On March 8, 2016, Amarin Pharma, Inc., advised Judge Paul Engelmayer of the United States District Court for the Southern District of New York that the company had reached agreement with the Government on the resolution of the parties’ dispute over Amarin’s entitlement to engage in certain types of communication to physicians regarding the health benefits of the company’s drug, VASCEPA.[1] Judge Engelmayer signed the proposed stipulation and order later that day.[2]

The settlement is noteworthy for the obvious reason that it continues the Government’s string of losses in First Amendment cases involving the Federal Food, Drug, and Cosmetic Act. But it also matters because it entitles Amarin to use a special advisory comment process for off-label materials, and did not condition resolution of the litigation on Amarin’s agreement to vacate the court’s powerful August opinion finding the FDA’s rejection of Amarin’s proposed claims unconstitutional. It is also important, however, because it appears to qualify Amarin’s victory somewhat, by holding the company accountable for the continued accuracy of its claims and permitting the Government to proceed against Amarin based on shifts in the science supporting those claims.

The Amarin Case

VASCEPA is a prescription drug approved by the FDA for use in lowering cholesterol in certain patient populations. The FDA had previously asserted, in administrative proceedings with Amarin and later in litigation, that it would have constituted impermissible “off-label promotion” for Amarin to describe to physicians the cardiovascular benefits of VASCEPA.[3] The FDA’s position was that Amarin had not completed a large clinical trial (known as REDUCE-IT) demonstrating those benefits.[4] Based on the results of outcome studies of other cholesterol-lowering drugs, the agency had begun to doubt its previously well-established policy that drugs that lower cholesterol, as VASCEPA concededly had been shown to do, also reduce the risk of certain cardiovascular events.[5] Amarin sued on May 7, 2015, and Judge Engelmayer entered an Opinion and Order on August 7, 2015, accepting Amarin’s position and outlining the specific statements that Amarin was permitted to use in communications with physicians about VASCEPA.[6] These statements were accompanied by contextual information designed to assure that physicians would not be misled regarding the benefits of VASCEPA in reducing cardiovascular risk.

The terms of the settlement were the subject of intense speculation while the parties sought repeated stays from the court to permit continued negotiation between August 2015 and March 2016.[7] The settlement terms are, indeed, groundbreaking in ways that have been identified by legal observers, but they are also important for reasons that may be less obvious.

  1. The settlement is a near-total victory for Amarin, in that the company obtained the Government’s agreement “to be bound by the Court’s conclusion that Amarin may engage in truthful and non-misleading speech promoting the off-label use of Vascepa®, . . . and . . . such speech may not form the basis of a prosecution for misbranding.”[8] More broadly, the proposed stipulation and order provides that nothing in it “shall be construed to limit Amarin’s constitutional rights to free speech concerning Vascepa®.”[9] Judge Engelmayer’s opinion focused on defining certain statements Amarin would be allowed to make about the unlabeled clinical benefits of the drug, along with accompanying contextual information and disclaimers. The settlement, however, entitles Amarin to communicate about the off-label use of VASCEPA using any claims and information available to it, provided the communications are truthful and non-misleading.
  2. Amarin is entitled to invoke a tailor-made procedure for the review of promotional pieces for VASCEPA that FDA has refused to make available to other companies. Going forward, Amarin may obtain FDA feedback on two proposed communications each calendar year until December 31, 2020, by submitting them to FDA for comment prior to dissemination to doctors. FDA will then have 60 days to raise any concerns or objections; Amarin must respond within 45 days. If FDA and Amarin do not reach an agreement 30 days later, either party may file a motion for judicial resolution with the court. If both parties agree, these timelines may be extended. The FDA may also contact doctors after a dispute over a particular communication. The special procedure given to Amarin under the settlement terms is distinct from the familiar advisory comment process available to other manufacturers. That process suffers from well-known limitations that have made it highly challenging to use—primarily, the length of time it takes to receive comments, but also the lack of clarity in the comments and their high degree of restrictiveness. The Medical Information Working Group (MIWG), a coalition of drug and device manufacturers, asked FDA for an improved advisory opinion process in 2010.[10] FDA rejected the request the following year.[11]
  3. The Government did not ask the court to vacate the August 7 opinion, which means that it remains available for citation and reliance by industry. In the past, FDA and its counsel have proven adept at both extricating the agency from First Amendment cases and eradicating unhelpful traces of that litigation. In the mid-1990s, the Washington Legal Foundation (WLF) challenged FDA’s restrictive policies on accurate off-label speech by manufacturers. WLF prevailed, and obtained an injunction prohibiting FDA from enforcing both those policies and intervening legislative provisions.[12] On appeal, the Government reframed the case by arguing that the regulatory scheme did no more than provide a “safe harbor” from misbranding and intended use enforcement actions. As a result, the case was rendered moot, and the underlying decision vacated.[13]

The Government has also sought to minimize the impact of its First Amendment losses in FDCA and False Claims Act cases by construing pro-speech decisions narrowly. In one Statement of Interest, the Department of Justice (DOJ) argued “the case before this court does not implicate . . . First Amendment concerns” and therefore does not affect False Claims Act liability, which is premised on the submission of a false claim, and not on speech qua speech.[14] “The FCA does not prohibit speech; rather, it is a remedy for actions that cause the submission of a false claim for payment to the government,” the statement said.[15] More recently, DOJ filed another statement of interest arguing “the First Amendment is not implicated here and poses no limitation on off-label marketing claims under the FCA,” because “off-label promotion by a pharmaceutical company can be evidence of that defendant’s having caused physicians to submit false claims.”[16]

In Amarin, the company did not seek, and Judge Engelmayer did not grant, any form of relief that would have affected FDA’s policies or procedures more broadly, as in the WLF case. But neither did Judge Engelmayer take any action to preclude regulated entities from citing his decision or diminish the significance of the opinion from the perspective of First Amendment doctrine. Other recent cases involving First Amendment limitations on the FDA’s administration of the FDCA—Allergan, Par, and Caronia— should have led FDA to change its approach to truthful, non-misleading speech about off-label uses to permit more such speech. But, like Amarin, these cases involved specific factual situations, potentially confining their holdings to a narrower set of facts, at least in the Government’s view. In principle, it is possible to conceive of a broad First Amendment challenge to the entire FDA regulatory scheme governing off-label promotion. If that case were successfully brought, then it would have the kind of lasting impact not likely to follow from Amarin.

  1. In Amarin, FDA made its most forceful argument yet in support of the status quo. Yet Judge Engelmayer unhesitatingly rejected the Government’s assertion that it can bring a misbranding action “where the acts to promote off-label use consist solely of truthful and non-misleading speech[.]”[17] “The Court’s considered and firm view,” Judge Engelmayer held, “is that, under Caronia, the FDA may not bring such an action based on truthful promotional speech alone, consistent with the First Amendment.”[18] Yet nothing indicates FDA believes it has to change its approach, and the agency’s lack of action to address First Amendment concerns makes it clear that FDA remains even more staunchly resistant to change. Prescription drug and medical device manufacturers were assured nearly two years ago that FDA had undertaken a comprehensive analysis of the regulatory scheme, with the ultimate objective of conforming it to constitutional limitations.[19] Yet nothing concrete has emerged from that process, and it appears that FDA and HHS officials do not intend to alter the existing framework.
  2. Amarin remains vulnerable to allegations that its claims for VASCEPA are illegal, based on scientific developments such as the availability of data from the REDUCE-IT trial. The settlement order states that the defendants agree “to be bound by the Court’s conclusion that, based on the information known as of August 7, 2015, the combination of statements and disclosures that Amarin proposes to make to doctors relating to use of Vascepa . . . is truthful and non-misleading.”[20] The stipulation and order provides, further, that “Amarin bears the responsibility, going forward, of assuring that its communications to doctors regarding off-label use of Vascepa remain truthful and non-misleading.”[21] Amarin has announced that an independent data monitoring committee will conduct an interim review of safety and efficacy this year, and the company projects that the REDUCE-IT study will be completed some time in 2017 “with results anticipated to be published in 2018.”[22] It remains to be seen whether and how Amarin’s communications change in view of the evolving scientific record, and whether FDA commences regulatory action to vindicate its own interpretation of the data.

The most significant conclusion to be drawn from Amarin might be that it does not matter how emphatically the courts reject FDA’s arguments in defense of continued restrictions on accurate speech about new uses of lawfully marketed products. Even if—against a backdrop of sustained industry pressure and congressional attention—a court decides a case in industry’s favor according to a rationale that should compel FDA to effect major changes in the existing regulatory approach, FDA will continue to insist that “off-label promotion” is categorically illegal, assuring that the chill on manufacturer speech will persist. To be sure, the string of losses in First Amendment cases has led DOJ to be more selective in its efforts to criminalize accurate off-label speech. Nevertheless, from the Government’s conduct and statements post-Amarin, it is reasonable to conclude that the only option available to regulated entities interested in communicating broadly and accurately about the full range of their products’ uses in reliance on clearly articulated regulatory policies—or, more modestly, interested in using a relatively efficient process for FDA prior review of proposed off-label communications—is litigation.

Related Articles:

“FDA Loses Amarin Litigation; Court Grants Preliminary Relief,” Sidley Global Life Sciences: U.S. FDA Update, Coleen Klasmeier and Paul E. Kalb, M.D.

“District Court Holds that First Amendment Bars Prosecution for Misbranding Where Conduct is Truthful, Non-Misleading Speech about Off-Label Uses, Declines to Rule on Potential FCA Liability,” Original Source, Paul E. Kalb, M.D., Coleen Klasmeier, Jaime L.M. Jones and Brenna Jenny