Troubling news has recently emerged regarding birth defects linked to the powerful drug Zofran. This anti-nausea drug was developed exclusively for adult cancer patients but the drug manufacturer later marketed the drug for the off-label use to prevent or lessen morning sickness in pregnant women. The lawsuits allege that the manufacturer did little to no testing on the hazards of the drug to a fetus and that, in fact, the drug’s active ingredient has caused a variety of birth defects. One recent lawsuit filed in federal district court in Massachusetts makes the following allegations in the complaint:
Zofran is a powerful drug developed by drug giant GlaxoSmithKline (“GSK”) to treat only those patients who were afflicted with the most severe nausea imaginable – that suffered as a result of chemotherapy or radiation treatments in cancer patients. The U.S. Food and Drug Administration (“FDA”) approved Zofran in 1991 for use in cancer patients who required chemotherapy or radiation therapy. Although the only FDA approval for this drug was for seriously ill patients, GSK marketed Zofran “off label” as a safe and effective treatment for the very common side effect of a normal pregnancy – pregnancy related nausea and vomiting – otherwise known as “morning sickness.” GSK did this despite having knowledge that such representations were utterly false, as GSK had never once undertaken a single study on the effects of this powerful drug on a pregnant mother or her growing child in utero. Unlike another anti-nausea prescription drugs available on the market – which are FDA-approved in the United States for treating morning sickness in pregnant women – GSK never conducted a single clinical trial before marketing Zofran to pregnant women. GSK simply chose not to study Zofran in pregnant women or seek FDA approval to market the drug for treatment during pregnancy. GSK avoided conducting these studies because they would have hampered its marketing of Zofran and decreased profits by linking the drug to serious birth defects. GSK’s conduct was tantamount to using expectant mothers and their unborn children as human guinea pigs.
As a result of GSK’s fraudulent marketing campaign, Zofran was placed into the hands of unsuspecting pregnant women throughout the United States. These women ingested the drug because they innocently believed that Zofran was an appropriate drug for use in their circumstance. When they ingested the drug, these pregnant women had no way of knowing that Zofran had never been studied in pregnant women, much less shown to be a safe and effective treatment for pregnancy–related nausea. By contrast, GSK knew that Zofran was unsafe for ingestion by expectant mothers. In the 1980s, GSK conducted animal studies which revealed evidence of toxicity, intrauterine deaths and malformations in offspring, and further showed that Zofran’s active ingredient transferred through the placental barrier of pregnant mammals to fetuses. A later study conducted in humans confirmed that ingested Zofran readily crossed the human placenta barrier and exposed fetuses to substantial concentrations. GSK did not disclose this information to pregnant women or their physicians. In 1992, GSK began receiving mounting evidence of reports of birth defects associated with Zofran. GSK received at least 32 such reports by 2000, and has received more than 200 such reports to date. GSK never disclosed these reports to pregnant women or their physicians. In addition, scientists have conducted large-scale epidemiological studies that have demonstrated an elevated risk of developing birth defects. GSK has not disclose this to pregnant women or their physicians. Instead, GSK sales representatives specifically market and promoted Zofran as a morning sickness drug.
In 2012, GSK pled guilty to criminal charges lodged by the United States of America, through the Department of Justice, for its “off-label” promotion of its drugs for uses never approved by the FDA. At or around the same time, GSK also entered civil settlements with United States that included more than $1 billion in payments to the federal government for its illegal marketing of various drugs, including Zofran specifically. GSK’s written agreement with the United States reports GSK’s settlement of claims that GSK:
(a) “promoted the sale and use of Zofran for a variety of conditions other than those for which its use was approved as safe and effective by the FDA (including hyperemesis and pregnancy-related nausea)”
(b) made and/or disseminated unsubstantiated and false representations about the safety and efficacy of Zofran concerning the uses described in subsection (a) [hyperemesis and pregnancy-related nausea]”
(c) “offered and paid illegal remuneration to health care professionals to induce them to promote and prescribe Zofran”
GSK’s conduct has caused devastating, irreversible, and life-long consequences and suffering to innocent newborns and their families.
GSK is the successor in interest to Glaxo, Inc. and Glaxo Wellcome Inc. Glaxo, Inc. was the sponsor of the original New Drug Application (“NDA”) for Zofran. Glaxo, Inc., through its division Cerenex Pharmaceuticals, authored the original package insert and labeling for Zofran, including warnings and precautions attendant to its use. Glaxo Wellcome Inc. sponsored additional NDAs for Zofran, monitored and evaluated post-market adverse event reports arising from Zofran, and authored product labeling for Zofran.
Zofran is a prescription drug indicated for the prevention of chemotherapy-induced nausea and vomiting, radiation therapy-induced nausea and vomiting and post operative nausea and/or vomiting:
INDICATIONS AND USAGE
Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplaitn > 50 mg/m2.
Prevention of nausea and vomiting associated with initial and reapeat courses of moderately emetogenic cancer chemotherapy.
Prevention of nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction of the abdomen, or daily fractions of the abdomen.
Prevention of postoperative nausea and/or vomiting.
The medical term for nausea and vomiting is emesis, and drugs that prevent or treat nausea and vomiting are called anti-emetics. Zofran is part of a class of anti-emetics called selective serotonin 5HT3 receptor antagonists. The active ingredient in Zofran is ondanestron hydrocholoride, which is a potent and selective antagonist at the 5-hydroxytryptamine receptor type 3 (5-HT3). Although 5-hydroxytryptamine (5HT) occurs in most tissues of the human body, Zofran is believed to block the effect of serotonin at the 5HT3 receptors located along vagal afferents in the gastrointestinal tract and at the receptors located in the area postrema of the central nervous system (the structure in the brain that controls vomiting), Put differently, Zofran antagonizes, or inhibits, the body’s serotonin activity, which triggers nausea and vomiting.
Zofran was the first SF-IT3 receptor antagonist approved for marketing in the United States. Other drugs in the class of 5HT3 receptor antagonist include Kytril®. (granisetron) (FDA-approved 1994), Anzemet®, (dolasetron) (FDA-approved 1997) and Aloxi® (patimosetton) (FDA-approved 2003). Zofran is available as an injection (2 mg/mL), a premixed injection 32 mg/50ml and 4mg/50 ml), oral tablets (4 mg, 8 mg and 24 mg); orally disintegrating tablets (4 mg and 8 mg) and an oral solution (4mg/5mL). More specifically, GSK has obtained FDA approval for the following formations of Zofran:
NDA 20-007 – Zofran Injection (FDA approved January 4, 1991)
NDA 20-103 – Zofran Tablets (FDA approved December 31, 1992)
NDA 20-403 – Zofran Premixed Injection (FDA approved January 31, 1995)
NDA 20-605 – Zofran Oral Solution (FDA approved January 24, 1997)
NDA 20-781 – Zofran (a/k/a Zofran-Zydis) Orally Disintegrating Tablets (FDA approved January 27, 1999)
The FDA has never approved Zofran for the treatment of morning sickness or any other condition in pregnant women. For GSK to market Zofran lawfully for the treatment of morning sickness in pregnant women, it must first adequately test the drug (including performing appropriate clinical studies) and formally submit to the FDA evidence demonstrating that the drug is safe and effective for treatment of morning sickness. A team of the FDA’s physicians, statisticians, chemists, pharmacologists, microbiologists and other scientists would then have an opportunity to: (a) review the company’s data and evidence supporting its request for approval to market the drug; and (b) determine whether to approve the company’s request to market the drug in the manner requested. Without first obtaining approval to market a drug for the treatment of pregnant women, a pharmaceutical company my not legally market its drug for that purpose.
GSK has not performed any clinical studies of Zofran use in pregnant women. GSK, however, had the resources and know-how to perform such studies, and such studies were performed to support another prescription drug that, unlike Zofran, is FDA-approved for the treatment of morning sickness. GSK also has not submitted to the FDA any data demonstrating the safety or efficacy of Zofran for treating morning sickness in pregnant women. Instead, GSK has illegally circumvented the FDA-approval process by marketing Zofran for the treatment of morning sickness in pregnant women without applying for the FDA’s approval to market Zofran to treat that condition or any other condition in pregnant women. This practice is known as “off-label” promotion, and in this case constitutes fraudulent marketing.
Since at least the 1980s, when GSK received the results of the preclinical studies that it submitted in support of Zofran’s NDA 20-007, GSK has known of the risk that Zofran ingested during pregnancy in mammals crosses the placental barrier to expose the fetus to the drug. For example, at least as early as the mid-1980s, GSK performed placental-transfer studies of Zofran in rats and rabbits, and reported that the rat and rabbit fetuses were exposed prenatally to Zofran during pregnancy. The placental transfer of Zofran during human pregnancy at concentrations high enough to cause congenital malformations has been independently confirmed and detected in every sample fetal tissue taken in published study involving 41 pregnant patients. The average fetal tissue concentration of Zofran’s active ingredient was 41% of the corresponding concentration in the mother’s plasma. GSK reported four animal studies in support of its application for approval of NDA 20-0007: (1) Study No.R10937 I.V. Segment II teratological study of rats; (2) Study No. R10873 I.V. Segment II teratological study of rabbits; (3) Study No. R10590 Oral Segment II teratological study of rats; (4) Study No. L 10649 Oral Segment II teratolgoical study of rabbits. These preclinical teratogenicity studies in rats and rabbits were stated by the sponsor, GSK, to show no harm to the fetus, but the data also revealed clinical signs of toxicity, premature births, intrauterine fetal deaths, and impairment of ossification (incomplete bone growth. Study No. R10937 was a Segment II teratological study of pregnant rats exposed to Zofran injection solution. Four groups of 40 pregnant rats (160 total) were reportedly administered Zofran through intravenous (I.V.) administration at does of 0, .5, 1.5, and 4 mg/kg/day, respectively. Clinical signs of toxicity that were observed in the pregnant rats included “low posture, ataxia, subdued behavior and rearing, as well as nodding and bulging eyes.” No observations were reported as teratogenic effects. Study No. R10873 was a Segment II teratological study of pregnant rabbits exposed to Zofran injection solution. Four groups of 15 pregnant rabbits (60 total) were reportedly given Zofran doses of 0, 0.5, 1.5, and 4mg/kg/day, respectively. In this study, there was a reported increase in the number of intra-uterine deaths in the 4 mg/kg group versus lower-dose groups. The study also reported maternal weight loss in the exposed groups. Developmental retardation in off-spring and fetuses were noted – namely areas of parietal (body cavity) were not fully ossified, and hyoid (neck) failed to ossify completely. Study No. R10590 Oral Segment II teratolgical study of rats. Four groups of 30 pregnant rats (120 total) were given Zofran orally at doses of 0, 1,4 and 15 mg/kg/day, respectively. Subdued behavior, labored breathing, which is a symptom of congenital heart defects, and dilated pupils were observed in the 15 mg/kg/day group. Body weight, gestational duration and fetal examination were reported as normal, but “slight retardation in skeletal ossification” was noted in the offspring. Study No. L10649 Oral Segment II teratolgoical study of rabbits. Four groups of 14018 pregnant rabbits (56-64 total) were given Zofran orally at doses of 0, 1, 5.5 and 30 mg/kg/day. The study reported lower maternal weight gain in all of the exposed groups, as well as premature delivery and “total litter loss,” referring to fetal deaths during pregnancy in the 5.5 mg/kg/day group. Examination of the fetuses showed “sleight developmental retardation as evident by incomplete ossification or asymmetry of skeleton.”
Even if animal studies do not reveal evidence of harm to a prenatally exposed fetus, that result is not necessarily predictive of human response. For example, a drug formerly prescribed to alleviate morning sickness, thalidomide, is an infamous teratogenic in humans, but animals studies involving the drug failed to demonstrate such an increased risk of birth defects in animals. GSK conducted studies of thalidomide and toxicity before GSK developed Zofran and before it marketed Zofran for the treatment of morning sickness in pregnant women. Moreover, since at least 1993, GSK has stated in its prescribing information for Zofran that “animal reproduction studies are not always predictive of human response.” Therefore, GSK has been aware since at least when it began marketing and selling Zofran that GSK could not responsibly rely on its animal studies on the basis for promoting Zofran use in pregnant women. But that is what GSK did.
At least as early as 1992, GSK began receiving reports of birth defects associated with the use of Zofran by pregnant women. By 2000, GSK had received at least 32 reports of birth defects arising from Zofran treatment in pregnant women. These reports included congenital diaphragmatic anomaly, congenital musculoskeletal anomalies, and orofacial anomalies, among others. In many instances, GSK received multiple reports in the same month, the same week and even the same day. For example, on or about September 13, 2000, GSK received three separate reports involving Zofran use and adverse events. For two of those incidents, the impact on the baby was so severe that the baby died. From 1992 to the present, GSK has received more than 200 reports of birth defects in children who were exposed to Zofran during pregnancy. The most commonly reported birth defects arising from Zofran use during pregnancy and reported to GSK were congentital heart defects, though multiple other defects such as orofacial defects, intrauterine death, still birth, and severe malformations in newborns were frequently reported. The number of events actually reported to GSK was only a small fraction of actual incidents.
Epidemiology is a branch of medicine focused on studying the causes, distribution, and control of diseases in human populations. Three recent epidemiological studies have examined the association between prenatal exposure to Zofran and the risk of congenital heart defects in babies. These studies include: (1) Pasternak, et al., Ondansetron in Pregnancy and Risk of Adverse Fetal Outcomes, New England Journal of Medicine (Feb. 28, 2013) (the “Pasternak Study”); (2) Andersen, et al., Ondansetron Use in Early Pregnancy and Risk of Congenital Malformations – A Register Based Nationwide Control Study, presented as International Society of Pharmaco-epidemiology, Montreal, Canada (2013) (the “Andersen Study”); and (3) Danielsson, et al., Ondansetron During Pregnancy and Congenital Malformations in the Infant (Oct. 31, 2014) (the “Danielsson Study”). Each of these studies includes methodological characteristics tending to bias its results toward under-reporting the true risk of having a child with a birth defect. Notwithstanding these characteristics biasing the results toward the null hypothesis, all three studies show elevated risk ratios of cardiac malformations, including risk ratios greater than 2.0. In other words, the studies report that a mother exposed to Zofran had more than a doubled risk of having a baby with a congenital heart defect as compared to a mother who did not ingest Zofran during pregnancy.
The Pasternak Study included data from the Danish National Birth Registry and examined the use of Zofran during pregnancy and risk of adverse fetal outcomes. Adverse fetal outcomes were defined as: spontaneous abortion, stillbirth, any major birth defect, pre-term delivery, low birth weight, and small size for gestational age. There were 608, 385 pregnancies between January 2004 and March 31, 2011 examined. The unexposed group was defined as women who did not fill a prescription for ondansetron during the exposure time window. The exposure time window was defined as the first 12-week gestational period. Notably, the median fetal age at first exposure to Zofran was ten weeks, meaning that half of the cases were first exposed to Zofran after organogenesis (organ formation). This characteristic of the study led to an under-reporting of the actual risk of prenatal Zofran exposure. The study’s supplemental materials indicated that women taking Zofran during the first trimester, compared to women who did not take Zofran, were 22% more likely to have offspring with a septal defect, 41% more likely to have offspring with a ventricular septal defect and greater than four-times more likely to have offspring with atrioventricular septal defect. The Andersen Study was also based on data collected form the Danish Medical Birth Registry and National Hospital Register, the same data examined in the Pasternak Study. The Andersen study examined the relationship between Zofran use during the first trimester and subgroups of congenital malformations. Data from all women giving birth in Denmark between 1997 and 2010 were included in the study. A total of 903, 207 births were identified in the study period with 1,368 women filling prescriptions of Zofran during the first trimester. The Andersen Study therefore used a larger data set (13 years) compared to the Pasternak Study (seven years). Exposure to the drug was also defined as filling a prescription during the first trimester, and prescription data were obtained from the National Prescription Registry. The Andersen study reported that mothers who ingested Zofran during their first-trimester of pregnancy were more likely than mothers who did not to have a child with a congenital heart defect, and had a two-to four-fold greater risk of having a baby with a septal cardiac defect.
The Danielsson Study investigated risks associated with Zofran use during pregnancy and risk of cardiac congenital malformations from data available through the Swedish Medical Birth Registry. The Swedish Medical Birth Registry was combined with the Swedish Register of Prescribed Drugs to identify 1,349 infants born to women who had taken Zofran in early pregnancy from 1998 – 2012. The total number of births in the study was 1,501,434 infants, and 43,658 had malformations classified as major (2.9%). Among the major malformations, 14,872 had cardiovascular defects (34%) and 10,491 had a cardiac septum defect (24%). The Danielsson study reported a statistically significantly elevated risk for cardiovascular defects for mothers taking Zofran versus those who did not. The results reported that the mothers who took Zofran during early pregnancy had a 62% increased risk of having a baby with a cardiovascular defect. Further, mothers who took Zofran during pregnancy had a greater than two-fold increased risk of having a baby with a septal cardiac defect, compared to mothers who did not take Zofran during pregnancy.
In summary, since at least 1992, GSK has had mounting evidence showing that Zofran presents an unreasonable risk of harm to babies who are exposed to the drug during pregnancy. GSK has been aware that Zofran readily crosses human placental barriers during pregnancy. GSK has also been aware that the animal studies of Zofran cannot reliably support an assertion that Zofran can be used safely or effectively in pregnant women. Since 1992, GSK has received hundreds of reports of major birth defects associated with prenatal Zofran exposure. GSK also has had actual and/or constructive knowledge of the epidemiological studies reporting that prenatal Zofran exposure tan more than double the risk of developing congenital heart defects. As alleged below, GSK not only concealed this knowledge from healthcare providers and consumers in the United States, and failed to warn of the risk of birth defects, but GSK also illegally and fraudulently promoted Zofran to physicians and patients specifically for the treatment of morning sickness in pregnant women.
Under federal law governing GSK’s drug labeling for Zofran, GSK was required to “describe serious adverse reactions and and potential safety hazards, limitations in use imposed by them , and steps that should be taken if they occur.” 21 C.F.R § 201.57(e). GSK was also required to list adverse reactions that occurred with other drugs in the same class of Zofran. Id. § 201.57(g). In the context of prescription drug labeling, “an adverse reaction is an undesirable effect, reasonably associated with use of a drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence.” Id. Federal law also required GSK to revise Zofran’s labeling “to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug; a causal relationship need not have been proved.” Id. § 201.57(e).
GSK has received hundreds of reports of birth defects associated with non-FDA-approved use of Zofran in pregnant women. GSK has failed, however, to disclose these severe adverse events to healthcare providers or expectant mothers. Under 21 C.F.R. § 314.70(c)(2)(i), pharmaceutical companies were (and are) free to add or strengthen – without prior approval from the FDA- a contraindication, warning, precaution, or adverse reaction. GSK thus had the ability and obligation to add warnings, precautions, and adverse reactions to the product labeling for Zofran without prior approval from the FDA. GSK failed to do so.
Under 21 C.F.R. § 201.128, “if a manufacturer knows, or has knowledge of facts that would give him notice, that a drug introduced into interstate commerce by him is to be used for conditions, purposes, or uses other than the ones for which eh offers it, he is required to provide adequate labeling for such a drug which accords with such other uses to which the article is to be put.” At least as of 1998, GSK knew well from its off-label promotion and payments to doctors, and its conspicuous increase in revenue from Zofran, and its market analyses of prescription data, that physicians were prescribing Zofran off-label to treat morning sickness in pregnant women and that such usage was associated with a clinically significant risk of hazard – birth defects. GSK had the ability and obligation to state prominently in the Indications and Usage section of its drug label that there is a lack of evidence that Zofran is safe for treatment of morning sickness in pregnant women. GSK failed to do so, despite GSK’s knowledge that (a) the safety of Zofran for use in human pregnancy has not been established, and (b) there have been hundreds of reports of birth defects associated with Zofran use during pregnancy, and (c) epidemiology studies report an increased risk of birth defects in babies exposed to Zofran during pregnancy. From 1993 to the present, despite mounting evidence of the birth defect risk, GSK’s prescribing information for Zofran has included the same statement concerning use of Zofran during pregnancy: “Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been preformed in pregnant rats and rabbits at I.V. doses up to 4 mg/kg per day and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used drug should be used during pregnancy only if clearly needed.”
By contrast, the Product Monograph for Zofran in Canada states “the safety of ondansetron for use in human pregnancy has not been established,” and that “the use of ondansetron in pregnancy is not recommended.” In the United States, GSK has at all relevant times failed to include any warning disclosing any risks of birth defects arising from Zofran use during pregnancy in Zofran’s prescribing information or other product labeling. GSK’s inclusion of the phrase “Pregnancy Category B” in Zofran preserving information refers the FDA’s pregnancy categorization scheme applicable to prescription drugs in the United States. The FDA has established five categories to indicate the potential of a drug to cause birth defects if used during pregnancy. The current system of pregnancy labeling consists of five letter-categories (A, B, C, D and X, in order of increasing risk). GSK had the ability, and indeed was required, to update Zofran’s label to reflect at best a Pregnancy Category D designation or alternatively a Category X designation for Zofran:
Pregnancy Category D. If there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits form the use of the drug in pregnant women may be acceptable despite its potential risks (for example, if the drug is needed in a life-threating situation or serious disease for which safer drugs cannot be used or are ineffective), the labeling must state: “Pregnancy Category D. See “Warnings and Precautions” section. Under the “Warnings and Precautions” section, the labeling must state: “[drug] can cause fetal harm when administered to a pregnant woman…. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazard to a fetus. 21 C.F.R § 201.57(f)(b)(i)(d).
Pregnancy Category X. If studies in animals or humans have demonstrated fetal abnormalities or if there is positive evidence of fetal risk based on adverse reaction reports from investigation or marketing experience, or both, and the risk of the use of the drug in pregnant woman clearly outweighs any possible benefit (for example, safer drugs or other forms of therapy are available), the labeling must state: “Pregnancy Category X. See ‘Contraindications’ section.” Under “Contraindications, “the labeling must state: “(Name of drug) may (can) cause fetal harm when administered to a pregnant woman…. (Name of drug) is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Id. § 201.57(f)(b)(i)(e).
Beginning at least in 1992, GSK had positive evidence of human fetal risk posed by Zofran based more than 200 reports to GSK of birth defects, as well as epidemiology studies, and placental-transfer studies reporting on Zofran’s teratogenic risk. GSK has never updated Zofran’s labeling to disclose that Zofran can cause fetal harm when administered to a pregnant woman, and GSK has failed to warn of the potential hazards to a fetus arising from Zofran use during pregnancy. The FDA recently promulgated a final rule declaring that, as of June 2015, it will require pharmaceutical manufacturers to remove the current A, B, C, D, or X pregnancy categorization designation from all drug product labeling and instead summarize the risks of using a drug during pregnancy, discuss the data supporting the summary, and describe relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation. 79 Fed. Reg. 72064 (Dec. 4, 2014). In promulgating this rule, the FDA “determined that retaining the pregnancy categories is inconsistent with the need to accurately and consistently communicate differences in degrees of fetal risk.”
In summary, GSK marketed and sold Zofran without adequate warning to healthcare providers and consumers that Zofran was causally associated with an increased risk of birth defects, and that GSK had not adequately tested Zofran to support marketing and promotion for use in pregnant women. This rendered the warnings accompanying Zofran inadequate and defective.
GSK has known that the safety of Zofran for use in human pregnancy has not been established. But with more than six million annual pregnancies in the United States since 1991 and an estimated 70-85% incidence of pregnancy-related nausea, the absence of prescription medication that was approved by the FDA for pregnancy-related nausea presented an extremely lucrative business opportunity for GSK to expand its sales of Zofran. GSK seized that opportunity, but the effect of its conduct was tantamount to experimenting with the lives of unsuspecting mothers-to-be and their babies in the United States and in this Commonwealth.
After the FDA approved Zofran in 1991, and despite available evidence showing that Zofran presented an unreasonable risk of harm to babies exposed to Zofran prenatally, GSK launched a marketing scheme to promote Zofran to obstetrics and gynecology (Ob/Gyn) healthcare practitioners, among others, as a safe treatment alternative for morning sickness in pregnant women. On March 9,1999 the FDA’s Division of Drug Marketing, Advertising and Communications (DDMAC) notified GSK that the FDA had become aware of GSK’s promotional materials for Zofran that violated the Federal Food Drug and Cosmetic Act and its implementing regulations. The FDA reviewed the promotional material and determined that “it promotes Zofran in a manner that is false or misleading because it lacks fair balance.” (FDA Ltr. To Michele Hardy, Director, Advertising and Labeling Policy, GSK, Mar. 9, 1999). GSK’s promotional labeling under consideration included promotional statements relating the effectiveness of Zofran, such as “Zofran Can,” “24-hour control,” and other promotional messages. But the promotional labeling failed to present any information regarding the risks associated with use of Zofran. In its March 9, 1999 letter, the FDA directed GSK to “immediately cease distribution of this and other promotional materials for Zofran that contain the same or similar claims without balancing risk information.” GSK blatantly disregarded this mandate by the FDA. For example, in 2002, GSK’s marketing materials to Ob/Gyn practitioners emphasized Zofran’s “Pregnancy Category B” designation on the very first page of the marketing material, creating a false impression that the safety of use in pregnancy has been established. GSK’s materials failed to disclose any of its internal information concerning the risks of birth defects associated with Zofran treatment during pregnancy. GSK’s promotion of Zofran for use in pregnancy eventually led to a federal governmental investigation.
On July 2, 2012 the Department of Justice announced that GSK “agreed to plead guilty and pay $3 billion to resolve its criminal and civil liability arising from company’s unlawful promotion of certain prescription drugs,” which included Zofran among numerous others. See DOJ Press Release, GlaxoSmithKline to Plead Guilty and Pay $3 Billion to Resolve Fraud Allegations and Failure to Report Safety Data (July 2, 2012). Part of GSK’s civil liability to the government included payments arising from the fact that: (a) GSK promoted Zofran and disseminated false representations about the safety and efficacy of Zofran concerning pregnancy-related nausea and hyperemesis gravidarum, a severe form of morning sickness; and (b) GSK paid and offered to pay illegal remuneration to health care professionals to induce them to promote and prescribe Zofran.