target vessel revascularization – that's when you go in and put in a second stent – that's normally not a platelet-mediated event, [and therefore,] it's not the type of event that would have been reduced by Plavix in the first place," she said. "So, there are some nuances that make the study challenging to interpret."
Mega was the lead author of a meta-analysis published in JAMA two years ago that looked at multiple studies involving more than 9,000 patients treated with Plavix, 91 percent of whom underwent PCI and 54 percent of whom had ACS. Patients in these studies experienced death, stroke, myocardial infarction, or stent thrombosis. In contrast to the Holmes et al. findings, Mega and colleagues reported that Plavix-treated patients with 1 or more loss-of-function CYP2C19 alleles had "significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis," than non-carriers.
"If you're looking for a pharmacogenetic interaction, the places where we have seen it makes a difference is places where Plavix is indicated," Mega told PGx Reporter. "So, the drug is indicated for patients who are undergoing PCI; that's a place where you'd want to see if you have a pharmacogenetic interaction."
Because study population heterogeneity commonly confounds the results of meta-analyses, Lesko doesn't believe these types of studies are optimal tools for regulatory decision making. "I was involved with a lot of meta-analyses at the FDA," he recalled. "[Meta-analysis] can be either very good or not very good … I always looked at meta-analysis as exploratory. It can be a basis for looking at the future of new studies, but I never felt it was confirmatory of any conclusions."
Ultimately, both Lesko and Mega believe that the Holmes et al. study is positive in that it shows that CYP2C19 loss-of-function alleles impact Plavix response in the subpopulation of patients where they believe testing has the most clinical utility: in patients with stents at high risk of cardiac events. Holmes and his colleagues note in the paper that stent thrombosis had the strongest association with CYP2C19 loss-of-function alleles, but this link appeared to weaken when considered within the larger studies included in the meta-analysis.
"If you look at their paper, [Holmes et al. do find] there is an association between genotype and things like stent thrombosis or myocardial infarction — outcomes where we think Plavix makes a difference," Mega said. "So, I don't disagree with the data in there. It's quite confirmatory of what's been seen. But the overall conclusion, because it was such a broad study, ends up being challenging to interpret."
Another Labeling Change?
Alongside these conflicting meta-analyses, researchers are starting to gather data from prospectively designed studies that could definitively elucidate the mechanism by which CYP2C19 genotypes influence Plavix response.
For example, Mega and several other researchers conducted the ELEVATE-TIMI 56 study investigating whether Plavix doses of between 75 mg and 300 mg/day improved responses in patients with one or two CYP2C19 loss-of-function alleles. The data, reported in JAMA last year, showed that patients with one CYP2C19*2 allele on a triple dose of Plavix (225 mg/day) had platelet reactivity levels similar to non-carriers treated with the standard dose (75 mg/day).
"In contrast, for CYP2C19*2 homozygotes, doses as high as 300 mg daily did not result in comparable degrees of platelet inhibition," the study authors concluded.
As data from this prospective study involving more than 300 patients continues to incrementally advance knowledge of Plavix PGx, it may not be long before the agency decides to provide more specific labeling guidance.
Since the last labeling update in 2010, "I think there is enough data out there now that points towards certain doses that would be effective in those populations," Lesko said. "The Mega study was powered with enough subjects by genotype to have label-worthy dosing information for the different genotypes."
Additionally, he noted that the FDA should better define the high-risk patients in the black-box warning in terms of disease state, and should emphasize PGx data on poor metabolizers versus intermediate metabolizers.
An FDA spokesperson told PGx Reporter that the agency "is aware of the Mega study" and is hoping to review the patient level data "in order to determine if it would support a labeling update" for Plavix.
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