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Lawsuit in Hawaii against Plavix Sponsors Alleges Burden is on Pharma to Market PGx Information

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Can drugmakers be held liable for failing to aggressively warn consumers that patients with certain genetic markers will not respond or will have limited response to their drugs beyond just mentioning this information in drug labeling? This is the issue at the heart of the lawsuit that Hawaii Attorney General David Louie has brought against Plavix manufacturers Bristol-Myers Squibb and Sanofi-Aventis.

In mid-March, Louie filed a lawsuit alleging on behalf of the state of Hawaii that BMS and Sanofi have been deceptively marketing and unfairly labeling Plavix since its launch more than 15 years ago by failing to alert consumers that the drug has "a diminished or no effect on approximately 30 percent of the [Hawaiian] population because they metabolize the drug poorly due to their genetic traits or because they take other drugs that affect the body's ability to metabolize Plavix."

The lawsuit brings into focus the complex environment in which drugmakers must evaluate emerging pharmacogenetic data about their therapies and make marketing decisions. However, some industry observers believe that the specter of legal liability might ultimately spur pharmaceutical companies to re-evaluate the way they educate doctors and consumers about PGx associations on their drugs, amid evolving evidence backing these associations and despite reduced drug profits.

The US Food and Drug Administration approved the anti-platelet agent Plavix (clopidogrel) in November 1997 for the reduction of atherosclerotic events. In 2010, the agency issued a boxed warning alerting doctors and patients that in order for the body to metabolize the drug, the CYP2C19 enzyme must convert Plavix into its active form. However, patients with certain variations in the CYP2C19 gene have a diminished ability to process the drug compared to those with a normal version of the gene, and these poor metabolizers are at heightened risk for cardiovascular events after having acute coronary syndrome or a stent procedure, the label states.

In the lawsuit, Louie highlighted that between 38 percent and 79 percent of Pacific Islanders, and between 40 percent and 50 percent of East Asians, have been reported to harbor genetic alterations that can predispose them to be Plavix poor metabolizers. According to 2010 demographics for Hawaii, Asians comprise 39 percent and Pacific Islanders make up 10 percent of the state's population

"Plavix does not prevent heart attacks, strokes, or vascular death in such patients," Louie's office alleged in a statement. "Rather, Plavix puts them at considerable risk for gastrointestinal bleeding and other complications associated with Plavix."

The attorney general is also taking the drug manufacturers to task for not publicizing the fact that genetic tests were available that could predict which patients would not respond optimally to Plavix. If patients had known about their poor metabolizer status for Plavix, they could have taken aspirin, which costs "roughly one percent of what Plavix costs … and is often safer … and equally, if not more, effective than Plavix," Louie's office asserts in the lawsuit. However, BMS and Sanofi also "deceptively and unfairly" promoted their expensive drug ($4/pill) as more efficacious and safer than aspirin ($0.04/pill), they accused.

The attorney general estimates that BMS and Sanofi made well over $100 million in Plavix sales in Hawaii since launching the drug, and is seeking a maximum penalty of $10,000 for each wrongful marketing act the drugmakers committed with regard to labeling and marketing the drug in the state; $10,000 in penalties for each deceptive act directed towards the elderly; and asking the companies to pay back all Plavix profits they earned.

"Since at least March 1998, defendants knew or should have known that Plavix has diminished or no effect on approximately 30 percent of [the] patient population," the complaint states. “Defendants failed to disclose that negative efficacy information because it would adversely affect the number of Plavix prescriptions written and, thus, sales and revenues." In addition to the lawsuit in Hawaii, attorneys general from a number of others states have brought legal action against BMS and Sanofi for failing to accurately present the efficacy of Plavix in specific subpopulations. Many of these suits also mention the diminished effect of the drug on CYP2C19 poor metabolizers.

BMS refused to comment on pending litigation, but said in an e-mail:, "Plavix is one of the most studied medicines with over a decade of real-world experience in patients with acute coronary syndrome, recent stroke, recent heart attack, and peripheral arterial disease. Plavix has been prescribed to more than 115 million patients worldwide, including more than 50 million in the US."

Responsible for more than labeling

The major issue raised by the Plavix lawsuits in Hawaii and other states, according to life sciences industry legal expert John Conley, is whether state statutes on drug marketing and labeling can coexist with federal regulations. Conley, a lawyer at Robinson, Bradshaw & Hinson, cited as precedent Wyeth vs. Levine, a case in which the US Supreme Court ruled in 2009 that even after garnering FDA marketing approval for a drug, pharma companies can still be held liable for inaccurate labeling and marketing under more stringent state laws.

In Wyeth vs. Levine, the plaintiff was a musician who had to have her arm amputated after being injected with Phenergan, an anti nausea treatment marketed by Wyeth (purchased by Pfizer in 2009), and getting gangrene. The Supreme Court affirmed the Supreme Court of Vermont's decision in the case and stated that FDA-approved labeling for a drug is a standard for drugmakers to follow, but manufacturers can add stricter language on labeling and marketing materials to comply with state laws. Justice John Stevens wrote that Wyeth misunderstood the central premise of the Food, Drug, and Cosmetic Act and FDA regulations, which holds that "the manufacturer bears responsibility for the content of its label at all times," not the agency.

"In Wyeth, the Supreme Court held that that FDA requirements are only a floor, not a ceiling," Conley said. "So, the states can't say you don't have to do as much [as the FDA requires,] but they can say you have to do more."

With regard to Plavix, the state attorneys general are suing drug manufacturers under the Unfair & Deceptive Acts & Practices (UDAP) statutes, which aim to protect consumers from unscrupulous business practices. Under these laws, the state attorneys general are alleging that the drugmakers "failed to disclose that Plavix would be ineffective either for the elderly or for certain ethnic populations like in Hawaii," Conley said. "And the defense is going to be that [the sponsors] had Plavix approved through the FDA, and that included labeling, and the states can't displace the FDA."

The other issue raised by the Plavix cases in Hawaii and in other states is whether lawsuits like this can be brought as a class action. For example, can all CYP2C19 poor metabolizers in Hawaii who received Plavix band together and allege injuries by BMS and Sanofi due to deceptive marketing? Historically, it has been challenging to advance mass, personal injury class actions lawsuits, Conley observed.

"With strong guidance from the Supreme Court, the lower courts have tended to say that in a class action the common issues among all the class members have to predominate. The cases have to be more alike than different," he explained. "But in a personal injury mass tort situation that's tough to show, because everybody tends to have an individualized injury. It depends on who you are, what your health situation is, what your economic situation is."

Without pharma support

The outcome in Wyeth vs. Levine is particularly relevant with regard to the deceptive marketing lawsuit from the Hawaii attorney general, since one of the allegations from plaintiffs' lawyers is that BMS and Sanofi failed to promote the availability of genetic tests that could identify best responders to Plavix. This allegation is supported by some molecular diagnostics firms and industry observers who believe that BMS and Sanofi haven't done enough to educate doctors and patients that people with certain CYP2C19 polymorphisms wouldn't respond optimally to their drug.

Although Spartan Bioscience, a developer of CYP2C19 testing, has reached out to the drug companies marketing anti-platelet treatments, they have not expressed much interest in embracing PGx testing strategies the development or marketing of their drugs. "We understand their point of view because it would mean that they would segment off the market for their drug," Spartan CEO Paul Lem told PGx Reporter. "They obviously want one blockbuster drug for everyone."

The FDA has greenlighted a number of genetic tests that determine CYP2C19 genotypes that doctors can use to guide therapeutic strategies for patients with various drugs, but the agency has not to date approved a companion test specifically indicated to predict best responders to Plavix. In Lem's view, without the financial and research support of a drug company, it's extremely challenging for a diagnostics shop to conduct the large and expensive validation studies necessary to take a pharmacogenetic companion test through the FDA. And the fact that BMS and Sanofi provided no support to firms developing CYP2C19 tests, such as Spartan, is the main reason there are no FDA-approved companion tests for Plavix, Lem asserted.

"In order to get a companion diagnostic indication from the FDA, a company like ours would have to run a large trial that shows an impact on patient outcomes," he said. "We would actually have to purchase the drugs used in the studies from these companies." In order to perform validation studies for its CYP2C19 test, Spartan purchased branded anti-platelet drugs at a price of around $2,500 per patient.

Last year, Spartan received 510(k) clearance from the FDA for its CYP219 test as a tool that doctors can use to determine therapeutic strategies for patients with drugs metabolized by the CYP2C19 enzyme. One of the studies Spartan submitted to garner clearance was a comparison of the accuracy of its test against DNA sequencing in 300 patients. In order to prospectively show that its CYP2C19 test could improve outcomes specifically in Plavix-treated patients, Spartan would have had to enroll around 5,000 patients, Lem estimates, and give them the drug with and without out the help of genetic testing. But such a study was prohibitively expensive.

"If pharma actually got involved, there would be many more pharmacogenomic and companion diagnostic tests," Lem said. "They actually have the financial resources to help with the clinical study and then the marketing muscle after the study is done to encourage adoption by physicians."

Ramanath Vairavan, senior VP of sales and marketing at AutoGenomics, also told PGx Reporter several years ago, that the company had tried to enlist the support of BMS to educate doctors about CYP2C19 testing to guide therapeutic strategies with drugs metabolized by the enzyme. But those efforts were in vain, Vairavan said, likely because the drug firms were concerned that PGx testing would cut into their drugs sales.

AutoGenomics received 510(k) clearance from the FDA in 2010 for its Infinity CYP2C19 Assay, which is also indicated as a tool to guide treatment strategies with drugs metabolized by the CYP2C19 enzyme. Without pharma support, AutoGenomics has worked with reference labs to market to and educate cardiologists about the benefits of CYP2C19 genetic testing.

In Lem's view, the lawsuits in Hawaii and other states against BMS and Sanofi can put pressure on pharma to think differently about when to support and promote pharmacogenetic testing, even if such an intervention would limit the market for their drugs. "Companies often do things because they can make money or not lose money due to litigation," Lem said. "I think the fact that the attorneys general of these large states are involved will give big pharma pause with regard to some of the drugs in their pipeline, and maybe give them that little push that not only can they rescue some of their Phase III drugs by targeting them to a smaller population but it might even help them avoid litigation."

A complicated history

Plavix's labeling to include pharmacogenetic information, and BMS and Sanofi's involvement — or lack of involvement as the Hawaii lawsuit alleges — in promoting this information, is a complex story that highlights the market tensions and scientific challenges hindering widespread adoption of personalized medicine approaches. The FDA's update to Plavix's label to include PGx information in 2009 and then the boxed warning in 2010, came as the drug was getting close to losing patent protection and newer anti-platelets were entering the market.

After losing patent protection in 2012, Plavix last year saw its worldwide revenues plummet by 90 percent due to generic competition, from $2.5 billion in 2012 to $258 million in 2013. Industry observers have opined that with only a few years left of market exclusivity, there was little incentive for BMS and Sanofi to support the development of a companion test that gauged CYP2C19 polymorphisms associated with variable responses to the agent. Then, there was growing market competition from the likes of Lilly's Effient, which didn't have the PGx variability of Plavix, and competing sales teams highlighted this fact.

Meanwhile, Louie believes BMS and Sanofi had plenty of opportunity to incorporate education about CYP2C19 polymorphisms into its marketing for Plavix. The Hawaii lawsuit alleges that the drugmakers knew about the limited response certain ethnic groups have to Plavix since at least 1998, but still chose to market the drug in all comers. The lawsuit mentions a number of published studies on CYP2C19 genotypes and their impact on Plavix response before the FDA issued a boxed warning in 2010. Additionally, although in its NDA, the sponsors "claimed not to understand exactly how the drug was metabolized," the lawsuit points out that in the 1997-approved labeling, the drug sponsors note that Plavix is metabolized by CYP450 enzymes, including CYP2C19.

BMS and Sanofi will likely maintain that they weren't sure about the impact of CYP2C19 polymorphisms on Plavix response and that there is still not consensus in the scientific literature in this regard. Indeed, there has been conflicting published data on the association between CYP2C19 genotypes and Plavix-related adverse cardiac outcomes, which in turn has hindered adoption among many cardiologists. In fact, prominent cardiologists have spoken out publicly both for and against Plavix PGx testing.

In 2012, for example, Cleveland Clinic cardiologist Steven Nissen in an editorial in the Journal of the American Medical Association, accused the FDA of "irrational exuberance" in prematurely updating Plavix's label with PGx information. Meanwhile, Eric Topol at Scripps Health has been a proponent of CYP2C19 genotyping for patients undergoing stent procedures and has adopted testing among such high-risk patients at his institution.

Amid these conflicting views, very few community practices have adopted PGx testing for Plavix. Some academic centers, such as the University of Florida, have begun pre-emptively testing all patients presenting at its catheterization lab with multi-gene tests and saving the results in electronic medical records for use in the future should a doctor wish to prescribe Plavix.

Meanwhile, the FDA has refuted allegations that it updated the label for Plavix based on premature clinical evidence. The agency 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.

Experts and proponents of PGx testing for Plavix have pointed out that the negative studies, like the one in 2010 sponsored by BMS and Sanofi, and another in 2012 by Holmes et al., involved heterogeneous populations, which likely confounded the findings. When research has been focused on patients at high risk of experiencing cardiac events, such as those undergoing stent procedures, the hypothesis that CYP2C19 poor metabolizers are at heightened risk for cardiac events has proven true. Several of these studies have been led by Jessica Mega of Brigham and Women's Hospital.

Conley expects that all this history will be "aired out again" in the context of the Plavix lawsuits in Hawaii and other states. "The defendants will say that they … did what they were told [by the FDA] and now they're being told they should be doing something different," he said. In turn, Conley noted that the plaintiffs' lawyers could ask the FDA to testify about their role in reviewing the available data on Plavix pharmacogenetics and in updating labeling.

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