The FDA's proposed settlement Tuesday with Amarin Corp. plc is not an "olly olly oxen free" on truthful, non-misleading, off-label promotion of drugs and medical devices, but it could lead to more litigation or a "Mother, may I" approach that may eventually pressure the agency into issuing less restrictive off-label guidelines, Lisa Dwyer, a partner at King & Spalding LLP, told BioWorld Today.

The settlement, which is awaiting court approval, resolves legal concerns raised by Amarin last year when it sought a declaratory judgment and injunctive relief from the FDA's threatened disciplinary action should the Dublin-based company engage in truthful off-label promotion of Vascepa (eicosapentaenoic acid). That threat was included in a complete response letter for a new indication for the triglyceride-lowering drug.

The FDA was forced to settle after federal Judge Paul Engelmayer granted the drug developer a preliminary injunction last August and gave the agency a crash course on the meaning of the U.S. Second Circuit Court of Appeals' 2012 ruling in United States v. Caronia, which overturned a criminal conviction of a sales rep for his truthful, off-label comments about a narcolepsy drug. (See BioWorld Today, Jan. 22, 2014, and Aug. 11, 2015.)

Invoking Caronia, Engelmayer held that the FDA may not bring a misbranding action "based on truthful promotional speech alone, consistent with the First Amendment." As a judge in the U.S. District Court for the Southern District of New York, Engelmayer is bound by the Second Circuit decision, which the FDA chose not to appeal.

Since Tuesday's settlement applies only to Amarin's promotion of Vascepa, Dwyer warned that it would be risky for drug and device companies to stray outside the four corners of existing FDA policy on off-label communication. However, "it's just one more reminder that the government is losing these cases over and over again," she said.

The Amarin agreement comes on the heels of a Texas jury acquitting Vascular Solutions Inc. (VSI), of Minneapolis, and its CEO Howard Root late last month of criminal charges based on alleged off-label promotion of its Vari-Lase Short Kit. In that case, a federal judge outside the Second Circuit instructed the jury that truthful speech is a defense against alleged misbranding violations of the Federal Food, Drug and Cosmetics Act.

In December, the FDA settled off-label charges with Pacira Pharmaceuticals Inc. over its promotion of Exparel (bupivacaine liposome injectable suspension) for use as an anesthetic in specific surgeries. The FDA had sent the Parsippany, N.J., company a warning letter saying Exparel's approval for use as a local post-surgical anesthetic didn't permit Pacira to promote its use in specific types of surgery. The agency rescinded the warning letter and agreed to a settlement after the company filed for declaratory judgment.

The acquittal and recent settlements point a way forward for companies looking to have honest discussions about product uses that may be off-label or in gray areas. The way Dwyer sees it, drug and device firms have two choices. Following the example of Amarin and Pacira, they can go to court to seek declaratory judgment that proposed comments are truthful and not misleading.

The second option is what Dwyer calls the "Mother, may I" approach – asking the FDA for preapproval. Under its settlement with the FDA, Amarin may submit up to two proposed communications per year about the off-label use of Vascepa to see if they raise any flags with the agency. What's unique about the provision is that it forces the agency to respond within 60 calendar days, Dwyer said.

Although the FDA wouldn't have a similar deadline in responding to other firms asking "Mother, may I," the option could still be a win-win, especially for the agency. Through preapproval, the FDA could make off-label policy decisions in a one-off basis without setting a broader precedent or having to resolve larger internal policy issues that seem to be delaying guidance on the subject, according to a King & Spalding client alert.

If the agency didn't respond in a reasoned and timely manner, the drug or device company could then proceed with a declaratory judgment action.

Dwyer acknowledged that preapproval could result in a backlog at the agency, given the FDA's limited resources. That might make it finally revise its off-label guidance or put pressure on Congress to force the agency's hand.

The FDA has been dragging its feet on new guidance for years. Responding to a citizen petition in 2014, the agency promised to issue comprehensive draft guidance on off-label communications that year. Industry is still waiting. King & Spalding chalks the agency's inaction up to a lack of consensus among senior leadership at the FDA and in the Department of Health and Human Services.


Meanwhile, drug and device companies continue to pay for the agency's refusal to address their First Amendment rights in promoting their products. Resorting to court action, or even seeking preapproval, can be costly in terms of both time and money. And there's always the fear that criminal charges, and the public shaming that comes with those charges, could be right around the corner.

After being acquitted, VSI's Root railed at the "obscene legal process" he and his company were forced to endure. "We were subjected to five years of attacks, which forced us to hire 10 separate law firms at a cost of over $25 million to defend against a criminal prosecution that clearly was never warranted by the facts. . . . To say that this prosecution was wrong-headed and disproportionate would be the understatement of the year," he said.

Although VSI and Root were acquitted of all charges, the government continued to press criminal obstruction-of-justice charges against one of the company's sales representatives "because he refused to change his grand jury testimony to match what these prosecutors wanted to hear," Root said.

The CEO also called on the Department of Justice (DoJ) to issue a new press release correcting "the multiple false and misleading public allegations" its officials made when they brought the criminal action against VSI and him following a whistleblower complaint.

"Gratuitous public allegations are easy for the Department of Justice to make when a lawsuit starts and the accused is unable to respond. But now that the trial is over and the jury has rejected all of the government's accusations, the Department of Justice needs to set the record straight in the interests of justice," Root said.

In its pretrial news releases, the DoJ accused Root of leading a deceptive sales campaign and claimed that VSI "put profits over patient safety." Root pointed out that no serious adverse events were reported for the Vari-Lase Short Kit, which produced only $534,000 in the seven years it was on the market – that's about 0.1 percent of VSI's U.S. sales of all products during those years.