Reglan, or its generic equivalent, metoclopramide (MCP), is a dopamine antagonist/neuroleptic1 drug indicated for patients with gastroesophageal reflux (GERD), diabetic gastroparesis, to prevent nausea and vomiting associated with chemotherapy or post operatively, and to aid in other limited medical procedures. Although Reglan is only indicated for short-term use (4 to 12 weeks), the medical conditions are all long-term problems.  This creates an issue because the risks of serious side effects increase dramatically after 12 weeks of use. Most notable of these side effects are Tardive Dyskinesia (TD), which can include involuntary movements of limbs and facial grimacing, torticollis, rhythmic protrusion of the tongue, bulbar speech, dystonic reactions, tremors, akathisia, and other abnormal movements. In certain cases, these symptoms can be irreversible and there is no widely effective treatment at this time.

In light of the serious risks associated with the drug, one would expect careful administration for only those patients who fail to respond to safer alternatives. Unfortunately, studies have consistently shown that over one-third of all prescriptions are written for use in excess of 12 weeks. Further, those most likely to prescribe the drug—gastroenterologists and primary care doctors—are typically neither aware of the potential side effects nor properly trained to identify them.

Not surprisingly, the labeling provided little assistance for several reasons: (1) Reglan/MCP has not been listed in the Physicians’ Desk Reference since 2001; (2) the labeling grossly underestimates the risk of TD associated with all use and, most notably, long-term use; and (3) it implies that most TD can be reversed and are easily treatable.

Recognizing the inadequate nature of the label and warnings, in February 2009 the FDA issued an advisory requiring the addition of a Boxed Warning for Reglan/MCP. This new warning spells out that “Chronic treatment with metoclopramide can cause tardive dyskinesia, a serious movement disorder that is often irreversible.” Additionally, the new Boxed Warning now tells physicians and patients that “Prolonged treatment (greater than 12 weeks) with metoclopramide should be avoided in all but rare cases.”  Finally, the FDA is now requiring that manufacturers implement a Risk Evaluation and Mitigation Strategy (that each patient be given a Medication Guide) because the FDA has determined that the use of Reglan/MCP “pose[s] a serious and significant public health concern requiring the distribution of a Medication Guide.” This Medication Guide, setting out all the risks of the drug and to be given to all users “is necessary for the patients’ safe use of Reglan (metoclopramide).”

Although more cases have been and are being prosecuted across the country, the addition of the Boxed Warning has brought to the forefront the serious issues associated with this drug.  Many more cases have been filed across the country since the Boxed Warning was issued by the FDA. In anticipation of this increase in litigation, a motion was made with the Judicial Panel on Multidistrict Litigation for the formation of a federal MDL. Ultimately, the Federal Judicial Panel ruled against the formation of an MDL. Since that time, coordinating courts have been established in state courts for Reglan litigation in Philadelphia, Pennsylvania; Newark, New Jersey; and San Francisco, California. Lastly, numerous suits against brand name and generic manufacturers are set to begin trial in the next year in state and federal courts across the nation and in the state court consolidation in Philadelphia.

Foster v. American Home Products Corp.3 

The United States Court of Appeals for the Fourth Circuit was the first Federal Appellate Court to discuss the obligations of a generic drug manufacturer regarding the labeling of its products. In addressing the issue in Foster, the court expressly held that a generic manufacturer cannot satisfy its obligation by simply copying the label for a brand-name drug, without ensuring that the information contained therein is adequate and accurate:

We do not accept the assertion that a generic manufacturer is not responsible for negligent misrepresentations on its product’s label if it did not initially formulate the warnings and representations itself . . . .
[A]s an expert, a manufacturer of generic products is responsible for the accuracy of labels placed on its products.  Although generic manufacturers must include the same labeling information as the equivalent name brand drug, they are also permitted to add or strengthen warnings and delete misleading statements on labels, even without prior FDA approval. The statutory scheme governing pre-marketing approval for drugs simply does not evidence Congressional intent to insulate generic drug manufacturers from liability for misrepresentations made regarding their products, or to otherwise alter state products liability law.  Manufacturers of generic drugs, like all other manufacturers, are responsible for the representations they make regarding their products.4

Subsequent to the ruling in Foster, numerous U.S. District Courts applied the same reasoning to cases in which generic drug companies claimed that they were incapable of providing an accurate warning. It would not be until many years later, however, that another Federal Appeals Court weighed in on the issue.

Wyeth v. Diana Levine

In what is likely the biggest news in pharmaceutical law in the last few years, on March 4, 2009, the U.S. Supreme Court rendered its opinion in the case of Wyeth v. Diana Levine. Wyeth claimed that its drug had an FDA approved label, and thus no suit could be brought for a defective label; the U.S. Supreme Court disagreed. The decision put to rest (at least for the time-being) the full-on assault that drug maker defendants had waged against those they have injured based on federal preemption.

The heart of Wyeth’s argument in the case, which was echoed in virtually every other failure-to-warn drug case in the country, was that state-law claims such as Ms. Levine’s, make it impossible for drug makers to comply with both state-law duties underlying those claims and federal labeling duties imposed by the Food and Drug Administration (FDA). This irreconcilable conflict, according to Wyeth, meant that injured parties should be prohibited from filing state-law claims based on FDA-approved warnings. The Supreme Court wholly rejected Wyeth’s argument.

Ms. Levine lost her arm because Wyeth’s drug, Phenergan, was incorrectly administered to her through the IV-push method. Ms. Levine sued Wyeth in Vermont state court, claiming that the label on Phenergan did not contain an adequate warning about the risks associated with IV-push administration of the drug. A Vermont jury agreed and awarded Ms. Levine $7.4 million in damages. The Vermont Supreme Court affirmed, and Wyeth then appealed to the U.S. Supreme Court. Wyeth’s arguments on appeal were essentially two-fold. First, Wyeth argued that it would have been impossible to comply with the court-imposed, state law duty to modify the drug’s label without violating federal law. Second, Wyeth claimed that such state action created an obstacle to the purposes and objectives of Congress because it substituted the expert judgment of the FDA with that of a lay jury.

In a 6-3 opinion,6 the Court held that federal law did not preempt Ms. Levine’s failure to warn claims. Addressing Wyeth’s first point, the majority found that a manufacturer can indeed change its labeling to add or strengthen warnings for safety purposes without running afoul of federal regulation. The Court went on to state that “absent clear evidence that the FDA would not have approved a change to Phenergan’s label, we will not conclude that it was impossible for Wyeth to comply with both federal and state requirements.”7 In rejecting Wyeth’s second argument, the Court first pointed out that state law claims do not obstruct Congressional purposes and objectives as set forth in drug labeling regulation because “all evidence of Congress’ purposes is to the contrary.” In the 70-year history of the FDCA, Congress neither provided a federal remedy for those harmed by unsafe drugs nor expressly preempted state-law suits.

The Court further rejected Wyeth’s reliance on the preamble to a 2006 FDA regulation which stated that FDA approval of a drug’s label preempted conflicting or contrary state law. Not only were the statements included in violation of rule-making procedures, the Court said, but also reversed the FDA’s own long-standing position on the issue without explanation. Therefore, the FDA’s position warranted no deference.

In sum, the Court preserved an injured consumer’s right to sue a drug company for failure to adequately warn, indicating that “state law offers an additional, and important, layer of consumer protection that complements FDA regulation.”9 There might still be narrow circumstances that could legitimately support a preemption argument, but the likelihood is now quite rare. Of course, drug companies are surely analyzing the case in detail, attempting to fashion arguments around the holdings. It is unlikely that we have seen the last of preemption motions in drug cases.

Gladys Mensing v. Wyeth,10 Julie Demahy v. Actavis,11 and Beyond

Mensing and Demahy are both Circuit Court cases involving MCP. Both were decided in the last two years regarding generic manufacturers’ claim of federal preemption—efforts by the generic drug companies to seek immunity from liability. In both cases the generic manufacturers argued that at the time of first approval of the generic drug, their drugs’ labels had to follow an FDA requirement that they be identical to the brand-name label, therefore, state-law, failure-to-warn tort claims were preempted. In Mensing and Demahy, the Eighth and Fifth Circuit Courts of Appeal rejected that argument. Both courts acknowledged that although Levine concerned a brand-name manufacturer, the holding in Levine did carry “important implications” regarding the courts’ consideration of preemption in relation to the duties of generic drug manufacturers.12

Mensing v. Wyeth

In Mensing, the Eighth Circuit echoed the holding of the Foster Court and held that “[t]he regulatory framework makes clear that a generic manufacturer must take steps to warn its customers when it learns it may be marketing an unsafe drug.”13 The Court clearly stated that generic manufacturers are subject to 21 C.F.R. § 201.57(e)’s requirement that their labeling “shall be revised as soon as there is reasonable evidence of an association of a serious hazard with a drug[.]”14 The court went on to state that the regulation “does not permit generic manufacturers passively to accept the inadequacy of their drug’s label as they market and profit from it.”

Finally, in stating its conclusion, the court said, “In sum, we conclude that Mensing has stated a viable claim against the generic metoclopramide manufacturers. Far from prohibiting them from taking steps to warn their customers of new safety hazards, federal law requires such action.”15 

The defendants in Mensing appealed the Eighth Circuit’s ruling, and the United States Supreme Court granted cert. Briefing for both sides has been submitted, along with Amicus briefing from interested parties. The United States Solicitor General,16 the American Medical Association, 42 state Attorney’s General, along with several other impressive entities sided with plaintiffs, and encouraged the Court to deny preemption for generic drug companies. While not all the points made in the SG’s brief were in step with the plaintiff’s argument, the SG did write, in part, that: (1) “a generic pharmaceutical manufacturer, like a brand-name manufacturer, can (and indeed, must) inform FDA of new information about risks that may require a change in the label of its drug”; (2) “[defendants] could have asked FDA to coordinate appropriate DHCP [“Dear Health Care Provider,” or “Dear Doctor”] letters (or, by extension, to take other action with respect to labeling);” and (3) “holding a generic  pharmaceutical manufacturer liable on a failure-to-warn theory would not unacceptably frustrate the purposes of the Hatch-Waxman Amendments.”17 The oral arguments are scheduled for March 30, and a decision is expected before the end of the Court’s term in June.

Demahy v. Actavis

When the Mensing court issued its opinion, the Fifth Circuit had pending before it a case which presented the same issues of a generic manufacturer’s responsibilities regarding the labeling of its products. In 2010, the Fifth Circuit joined the Fourth and Eighth Circuits in holding that generic manufacturers have a duty to provide an accurate label in the case of Demahy v. Actavis. In its opinion, the Demahy court initially notes that the fact that currently 7 out of 10 prescriptions are filled with generic drugs argues strongly in favor of holding a generic manufacturer responsible for the information provided in its labeling.18

In discussing the responsibilities of a generic drug manufacturer, the court stated:

[M]anufacturers—name brand and generic alike—must act to warn customers when they learn that they may be marketing an unsafe drug. For their part, generic manufacturers are subject to the requirement that their labeling “be revised…as soon as there is reasonable evidence of an association of a serious hazard with a drug.”19

The Demahy court also followed Mensing in finding that generic drug manufacturers had the same record keeping and reporting requirements as branded manufacturers.20 The court went even further to acknowledge that the higher risk associated with long-term use of metoclopramide was noted in the medical literature in the 1980s and 1990s, and that there was nothing to indicate that monitoring such literature would result in significant additional expense to a generic drug manufacturer.

Beyond Mensing and Demahy:  The Sixth Circuit21 and Kellogg22 

In Morris, the U.S. District Court for the Western District of Kentucky ruled that the plaintiffs’ claims against the generic manufacturers of MCP were preempted by the FDCA and FDA regulation. Morris is currently pending before the Sixth Circuit, which invited the FDA to file an amicus curiae brief23 in the case. Much like the SG, the FDA in its brief expressed the opinions that: (1) “a generic pharmaceutical manufacturer, like a brand-name manufacturer, can (and indeed, must) inform FDA of new information about risks that may require a change in the labeling of its drug[;]” (2) “defendants could have asked FDA to coordinate appropriate “[Dear Doctor]” letters or take other action with respect to labeling;” and (3) “holding a generic pharmaceutical manufacturer liable on a failure-to-warn theory would not unacceptably frustrate the purposes of the Hatch-Waxman Amendments.”24   

In Kellogg, pending in the U.S. District Court for the District of Vermont, the court held that “a reasonable jury could conclude that inadequate, misleading and inaccurate information provided by the” brand-name and generic “Defendants was a proximate cause25 of [plaintiff’s] injury,” and denied both Wyeth’s and Actavis’ motion for summary judgment on the issue of proximate cause. Next, the Kellogg court ruled that it is “entirely foreseeable, that a physician will prescribe a drug in reliance upon information disseminated by the brand name manufacturer, and the patient will receive and ingest a generic equivalent,” instead.26 The court went on and wrote, “[the plaintiff] has pointed to triable issues of fact on the issue of reliance[,]” by a prescribing doctor on a brand-manufacture for a truthful labeling warning of the risks associated with a drug.27 Therefore, “[i]t is for a jury to decide whether the doctors relied on false or misleading information traceable to Wyeth,” the brand-name manufacturer.

To view the footnotes for this article, click here

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