The US Supreme Court held on May 20 that a judge, not a jury, must decide the question of whether federal law prohibited drug manufacturers from adding warnings to the drug label that would satisfy state law.[1] To succeed on a pre-emption defense on failure-to-warn claims, the drug manufacturer must present “clear evidence” that it fully informed the US Food and Drug Administration (FDA) of the justifications for the warning, and that the FDA, in turn, informed the drug manufacturer that the FDA would not approve the addition of the warning to the drug’s label. The Court remanded to the US Court of Appeals for the Third Circuit to decide the pre-emption question. Two concurring opinions provide the Third Circuit with roadmaps to opposite conclusions.

Background

Merck’s drug FOSAMAX® is FDA-approved for treatment and prevention of osteoporosis in postmenopausal women and in men and other indications. Osteoporosis occurs when the body resorbs old bone cells faster than it creates new ones. The active ingredient of Fosamax, alendronate sodium, belongs to a class of compounds called bisphosphonates that reduce bone resorption by specifically inhibiting the activity of bone-resorbing cells known as osteoclasts. This mechanism helps reduce the chance of having a hip or spinal fracture due to osteoporosis, but may also increase the risk of unusual fractures in a patient’s femur. These atypical femoral fractures occur when microscopic cracks from the stress of everyday activity progress to complete breaks rather than healing on their own.

Regulatory History

Merck scientists were aware as far back as 1990 and 1991 that there was at least a theoretical risk of these atypical femoral fractures based on Fosamax’s mechanism of action. Merck brought these concerns to the FDA’s attention during the review/approval process. In 1995, the FDA approved Fosamax’s label without requiring a warning, perhaps because the risks were only theoretical at that time. But post-approval adverse event reports of atypical femoral fractures in long-term Fosamax users accumulated, and Merck determined the increased risk was statistically significant.

In 2008, Merck filed a Prior Approval Supplement (PAS) with the FDA seeking approval to revise the Fosamax label to reference “low-energy femoral shaft fractures” and add a discussion of the risk of stress fractures to the Adverse Reaction and Precautions sections, respectively. The FDA accepted Merck’s edit to the Adverse Reaction section, but rejected Merck’s proposal to change the Precautions section because Merck’s justification was “inadequate.” The FDA invited Merck to resubmit its application to address the deficiencies. Rather than resubmitting, Merck abandoned the PAS and implemented changes to the Adverse Reaction section only via a Changes Being Effected (CBE) process that permits certain label changes without prior FDA approval.

In 2011, the FDA ordered addition of a warning about “atypical femoral fractures” to the Fosamax label. Merck resisted the change initially, proposing the warning refer to “stress fractures” instead. The FDA rejected the language because “stress fracture” did not accurately reflect the seriousness of the fractures associated with bisphosphonate use. Merck and the FDA ultimately agreed upon adding a discussion of atypical femoral fractures to the Warnings and Precautions section of the Fosamax label.

The Lawsuit

The plaintiffs/respondents, a group of more than 500 individuals who took Fosamax and suffered atypical femoral fractures between 1999 and 2010, sued Merck seeking tort damages for failure to warn about the risk of atypical femoral fractures prior to 2011. Merck argued that these state law claims should be dismissed as pre-empted by federal law that governs drug labeling standards and requirements. Merck also argued that the FDA would have rejected its attempt to add a warning before 2010. The district court granted summary judgment to Merck. The Third Circuit vacated and remanded. The Third Circuit held that whether the FDA would have rejected a proposed label change is a question of fact that must be answered by a jury, and that the Supreme Court’s opinion in Wyeth v. Levine, 555 U.S. 555, 571 (2009) required a highly probable standard of proof.

The Supreme Court’s Holding

The Supreme Court held that a judge, not the jury, must decide pre-emption as a matter of law. This includes deciding subsidiary factual disputes such as the question of what FDA would have done. The Court also clarified that to succeed in a pre-emption defense under these circumstances, the drug manufacturer must show that it fully informed the FDA of the justifications for the warning, and the FDA, in turn, informed the manufacturer that the FDA would not approve changing the drug’s label to include that warning. The Court vacated the Third Circuit’s opinion and remanded to that court for further proceedings. A pair of concurrences setting forth opposing views on the correct outcome gives the Third Circuit roadmaps to follow either way.

Justice Clarence Thomas’s concurring opinion concluded that Merck’s pre-emption defense fails because the FDA’s rejection of Merck’s PAS application in 2008 was not a final agency action with the force of law. Merck could also have taken additional steps to revise its label after the initial FDA rejection, such as resubmitting its application or adding a warning to the label through the CBE process without FDA pre-approval. Accordingly, Justice Thomas concluded that it was not impossible for Merck to satisfy both federal law and its alleged state-law duties, and its pre-emption defense fails as a matter of law.

Justice Samuel Alito’s concurring opinion (joined by Justices John Roberts and Brett Kavanaugh) leads to the opposite conclusion: that Merck’s pre-emption defense should succeed because the FDA would not have approved the new warning prior to October 2010. The FDA has a duty to initiate a label change if it becomes aware of new information that should be included in the drug label. 21 U.S.C. § 355(o)(4)(A). Justice Alito reasoned that inaction by the FDA in the face of new information reflects the agency’s determination that the label should not be changed. Here, the FDA (1) was aware of the potential issue of atypical femoral fractures dating back to the original Fosamax New Drug Application in the 1990s; (2) communicated extensively with Merck about the issue in 2008-2009 during review of Merck’s PAS; and (3) instituted a safety review of bisphosphonates focused on the risk of these fractures in 2009. It was not until after the results of that review published in 2010 that the FDA initiated the label change process.

Conclusion/Implications

The Court’s decision that impossibility pre-emption is a matter of law to be decided by judges should be helpful to drug manufacturers invoking that defense. The Court’s description of the evidence needed to support the defense gives manufacturers additional incentive and guidance to proactively communicate with the FDA regarding specific potential risks that come to light at any point in drug development or marketing. Justice Alito’s concurring opinion may also spur the FDA to take action, knowing that its inaction will be interpreted as an affirmative determination that no warning is needed.