The pro-pre-emption crowd, still reeling from the Supreme Court's decision rejecting pre-emption in the landmark Wyeth v. Levine, frequently defers to one statement from Justice Samuel Alito's dissent in the case. Chief Justice John Roberts and Justice Antonin Scalia joined Alito in noting, “This case illustrates that tragic facts make bad law.”

The tragedy in Levine is palpable. Diana Levine visited a Vermont health clinic in 2000 for treatment of a migraine. A nurse administered Wyeth's anti-nausea drug Phenergan via the IV-push method, a known risk factor for accidental arterial injection. The drug's label noted that when Phenergan entered the artery it could cause gangrene. This happened to Levine, and her hand and forearm had to be amputated, with clear impact on her career as a bass player and composer.

After settling with the clinic and nurse, Levine sued Wyeth under state tort claims, alleging the Phenergan label–while it warned of the danger of inadvertent intra-arterial injection–failed to warn that clinicians should use the IV-drip method rather than IV-push.

The Vermont trial court denied Wyeth's motion for summary judgment on an implied pre-emption argument–that the federal rule should be inferred to overrule the state's despite no explicit provision saying so (as is the case in express pre-emption).

The jury awarded Levine $7.4 million, which the court reduced to $6.7 million because of Levine's previous settlement. On appeal, the Vermont Supreme Court found that the jury award didn't conflict with FDA labeling requirements. In 2008 the U.S. Supreme Court granted cert in Levine, partly because of the importance of the hot-button pre-emption issue to the product-liability-battered pharmaceutical industry.

The justices delivered their opinion March 4. Voting 6-3, they ruled that federal approval of Phenergan's label did not pre-empt Levine's claim that the warning was inadequate.

While Levine establishes the litigation framework for future pre-emption claims, it's far from the last word on the legal doctrine–the court stopped short of rejecting the defense broadly. But its ruling will allow numerous failure-to-warn drug liability cases to go forward.

“They haven't closed the door on implied pre-emption, but it's not a very wide open door,” says Mark Gergen, a Berkeley Law School professor who co-authored an amicus brief in support of Levine.

Zero for Two

Wyeth had argued two forms of pre-emption, both of which the court rejected.

It first addressed Wyeth's contention that it is impossible to comply with both state and federal rules–”a demanding defense,” Justice John Paul Stevens' majority opinion noted. He pointed to the FDA's “changes being effected” (CBE) rule, which allows companies to update drug labels before formal approval of a full application that must show evidence the label requires a new warning. “Wyeth could have unilaterally added a stronger warning about IV-push administration,” Stevens wrote, adding that no evidence suggested the FDA would reject one.

In future failure-to-warn drug cases, “the battle will be about the administrative record,” says Mark Herrmann, a Jones Day partner who blogs on drug and device law. “They'd be looking for [instances where] the FDA has plainly focused on a particular risk and thought about the warnings that had to be given.”

Wyeth also argued conflict pre-emption–the idea that complying with state law conflicts with federal law. The court pointed out that Congress had not included an express pre-emption provision in the federal Food, Drug and Cosmetic Act (FDCA) as it had for medical devices, a provision that yielded the finding for pre-emption in last term's Riegel v. Medtronic. “If Congress thought state-law suits posed an obstacle to its objectives, it surely would have enacted an express pre-emption provision at some point during the FDCA's 70-year history,” Stevens wrote.

Wyeth's defense leaned on pre-emption wording in the preamble to a 2006 FDA regulation, which the court gave no deference because it is at odds with Congress' intent and because it was not subjected to scrutiny and comment.

“That will be a lesson to the federal agencies: If you want to make your determinations binding against the state, you're going to have to do so in the ordinary regulatory process,” says Bert Rein, a Wiley Rein partner, who represented Wyeth.

Spread Thin

In part for not having done so, the FDA may now face a deluge of label change proposals in response to Levine.

“I fear it will be buried in these CBE [changes being effected] applications because companies are going to have to really ratchet up the number of applications they submit to the agency–and the agency is already understaffed, underfinanced and overwhelmed,” says Sheldon Bradshaw, former chief counsel at the FDA and now a partner at Hunton & Williams.

Meanwhile, he says, the ruling will force companies to sift through volumes of label warnings to reassess their adequacy in light of Levine and possibly apply to add new wording.

“But even then, they're left vulnerable,” Bradshaw says. “I don't think Wyeth is any closer today to knowing what warning they were supposed to have added to that label than they were before the jury verdict.”

Some fear the threat of litigation in the wake of Levine will steer drug companies' labeling decisions more than public health considerations. A finding for pre-emption would not have shielded drug makers from all product liability drug claims–Levine addressed only failure-to-warn claims.

“What would have been interesting is if they dropped the other shoe after the devices case and then said that where you have this pervasive regulation … we should treat that as setting a ceiling as well as a floor,” Gergen says.

Such a broad ruling, he says, may have been the basis for finding for pre-emption in any situation where a regulatory agency is determining risk.

Since the court didn't bite, pharmaceuticals are bracing for an onslaught of litigation from a relieved plaintiffs' bar. Bradshaw predicts product liability suits will “go through the roof.”

And suits that were waiting in the shadows for the outcome of Levine may return, now that the court stopped short of roundly rejecting pre-emption. Five days after its Levine ruling, for instance, the high court vacated and remanded two pending drug cases for reconsideration in light of the new framework. Similar directions are being applied to other pharmaceutical liability cases across the country.

“There were a lot of cases stayed pending Levine, and those have all now come back to life again,” Herrmann says.

A Fine Balance

To fend off litigation, Levine may have drug makers struggling to balance adequate labels and overwarning, which presents some negative scenarios. The drug maker/FDA argument is that the most disastrous effects would be on the consumer. For example, a drug that helps many is taken off the market because its maker finds the risk of litigation to outweigh its value on the market. The warnings could also scare away patients the drug could help. Some suspect this was the case when the FDA mandated warnings on the Selective Serotonin Reuptake Inhibitor class of antidepressants (SSRIs) regarding an increase in suicidal thinking among adolescents taking the drugs. This led to a 20 percent drop-off in use of the drug by young people. When a Center for Disease Control study showed an unusual jump in suicides in young people that year, some connected it to the labeling change.

A balance between risk and warning will not come easily, but Bradshaw has his ideas.

“It seems to me that the FDA, which is the expert agency, [must give drug companies] the power to balance those risks and figure out which warnings should go on and which should stay off,” he says. “These are very complicated types of questions that you don't want lay juries and judges deciding.”

The “expert FDA vs. lay jury” maxim is common among those in favor of pre-emption, but Rein doesn't completely discount the role of the tort system.

“We never said there was zero role for litigation,” Rein says. “Litigation can test whether the FDA has really acted on a fully informed basis. But in situations where the FDA has had the available information and has waited and made a considered decision about what should be on the label, allowing litigation to second guess that decision is not consistent with the best interest of the public health.”

Gergen, despite his differing view of the issues in Levine, agrees: “It's pretty heroic to think the tort system is the best way to [balance risk in society]. But it is certainly better than the current.”