In 2014, the State of Hawai‘i sued the manufacturers of the antiplatelet medication Plavix in state court for violating Hawaii’s unfair or deceptive trade practices act, chapter 480, Hawai‘i Revised Statutes (“UDAP”). After a four-week, virtual, non-jury trial concluded in November 2020, the Hawai‘i trial court entered judgment awarding more than $834 million in civil penalties against Defendant Bristol-Myers Squibb Company and three U.S. subsidiaries of French drug manufacturer Sanofi. The court determined Defendants committed 834,012 UDAP violations in connection with their marketing and sale of Plavix in Hawai‘i between 1998 and 2010.

Background

Plavix is perhaps the best-known antiplatelet medication prescribed to reduce the risk of repeat heart attacks and strokes and to treat peripheral artery disease. But it is a “prodrug” that must be activated by enzymes produced by the patient’s liver. If the patient’s liver produces enzymes that properly activate Plavix, then the drug inhibits platelet aggregation (blood clots) and reduces the risk of repeat heart attacks, strokes, and other adverse cardiovascular events. On the other hand, if the patient’s liver produces enzymes that do not properly activate Plavix, that risk reduction may be lost, in whole or in part.

Variations in individual expression of “CYP2C19” (pronounced “Sip”-2C19)—a gene that plays an important role in the activation of many drugs – can adversely impact a patient’s ability to activate prodrugs like Plavix. For a number of years prior to U.S. Food and Drug Administration (FDA) approval of Plavix in 1998, independent research on the interplay between CYP2C19 and metabolization of other drugs suggested that race was a significant factor in determining whether a patient would be a poor or intermediate metabolizer of the drug. For example, prior to the launch of Plavix, independent researchers found that the presence of certain CYP2C19 loss-of-function alleles1 is more frequent in Japanese and Chinese patients, and that these loss-of-function alleles were a 100% predictor of whether Japanese and Chinese patients would be poor or intermediate metabolizers for a drug named S-Mephenytoin.

Despite pre-FDA-approval warning signs about links between race and poor metabolizers, those links received scant examination in manufacturer-sponsored clinical trials. In December 2008, however, the New England Journal of Medicine published an important independent study that drew a definitive link between carriers of reduced-function CYP2C19 alleles and higher rates of major adverse cardiovascular events, including stent thrombosis, among Plavix patients. This, together with the results of a study that showed reduced inhibition of platelet aggregation when Plavix was taken with a drug known to suppress CYP2C19 activity, prompted the FDA to insist Plavix’s manufacturers add language to the Plavix label explaining the CYP2C19 poor metabolizer phenomenon and noting the availability of genetic testing to determine whether an individual was a poor metabolizer. A “Black Box Warning” was added in early 20102.

Hawaii’s Case

The Hawai‘i Attorney General filed suit against the Plavix Defendants in March 2014. Hawai‘i alleged Defendants knew Plavix did not work fully, and sometimes not at all, for close to one-third of all Plavix patients, before product launch in 1998, and did not reveal this information to the FDA until much later. Hawai‘i further alleged the genetic issues were known to Defendants for at least several years before adding the Black Box Warning, and their failure to inform both Plavix patients and prescribing physicians about the genetic issue rose to the level of unfair and deceptive conduct.

After an unsuccessful removal attempt, a remand to state court, and a pleadings-stage motions practice, Defendants ultimately produced 12.5 million pages of documents they previously had produced to a separate group of plaintiffs who had sued them in consolidated federal multidistrict litigation. Following coordinated document review, discovery revealed Defendants had denied support and funding to studies and clinical trials focused on Plavix variability of response, as well as other studies of individual resistance to other drugs that might have implications for Plavix variability of response, out of concern for the potential impact such information might have on Defendants’ sales and profits.

Originally scheduled to begin in April 2020, the four-week, virtual non-jury trial was postponed until October 2020 by the onset of the COVID-19 pandemic. The Zoom trial was among the first civil virtual trials for the Hawai‘i Attorney General’s office. One of the benefits of the virtual trial was witnesses did not have to travel to testify. Indeed, witnesses testified in the Honolulu, Hawai‘i trial from locations across two oceans including Honolulu; Dana Point, California; Baltimore, Maryland; Boston, Massachusetts; Houston, Texas; and Paris, France. Similarly, defense counsel examined witnesses and presented argument from Dana Point, California.

At trial, Hawai‘i established Defendants’ unfair and deceptive conduct by focusing on Defendants’ response to their own data showing that Plavix did not work, or worked less effectively, for almost one-third of the population, as well as the early research linking race and drug metabolization. Did Defendants respond in a fair and honest manner to uncertainties regarding those links by disclosing them so that patients and physicians could decide what was best for the patients? Or did they try to hide or ignore the evidence to maximize sales and profits? Defendants’ decision to withhold support from studies suggestive of a Plavix resistance phenomenon, in Hawaii’s view, made it less likely the issue would be recognized and understood until after Defendants’ exclusive patent rights were to expire in 2012, i.e., until after the drug went generic and Defendants could no longer reap enormous profits from it.

Throughout the Hawai‘i case, Defendants tried to persuade the trial judge that the materiality of any omissions from the Plavix label should be judged from the viewpoint of prescribing physicians – not the FDA, not patients, and not even themselves. In Defendants’ view, this meant if physicians did not change their prescribing practices, omissions did not meet the materiality requirement to establish a UDAP violation. Hawai‘i countered by asserting that the materiality inquiry turns on an objective standard that focuses on the potential effect of an omission or misstatement on consumers’ choices, i.e., whether they would have elected to face the risks of Plavix or pursue an alternative form of treatment (such as aspirin).

Defendants also asserted their conduct was neither unfair nor deceptive based on the medical state-of-the-art regarding Plavix efficacy at various time points. First, Defendants argued medical research created significant uncertainty as to whether diminished antiplatelet effect in poor responders actually affected clinical outcomes. Defendants pointed to a 2016 label revision approved by the FDA, which removed from the Black Box Warning a statement about the association between the genetic issue and adverse clinical outcomes. Second, Defendants introduced evidence of recent studies they claimed showed East Asians with CYP2C19 loss-of-function alleles fared better than individuals from other racial backgrounds with the same condition. Hawai‘i countered these arguments by pointing out that a Black Box Warning about CYP2C19 remains on the Plavix label to this day, and by focusing on the deceptive intent reflected in Defendants’ own internal and inter-corporate documents, written contemporaneously by Defendants’ executives and medical and research personnel when they thought no one was looking or listening.

On February 15, 2021, approximately three months after the evidence was submitted, the court issued its Findings of Fact, Conclusions of Law, Decision and Order finding Defendants liable on the UDAP claim and awarding more than $834 million in civil penalties. The court first determined each prescription fill, refill, and non-retail purchase of Plavix included a label without information about the genetic issue and genetic testing and violated Hawaii’s UDAP statute. The court then determined there were 834,012 such violations during the 12-year period from product launch in 1998 to addition of the Black Box Warning in 2010. The Hawai‘i UDAP statute provides for a minimum civil penalty of $500 per violation and a maximum of $10,000 per violation. In closing arguments, Hawai‘i trial counsel proposed a $1,000 civil penalty for each violation, and the court adopted that figure in issuing its order.3 Defendants have indicated they intend to appeal.

Hawai‘i Attorney General Clare E. Connors, on behalf of the State of Hawai‘i, is represented in the litigation by Special Deputy Attorneys General L. Richard Fried, Jr. and Patrick F. McTernan of the Honolulu law firm of Cronin, Fried, Sekiya, Kekina & Fairbanks, and Dan Alberstone, Peter Klausner, Evan Zucker, and Elizabeth Smiley of the Los Angeles office of Baron & Budd, P.C., under the supervision of the Attorney General and Deputy Attorney Generals Bryan Yee and Mana Moriarty, with assistance from Deputy Solicitor General Nicholas McLean.

Other articles in this edition include:

Center for Consumer Protection logo

  1. An “allele” is a commonly occurring variant of a gene, as opposed to an uncommon variant, which would be called a “mutation.”    [↩]
  2. “Black Box Warning” is the common term for “boxed warnings,” which are “designed to call attention to serious or life-threatening risks.” A Guide to Drug Safety Terms at FDA, U.S. Food and Drug Administration, (November, 2012). See also 21 C.F.R. § 201.57(c)(1) which provides in part: “Certain contraindications or serious warnings, particularly those that may lead to death or serious injury, may be required by the FDA to be presented in a box.”  [↩]
  3. The court found that due to the size of the civil penalties award it was not necessary to address the state’s request for other relief, such as disgorgement and punitive damages.    [↩]

Related Posts