Amarin Announces a Proposed Settlement of its First Amendment Lawsuit Against FDA: Coming Full Circle in a New Era of the Regulation of Off-label Promotion

By David C. Gibbons & John R. Fleder –

On March 8, 2016, Amarin Pharma, Inc. (“Amarin” or “the Company”) and FDA filed a proposed Stipulation And Order Of Settlement (“Proposed Settlement Order”) with Judge Paul Engelmayer in the U.S. District Court for the Southern District of New York, that would bring to a close Amarin’s proactive challenge to FDA’s restrictions concerning the Company’s off-label promotion of Vascepa. We do not know when the Court will complete its review of the Proposed Settlement Order and finalize the settlement.

In sum, the parties agree that FDA will be bound by Judge Engelmayer’s prior conclusions that: (1) “Amarin may engage in truthful and non-misleading speech promoting the off-label use of Vascepa”; and (2) certain statements and disclosures that Amarin proposes to make to doctors are truthful and non-misleading.

Readers can review our previous posts about the Amarin litigation here and here. However, we summarize the relevant background of the litigation below. A more exhaustive review and analysis of the issues presented by the original suit can also be found in our article published in FDLI Update last Fall.

Background: Amarin Files Civil Suit Against FDA on May 7, 2015

The lawsuit brought by Amarin concerns its drug, Vascepa (icosapent ethyl), an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (“EPA”).  Vascepa is an approved drug indicated as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia (triglycerides ≥ 500 mg/dL).  See Vascepa (icosapent ethyl) Label, NDA 202057 (June 23, 2015).

As part of the Company’s planned development and marketing of Vascepa, Amarin designed and conducted a Phase 3 clinical study, the ANCHOR trial, to examine the effect of Vascepa on triglyceride levels among statin-treated patients with “persistently high” triglycerides (≥ 200 and ≤ 500 mg/dL), and entered into a Special Protocol Assessment (“SPA”) with FDA (the “ANCHOR SPA”). Amarin believed it had satisfied all of FDA’s requirements to obtain approval of Vascepa for this indication per the ANCHOR SPA agreement.  The ANCHOR study achieved its primary endpoint demonstrating statistically significant reductions in triglyceride levels with Vascepa, compared to placebo. Vascepa achieved statistically significant results for its secondary endpoints in the ANCHOR study as well.  In addition, Amarin met its obligation under the ANCHOR SPA to enroll at least 50% of a cardiovascular outcomes trial (the REDUCE-IT trial) to examine whether Vascepa would be effective in reducing cardiovascular events. Thus, Amarin submitted its sNDA for the persistently high triglyceride indication in February 2013, and anticipated a timely approval for this additional indication.

The company’s plan to obtain approval of the persistently-high triglyceride level indication was derailed when FDA called into question the clinical validity of the triglyceride lowering endpoint while the sNDA for this indication was under review, despite FDA having agreed to that endpoint in the ANCHOR SPA. Following an FDA-convened Advisory Committee meeting, where Committee members voted 9 to 2 against approval of Vascepa for that indication, FDA rescinded the ANCHOR SPA and issued a Complete Response Letter to Amarin requiring data showing a reduction in cardiovascular events prior to approval of the indication for persistently high triglycerides.  FDA concluded the Complete Response Letter “with a warning that any effort by Amarin to market Vascepa for the proposed supplemental use could constitute ‘misbrand[ing] under the Federal Food, Drug, and Cosmetic Act [(“FD&C Act”)].’”  Complaint at 27, Amarin Pharma, Inc. v. FDA, No. 15-3588 (S.D.N.Y. May 7, 2015).

The civil Complaint that Amarin filed claimed that FDA’s threat of prosecution for misbranding Vascepa had a chilling effect on Amarin’s commercial speech that was otherwise protected by the First Amendment.  For that reason, Amarin sought declaratory and injunctive relief to prevent the government from prosecuting the Company for truthful and non-misleading speech concerning Vascepa, detailing, in its complaint, certain off-label promotional content regarding Vascepa that the Company proposed to disseminate.

In its Complaint, Amarin stated that it sought only to “engage in truthful, non-misleading speech about Vascepa directly with healthcare professionals” (Compl. at 41), albeit on information that FDA had not approved to appear in Vascepa’s label.  First, Amarin wanted to disseminate the results of the ANCHOR study.  Amarin proposed to distribute summaries of Vascepa’s effect on triglycerides as well as secondary endpoints on other lipid parameters that were examined in the ANCHOR study.  Second, Amarin wanted to make the statement that “[s]upportive but not conclusive research shows that consumption of EPA and DHA [(docasohexanoic acid)] omega-3 fatty acids may reduce the risk of coronary heart disease,” a claim that EPA- and DHA-containing dietary supplements are allowed to make, under FDA’s rules.  Id. at 41, 31-37.  Third, Amarin sought to distribute reprints of “peer-reviewed scientific publications relevant to the potential effect of EPA on the reduction of the risk of coronary heart disease.”  Id. at 42.  Along with this information, Amarin proposed to make relevant “contemporaneous disclosures” to ensure that the messages the Company communicated to healthcare professionals concerning the use of Vascepa in patients with persistently high triglycerides was not misleading.

Preliminary Relief Granted to Amarin on August 7, 2015

Amarin filed a motion for preliminary injunction and, on August 7, the court handed down a 71-page opinion that gave Amarin an early victory in the case and presumably provided the impetus for the parties to settle.

Following United States v. Caronia, 703 F.3d 149 (2d Cir. 2012) (here), a Second Circuit criminal misbranding case, Judge Engelmayer granted Amarin’s motion for preliminary injunction against FDA.  The court held that Amarin’s dissemination of a summary of the ANCHOR study results as well as the reprints regarding the potential cardioprotective effect of EPA, “would be neither false nor misleading.”  Op. and Order at 55, Amarin Pharma, Inc. v. FDA, No. 15-3588 (S.D.N.Y. Aug. 7, 2015) (“August 7 Order”). The court held that certain statements and disclosures, proposed by Amarin and agreed upon by FDA, concerning the results of the ANCHOR study were “based on current information, truthful and non-misleading.”  Id. at 57.

The court also ruled on additional disclosures proposed by Amarin, but initially contested by FDA, that would be made contemporaneously with certain off-label statements concerning Vascepa.  In the end, the court approved a disclosure explaining FDA’s decision not to approve Vascepa for use in patients with persistently high triglycerides. The court indicated that such a disclosure was necessary, and the court itself proceeded to revise a disclosure “drawing upon both parties’ final positions, [that] achieve[d] a truthful and non-misleading result.”  Id. at 58.  The court noted that Amarin and FDA were “at liberty to pursue further refinements . . . .”  Id. at 60.

Finally, the court considered Amarin’s proposed cardiovascular disease claim.  During the litigation, Amarin proposed to revise the claim to read: “Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease. Vascepa should not be taken in place of a healthy diet and lifestyle or statin therapy.”  Id. at 63.  The court held that its “assessment, with Amarin, is that the coronary heart disease claim—given its qualified phrasing and its acceptance elsewhere by the FDA, and with the sentence added by Amarin—is presently truthful and non-misleading. Therefore, Amarin may today make that claim, too, without exposing itself to liability for misbranding.”  Id. at 64.

The court noted that circumstances could change the court’s “approval” of the aforementioned statements as truthful and non-misleading.  The court stated:

The Court has held that Amarin’s proposed communications, as modified herein, are presently truthful and non-misleading. But the dynamic nature of science and medicine is that knowledge is ever-advancing. A statement that is fair and balanced today may become incomplete or otherwise misleading in the future as new studies are done and new data is acquired. The Court’s approval today of these communications is based on the present record. Amarin bears the responsibility, going forward, of assuring that its communications to doctors regarding off-label use of Vascepa remain truthful and non-misleading.  [(Id. at 66.)]

The Court’s Ruling on First Amendment Protection for Amarin’s Off-Label Promotion

In addition to its rulings on the specific statements proposed by Amarin, the court also addressed Amarin’s general request for First Amendment protection for truthful and non-misleading off-label promotion.  The court heavily relied on the precedent-setting analysis in Caronia, although the Amarin court amplified Caronia’s central holding with regard to Amarin’s as-applied challenge to FDA’s threat of prosecution for off-label promotion.

FDA’s counter to Amarin’s challenge was a refinement of its long-standing position that it may use speech as evidence of misbranding, taking the position that it would not seek to prosecute Amarin for the speech in and of itself.  Rather, FDA, in its briefs as well as in its oral arguments, stated that it could lawfully use speech to establish the intent and the act of misbranding.  In addition to using Amarin’s speech as evidence of intent to misbrand Vascepa, FDA stated that it “may bring a misbranding action where Amarin’s only acts constituting promotion of Vascepa for an off-label use are its truthful and non-misleading statements about that use, provided that these acts support an inference that Amarin intended to promote that off-label use.”  Id. at 44.  FDA went on to argue that “it does not read Caronia to preclude a misbranding action where the acts to promote off-label use consist solely of truthful and non-misleading speech, provided that the evidence also shows that the drug had been introduced into interstate commerce and that the FDA had not approved it as safe and effective for the off-label use.”  Id. at 44-45.

The court flatly rejected FDA’s interpretation of Caronia and stated that “[t]he [c]ourt’s considered and firm view is that, under Caronia, the FDA may not bring such an action based on truthful promotional speech alone, consistent with the First Amendment.”  Id. at 45.  The court stated that, “[w]here the speech at issue consists of truthful and non-misleading speech promoting the off-label use of an FDA-approved drug, such speech, under Caronia, cannot be the act upon which an action for misbranding is based.”  Id. at 49.

The court rejected FDA’s legal arguments as to why Amarin’s off-label speech should be restricted. First, the court rejected FDA’s argument that Amarin’s proactive challenge constituted a “frontal assault” on FDA’s new drug approval process.  Id.  To this, the court pointed to the fact that the 1962 amendments predated First Amendment jurisprudence protecting commercial speech (see Cent. Hudson Gas & Elec. Corp. v. Pub. Serv. Comm’n, 447 U.S. 557 (1980)) and found that pharmaceutical speech qualifies for such protection (see Sorrell v. IMS Health, Inc., 131 S. Ct. 2653, 2672 (2011)).  August 7 Order at 49. Second, the court rejected FDA’s attempt to narrow the applicability of Caronia to only certain types of truthful and non-misleading off-label promotion. The court stated that Caronia applies “across the board to all truthful and non-misleading promotional speech.”  Id. at 51.  Finally, FDA reprised its argument that Caronia does not prohibit the use of speech as evidence of intent to promote a drug for off-label uses.  The court stated that the “construction [of the misbranding provision in the FD&C Act in accord with Caronia] applies no matter how obvious it was that the speaker’s motivation was to promote such off-label use.”  Id.  The court concluded by stating: “[i]n the end, however, if the speech at issue is found truthful and non-misleading, under Caronia, it may not serve as the basis for a misbranding action.”  Id. at 53.

The Settlement Agreement Filed on March 8, 2016, Resolving the Lawsuit

The comprehensive analysis of Amarin’s First Amendment claims by the court and its sweeping decision with regard to Amarin’s motion for preliminary injunctive relief propelled the litigants into settlement discussions that culminated over six months later. The Proposed Settlement Order filed in the court follows and indeed adopts the court’s key determinations in the August 7 Order. The first four paragraphs of the settlement terms provide, broadly, that Amarin will not be prosecuted for truthful and non-misleading promotion of Vascepa outside of its approved label. These terms include:

1. Amarin may engage in truthful and non-misleading speech promoting the off-label use of Vascepa to treat patients with persistently high triglycerides, and “under Caronia, such speech may not form the basis of a prosecution for misbranding.”
2. The communications regarding off-label use of Vascepa, as modified and approved in the court’s August 7 Order, are, based on information known at that time, truthful and non-misleading.
3. “Amarin bears the responsibility, going forward, of assuring that its communications to doctors regarding off-label use of Vascepa remain truthful and non-misleading.”
4. All settlement terms are to be interpreted consistent with the August 7 Order, and nothing in the Proposed Settlement Order shall be construed to limit Amarin’s constitutional rights to free speech concerning Vascepa.

Proposed Settlement Order at 2.

Two other provisions of the Proposed Settlement Order warrant attention. First, in addition to generally-available regulatory procedures available to companies regarding FDA review of promotional materials, Amarin may submit to FDA up to two proposed communication pieces per year regarding off-label use of Vascepa under a “preclearance procedure” detailed in the Proposed Settlement Order. Id. The proposed communication pieces that Amarin submits will be reviewed by FDA prior to Amarin disseminating such information. FDA has 60 calendar days to object, unless the parties agree on an extended timeframe. Should FDA object, Amarin must respond to FDA’s concerns or objections within 45 calendar days, again, unless extended by mutual agreement of the parties. FDA will notify Amarin within 30 calendar days of the specifics of any remaining dispute over the proposed communication pieces. Id. at 2-3. This preclearance process will be available to Amarin until December 31, 2020, and is the only provision of the Proposed Settlement Order that will terminate. Id. at 3.

Second, should any other dispute arise between the parties, the Proposed Settlement Order provides for a dispute resolution process. In an effort to promote dialog between the Company and FDA, the parties have agreed that, upon written notice of a dispute by one of the parties, the other party will have 60 days to cure or resolve the dispute. If the party is not satisfied by the other party’s proposed cure or resolution, that party will have 30 calendar days to respond. After this process has been followed, unresolved disputes may be brought before Judge Engelmayer, whose court retains jurisdiction over the Proposed Settlement Order. Id. at 3-4.

Finally, the Proposed Settlement Order applies to both Amarin as well as it representatives. Id. at 4.

Some Things We Have Gleaned from Recent Off-Label Promotion Cases

In a suit that followed on Amarin’s coat-tails in the Southern District of New York, Pacira Pharmaceuticals, Inc. (“Pacira”) challenged FDA’s limitations on Pacira’s promotion of its post-surgical analgesic drug, Exparel, to only those specific uses in which the drug has been studied and approved, despite the drug having a general use indication. See Pacira Pharms., Inc. v. FDA, No. 15-7055 (S.D.N.Y.). Pacira settled its First Amendment challenge against FDA regarding the promotion of its drug, Exparel (see our discussion on the litigation here and the settlement here). Both the terms of settlement and the revised label confirmed that Exparel’s use encompassed a broad range of surgeries, not limited to the clinical studies included in the label. Also, FDA stipulated that this broad use of Exparel does not represent the approval of a new indication, but rather clarifies Exparel’s use, “as initially approved” at the time Exparel’s NDA was approved, back in 2011, thus exculpating Pacira from prosecution related to its past, current, and future promotion of Exparel for specific surgery types that are encompassed by its general indication. We believe there are broader implications to this settlement for products bearing general indications in their label. As we noted previously, medical device companies frequently face this “general versus specific use” issue. We must remember that Pacira was a settlement of a specific legal dispute and does not provide legal conclusions from a court in litigation.

Second, on February 25, 2016, in a criminal case, United States v. Vascular Solutions, Inc., on which we previously posted here and here, a jury acquitted Vascular Solutions, Inc. (“VSI”) and its CEO, Howard Root, on allegations that the defendants engaged in a criminal conspiracy to violate the FD&C Act and sold misbranded medical devices. Judge Royce Lamberth, a Senior Judge in the U.S. District Court for the District of Columbia and sitting by designation in the U.S. District Court for the Western District of Texas, instructed the jury, consistent with Caronia and Amarin, that speech that is truthful and not misleading is not criminal. His instructions read, in part:

It is also not a crime for a device company or its representative to give doctors wholly truthful and non-misleading information about the unapproved use of a device. If you find that VSI’s promotional speech to doctors was solely truthful and not misleading, then you must find the Defendants not guilty of the misbranding offense.

Final Jury Instructions at 12, United States v. Vascular Solutions, Inc., 5:14-CR-00926 (W.D. Tex. Feb. 25, 2016) (emphasis added).

This was an important case because it showed us that a court outside of the Second Circuit may be following its lead in finding that truthful and non-misleading speech concerning off-label uses of a product does not violate the criminal misbranding provisions of the FD&C Act.

Which brings us back to Amarin . . . The Amarin Proposed Settlement Order may be a sign of how FDA will be regulating off-label promotion in the future. This is the first case where FDA has agreed to allow a company to engage in truthful and non-misleading off-label promotion outside the narrow scope of its two Guidance documents concerning the dissemination of information on unapproved uses of a product. See FDA, Draft Guidance for Industry: Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices (Dec. 2011); FDA, Revised Draft Guidance for Industry: Distributing Scientific and Medical Publications on Unapproved New Uses — Recommended Practices (Feb. 2014). The terms of the Proposed Settlement Order do not limit Amarin’s ability to make claims that were presented during the litigation. Rather, the Proposed Settlement Order broadly allows Amarin to disseminate any truthful and non-misleading off-label information and materials related to Vascepa’s use in patients with persistently high triglyceride levels. See Proposed Settlement Order at 1. As we discussed previously, however, FDA may believe that Amarin presents a somewhat unique sets of facts, given the regulatory history and NDA-quality data underlying the court’s preliminary decision that the speech was truthful and not misleading.

Where Do We Go From Here?

While pharmaceutical and medical device companies have come out on top in recent First Amendment litigation, companies should still tread cautiously in moving beyond their approved labeling.

A company’s review and approval of promotional pieces begins, but does not end, with a review of the product’s prescribing information and labeling. Companies should carefully consider communications it has had with FDA during the development and approval of the product as well as any post-marketing discussions. Often these communications, memorialized in official meetings minutes, regulatory correspondence, or contact reports, provide a rich understanding of FDA’s view on the claims that can be made within the scope of the approved prescribing information.

It is also important to understand that First Amendment protection only applies to speech that is both truthful and non-misleading.  While it may be relatively straightforward to determine what is or is not “truthful,” the nature of what may “mislead” is much more complicated and will heavily depend on the facts and circumstances. Indeed, the court, in Amarin, gave very practical advice when it said:

Although the FDA cannot require a manufacturer to choreograph its truthful promotional speech to conform to the agency’s specifications, there is practical wisdom to much of the FDA’s guidance, including that a manufacturer vet and script in advance its statements about a drug’s off-label use. A manufacturer that leaves its sales force at liberty to converse unscripted with doctors about off-label use of an approved drug invites a misbranding action if false or misleading (e.g., one-sided or incomplete) representations result. Caronia leaves the FDA free to act against such lapses.  [(August 7 Order at 53.)]

Finally, we note that the Amarin Proposed Settlement Order does not specifically address the issue of whether, to make a promotional claim, a company must have adequate substantiation for that claim. The government may assert that an unsubstantiated claim is unlawful without regard to the First Amendment, even if that claim is otherwise truthful and not misleading.

In sum, we expect that the next battleground for companies who seek to disseminate off-label information concerning their products will be whether an off-label claim is misleading and/or unsubstantiated.

We may take a deeper dive into these issues in future posts.

UPDATE:  Late on March 8, 2016, Judge Engelmayer signed the Stipulation And Order Of Settlement.