Labeling of medication warnings

Question: Which one of the following statements regarding medication warnings is incorrect?

A. The drug package “insert” or “label” contains, among other things, a drug’s pharmacology, indications, contraindications, risks and warnings.

B. The Physicians’ Desk Reference (PDR) is an annually updated drug compendium, which can be admitted into evidence as a learned treatise.

C. Drug labeling is a dual responsibility of the manufacturer and the Food and Drug Administration.

D. The FDA is solely responsible for a drug’s warnings and sets the absolute standard of care regarding side effects and complications.

E. State law can impose liability for negligent failure to warn even if the FDA has not included the warning in the drug’s label.

Answer: D. Should a prescription drug or medical device lead to harm, an injured party can sue the manufacturer who had placed it into the stream of commerce. In medical products liability, injured plaintiffs frequently claim a failure to warn of known risks. An example is the cardiovascular deaths caused by Vioxx, a nonsteroidal, anti-inflammatory drug that was withdrawn in 2004. Other examples alleging failure to warn are Actos-associated bladder cancer and Baycol-related rhabdomyolysis. At the time of product approval, the FDA sets out the labeling that goes with each drug, and then makes periodic changes to reflect new indications, warnings and risks. The manufacturer has the prime responsibility for submitting all updated information, especially of augmented risks that come with field experience. In 2012, for example, the FDA mandated the revision of the labeling of Lipitor and other statins to warn of the increased risk of diabetes.

Dr. S.Y. Tan

The drug manufacturer stands in the unique position as having the most detailed and up-to-date data and bears a serious responsibility to submit its full findings to the FDA, including its request for label change. Litigation over failure to warn of risks frequently turns on whether the drug manufacturer knew or should have known, had failed to inform the FDA, or whether the FDA itself had declined to make the changes, e.g., because of incomplete or premature data. Notwithstanding the FDA’s overarching federal status, a plaintiff may still attempt to use state tort law to hold a manufacturer liable should the federally approved labeling be silent on the matter.

Two U.S. Supreme Court cases sought to clarify the rules under which a drug manufacturer, when sued for failure to warn, may seek protection under its FDA-approved labeling. The first case involved Diana Levine, a Vermont musician and migraine sufferer, who lost her arm after the drug Phenergan, given by intravenous push, accidentally entered an artery and caused gangrene. Although the intravenous use of Phenergan is approved by the FDA and the risk of such use is clearly stated in the drug’s package insert, the lawsuit alleged that under state law, such a warning was inadequate and should have been strengthened to prohibit this mode of administration. A Vermont jury awarded damages of $6.7 million. On appeal, Wyeth, the defendant pharmaceutical company, maintained that its warning was appropriate, as it had been approved by the federal government through the FDA. It further argued that the drug’s package insert could not be unilaterally altered or modified without running afoul of federal regulations.

In a 6-3 decision,¹ the U.S. Supreme Court ruled that the manufacturer was in fact at liberty to issue a more stringent warning, and FDA approval does not bar lawsuits. The Court opined that “Federal law does not pre-empt Levine’s claim that Phenergan’s label did not contain an adequate warning about the IV-push method of administration.” Wyeth had argued that it was impossible for the company to provide additional warnings, since it was the FDA that made the sole determination of the nature and scope of a drug’s label. However, the court held that Wyeth never attempted to change the label to warn of the risk and failed to provide “clear” evidence that the FDA would have prevented it from changing its label. Without defining what constituted “clear” evidence, it rejected Wyeth’s broad assertion that unilaterally changing the Phenergan label would have violated federal law, which was based on the fundamental misunderstanding that the FDA, rather than the manufacturer, bears primary responsibility for drug labeling.

In 2019, the landmark case of Merck Sharp & Dohme Corp v. Albrecht et al.² reached the U.S. Supreme Court. This class-action suit involved more than 500 individuals who took Fosamax, an effective anti-resorptive drug for treating osteoporosis, and suffered atypical femoral fractures between 1999 and 2010. When the FDA first approved of the manufacture and sale of Fosamax in 1995, the Fosamax label did not warn of the then-speculative risk of atypical femoral fractures. But stronger evidence connecting Fosamax to atypical fractures developed after 1995, prompting the FDA to add a warning in 2011. Merck argued that plaintiffs’ state-law failure-to-warn claims should be dismissed as preempted by federal law. It conceded that the FDA regulations would have permitted Merck to try to change the label to add a warning before 2010 but believed the FDA would have rejected that attempt. In particular, it claimed that the FDA’s rejection of Merck’s 2008 attempt to warn of a risk of “stress fractures” showed that the FDA would also have rejected any attempt by Merck to warn of the risk of atypical femoral fractures. In short, Merck was relying on the legal doctrine of “impossibility preemption,” i.e., it was impossible to comply with both state law (adequate label warning of atypical fractures) and federal law (FDA control of warning labels). The plaintiffs’ position was that Merck’s proposed warning to the FDA had minimized the seriousness of the femoral fracture risk, characterizing them only as “stress fractures.”³

The Court’s earlier Levine decision had held that a state-law failure-to-warn claim is preempted where there is “clear” evidence the FDA would not have approved a label change. In the Albrecht decision, which also sided with the plaintiffs, the court indicated that “Clear evidence is evidence that shows the court that the drug manufacturer fully informed the FDA of the justifications for the warning required by state law and that the FDA, in turn, informed the drug manufacturer that the FDA would not approve a change to the drug’s label to include that warning.” The court also held that issues relating to presumption of impossibility are law-based, and thus it remains for the judge, not the jury, to make that determination.

Issuing timely warnings regarding medical products promotes patient safety, and the law appears to place the major onus on the manufacturer. Still, striking the proper balance is important. During oral arguments in Albrecht, Associate Justice Neil Gorsuch is said to have cautioned against “ ... incentives for companies to submit weakly supported label changes to the agency, knowing that when those label changes are rejected the companies will be free of further liability.” And as pointed out in the earlier cited Johnston article: “ ... a system that creates incentives for manufacturers to over-warn physicians and patients could harm patients by listing the important warnings of adverse effects among numerous less important warnings, which may discourage physicians and patients from choosing potentially useful drugs. On the other hand, a shift of responsibility for labeling to the FDA raises questions about whether the agency, which has resources that are dwarfed by the combined resources of industry, is necessarily capable to serve in this role ...”

Finally, this issue is more complex for devices because of the Medical Device Amendments Act of 1976 (MDA), which may preempt state-based lawsuits. In a claim brought after a Medtronic catheter ruptured in a patient’s coronary artery during heart surgery, the plaintiff alleged that the device was designed, labeled, and manufactured in a manner that violated New York common law. The case was appealed to the U.S. Supreme Court. The court held that the MDA preempted petitioner’s common-law claims challenging the safety or effectiveness of a medical device marketed in a form that received premarket approval from the FDA.⁴ The court ruled that MDA created a scheme of federal safety oversight for medical devices while sweeping back state oversight schemes.

Dr. Tan is professor emeritus of medicine and former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at siang@hawaii.edu.

References

1. Wyeth v. Levine, 555 U.S. 2 (2009).

2. Merck, Sharp & Dohme Corp. v. Albrecht et al., 587 U. S. ____ (2019).

3. Johnston MC et al., A new Supreme Court ruling on drug liability. JAMA 2019;322(7):607-8.

4. Riegel v. Medtronic, 128 S. Ct. 999 (2008).