A Victory for Amarin Further Erodes FDA Regulation of Off-label Promotion

By David C. Gibbons –

On Friday, August 7, Judge Paul Engelmayer, U.S. District Court for the Southern District of New York, handed down one of the most significant rulings concerning First Amendment protection for a pharmaceutical manufacturer’s off-label promotion of an otherwise approved drug.  Judge Engelmayer granted a motion for preliminary injunction in favor of Amarin Pharma, Inc. (“Amarin” or “the Company”) and did what some believed the court would not do: reach the merits of Amarin’s First Amendment claims.  

Background

The case before Judge Engelmayer concerned Vascepa (icosapent ethyl), an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (“EPA”) obtained from fish oil.  Vascepa is an approved drug indicated as an adjunct to diet to reduce triglyceride levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia.  Vascepa (icosapent ethyl), Label, NDA 202057 (June 23, 2015). 

Vascepa’s approval was based on a single phase 3 clinical trial (the MARINE trial), conducted in patients with “very high” triglycerides (≥ 500 mg/dL), pursuant to a Special Protocol Assessment (“SPA”) agreement with FDA. Generally, a SPA indicates FDA agreement that a study will support the approval of a drug or biologic product’s marketing application (or supplement to an approved application) if it is conducted according to the protocol and it achieves its agreed-upon objectives.  See FDCA § 505(b)(5)(B); see also FDA, Guidance for Industry: Special Protocol Assessment, 2 (May 2002).  Once FDA and a sponsor enter into a SPA agreement, there are only two narrow statutory bases for changes to the SPA – written agreement between FDA and the sponsor or where FDA finds a “substantial scientific issue essential to determining the safety or effectiveness of the drug” that is identified after the trial has begun.  FDCA § 505(b)(5)(C). 

Similar to the Company’s approach with the initial indication, Amarin designed a single phase 3 clinical trial to examine the effect of Vascepa on triglyceride levels among statin-treated patients with “persistently high” triglycerides (≥ 200 and ≤ 500 mg/dL), the ANCHOR trial, and entered into a separate SPA with FDA (the “ANCHOR SPA”). In connection with the ANCHOR SPA, Amarin also agreed to conduct a cardiovascular outcomes trial (the REDUCE-IT trial) to examine whether Vascepa would be effective in reducing cardiovascular events.  As a condition of the ANCHOR SPA, FDA required that the REDUCE-IT trial would need to be at least 50% enrolled before FDA would accept Amarin’s supplemental new drug application (“sNDA”) for use of Vascepa in patients with persistently high triglycerides.  When Amarin submitted its application for approval of the initial indication, FDA reviewed the ANCHOR data as a second, confirmatory trial and included the combined safety results from both trials in the first indication labeling.

Amarin believed it had satisfied all of FDA’s requirements to obtain approval of Vascepa for persistently high triglycerides, 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 enrollment obligations with respect to the REDUCE-IT trial.  Thus, Amarin submitted its sNDA for the persistently high triglyceride indication in February 2013and anticipated a timely approval for this additional indication.

However, FDA convened an Advisory Committee during which the agency called into question the clinical validity of the ANCHOR study endpoint of triglyceride lowering, despite having agreed to that endpoint in the SPA. Data from several high-profile cardiovascular outcomes trials reported out after the ANCHOR SPA was entered into by FDA and Amarin and cast doubt on the clinical benefit of triglyceride lowering and whether a reduction in triglyceride levels would translate into a reduction in cardiovascular events, in general.  Upon reviewing these data, FDA asked the Advisory Committee to weigh in on whether Vascepa’s triglyceride lowering effect was sufficient to approve the drug for use in patients with persistently high triglycerides. The Advisory Committee voted 9 to 2 against approval of Vascepa for that indication. Subsequently, FDA rescinded the ANCHOR SPA, something FDA has done only 10 times among approximately 1,000 SPAs, and issued a Complete Response Letter to Amarin indicating the need for data showing a reduction in cardiovascular events (i.e., data from the REDUCE-IT trial) prior to approval for persistently high triglycerides.  Amarin stated that 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 [(“FDCA”)].’”  Complaint at 27, Amarin Pharma, Inc. v. FDA, No. 15-3588 (S.D.N.Y. May 7, 2015).

The court had acknowledged the lawful use of FDA-approved drugs for off-label uses by doctors and the inability of FDA to regulate doctors so using those drugs.  The court cited to numerous studies of off-label use that shows such use is ubiquitous in clinical medicine, noting in some areas that off-label use is “the norm rather than the exception.”  Amarin at 5.  The court went on to say that the “therapeutic—indeed, sometimes life-saving—value of off-label uses of FDA-approved drugs has been widely recognized.”  Id. at 6. 

The court discussed how FDA has “long taken the position” that pharmaceutical manufacturers who market or promote off-label uses of approved drugs violate the FDCA.  Id. at 9.  The court described FDA’s long-standing position that off-label promotion of drug products risks criminal misbranding under the FDCA.  FDCA § 301(b).  A drug is misbranded if its labeling is “false or misleading in any particular.”  Id. § 502(a).  A drug is misbranded, according to the FDCA, if its labeling does not bear “adequate directions for use.”  Id. § 502(f).  FDA regulations define adequate directions for use as those under which a lay person can “use a drug safely and for the purposes for which it was intended.”  21 C.F.R. § 201.5.  The court, in its opinion, skipped a step, but it is important to note that labeling for prescription drugs, which are not safe for use except under supervision by a licensed health care provider, cannot bear adequate directions for use by a lay person, but can be subject to an exemption from this statutory requirement.  FDCA §§ 503(b), 502(f).  FDA regulations require that, to satisfy the conditions for this exemption, prescription drugs must have labeling that contains “adequate information for [] use . . . under which practitioners licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all conditions for which it is advertised or represented.”  21 C.F.R. § 201.100(d)(1) (emphasis added).  “Intended use” means the objective intent of the persons legally responsible for the labeling of drugs, which is determined by such persons’ expressions or may be shown by the circumstances surrounding the distribution of the article.  This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives.  21 C.F.R. § 201.128.  Where the intended use of a prescription drug differs from the use approved by FDA (as indicated in the drug’s approved labeling), FDA has asserted that the product is a “new drug” for which FDA approval is required.  Placing a new drug in interstate commerce without FDA approval is a violation of the FDCA.  FDCA § 505(a). 

FDA has argued that misbranding actions against manufacturers who engage in off-label promotion furthers public safety.  Amarin at 12.  The court noted, “FDA has stated, its goal in pursuing misbranding charges against manufacturers based on the off-label promotion of drugs is to encourage use of the FDA’s drug review and approval process.”  Id.  Prosecutions therefore, act as a deterrent for manufacturers to evade FDA’s drug approval process for new uses of approve drugs.  Id. at 13. 

Amarin’s Proactive Challenge to FDA

In a bold move, Amarin filed a civil complaint against FDA claiming 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 that would prevent FDA from prosecuting the Company for truthful, non-misleading speech concerning Vascepa, going so far as to detail, in its complaint, certain off-label promotional content regarding Vascepa that the Company proposed to disseminate.  Early in the litigation proceedings, Amarin filed a motion for preliminary injunction and the court heard oral arguments on the motion on July 7, 2015, and, on August 7, the court handed down a 71-page opinion in which it granted Amarin’s requests, as described below.

Amarin sought to disseminate three types of information relating to the use of Vascepa in patients with persistently high triglycerides.  Importantly, Amarin stated in its complaint that it did not intend to promote this use of Vascepa in direct-to-consumer advertising, but only sought to “engage in truthful, nonmisleading speech about Vascepa directly with healthcare professionals.”  Compl. at 41.  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.  Compl. 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.”  Compl. 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.  These disclosures included the statements: 

• FDA has not approved Vascepa to reduce the risk of coronary heart disease;
• FDA has not approved Vascepa for the treatment of statin-treated patients with mixed dyslipidemia and high (> 200 mg/dL and < 500 mg/dL) triglyceride levels;
• The effect of Vascepa on the risk of cardiovascular mortality and morbidity has
• not been determined;
• A cardiovascular outcomes study of Vascepa designed to evaluate the efficacy of Vascepa in reducing cardiovascular mortality and morbidity in a high risk patient population on statin therapy is currently underway; and
• Vascepa may not be eligible for reimbursement under government healthcare programs, such as Medicare or Medicaid, to reduce the risk of coronary heart disease or for treatment of statin-treated patients with mixed dyslipidemia and high (> 200 mg/dL and < 500 mg/dL) triglyceride levels. We encourage you to check that for yourself. [(Compl. at 42-43.)]

In response, and perhaps in light of FDA’s recent losing record on First Amendment cases, FDA attempted to moot Amarin’s case in a letter provided to Amarin and filed with the court.  In its letter, FDA stated that it “does not intend to object to Amarin’s proposed communications” if made in a truthful, non-misleading, and balanced manner.  Exhibit A to Letter from Ellen London to Judge Paul A. Engelmayer at 6, Amarin, No. 15-3588 (S.D.N.Y. June 8, 2015).  Essentially, FDA agreed that many of Amarin’s proposed communications were consistent with FDA policy on dissemination of reprints and other medical communications.  FDA also agreed that Amarin’s proposed contemporaneous disclosures regarding Vascepa’s regulatory status, approval limitations, and the status of the REDUCE-IT trial would help to balance Amarin’s presentation of Vascepa efficacy data in patients with persistently high triglycerides.  However, FDA insisted that certain additional disclosures be made with Amarin’s proposed off-label promotion and rejected Amarin’s ability to make claims similar to the qualified health claims of EPA-containing dietary supplements.  FDA justified its exercise of enforcement discretion regarding these claims in the dietary supplement context due to the different statutory and regulatory schemes governing dietary supplement as well as the lower level of scientific evidence required for such products.

The Court Granted Preliminary Relief to Amarin

Finding a ripe controversy as to the threat of prosecution under the FDCA, the court indicated that the central dispute, as to whether a preliminary injunction should be granted, was whether Amarin was likely to succeed on the merits.  In accord with binding precedent set by the Second Circuit in the criminal misbranding case, United States v. Caronia, 703 F.3d 149 (2d Cir. 2012) (here), Judge Engelmayer granted Amarin’s motion for preliminary injunction against FDA.  The court noted that Amarin sought protection for its speech “both at a general and a statement-specific level.”  Amarin at 28.

When addressing Amarin’s statement-specific request for relief, surprisingly, the court evaluated and ruled on each of Amarin’s proposed off-label statements concerning Vascepa along with FDA’s responses to the same.  The court held, noting that FDA did not dispute, 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.”  Amarin Pharma, Inc. v. FDA, No. 15-3588, 55 (S.D.N.Y. Aug. 7, 2015) (opinion and order granting preliminary injunction).  The court then considered the “agreed-upon statements and disclosures” proposed by Amarin.  These included statements concerning the results of the ANCHOR study on both primary and secondary endpoints.  The court held the statements, along with the proposed contemporaneous disclosures that would be made with such statements were “based on current information, truthful and non-misleading.”  Id. at 57. 

Next, the court discussed additional “contested disclosures” that would be made contemporaneously with certain off-label statements concerning Vascepa.  Amarin proposed to state: “FDA has not approved Vascepa for the treatment of statin-treated patients with mixed dyslipidemia and high (≥200 mg/dL and <500 mg/dL) triglyceride levels.”  However, FDA wanted the following added to this disclosure: “FDA declined to approve this indication because the available evidence does not establish that reducing triglycerides with a drug reduces the risk of cardiovascular events among patients already treated with statins,” to which Amarin disagreed.  Court filings evidenced the back-and-forth between Amarin and FDA concerning the appropriate disclosure indicating FDA’s lack of approval for the persistently high triglyceride indication.  In the end, the court agreed with FDA that a disclosure explaining FDA’s decision not to approve Vascepa for this off-label use was necessary, stating that a revised disclosure “drawing upon both parties’ final positions, achieves a truthful and non-misleading result.”  Id. at 58.  Judge Engelmayer then proceeded to provide such a revised disclosure that read:

Vascepa is not FDA-approved for the treatment of statin-treated patients with mixed dyslipidemia and high (≥ 200 mg/dL and < 500 mg/dL) triglyceride levels due to current uncertainty regarding the benefit, if any, of drug-induced changes in lipid/lipoprotein parameters beyond statin lowered low-density lipoprotein cholesterol on cardiovascular risk among statin-treated patients with residually high triglycerides. No prospective study has been conducted to test and support what, if any, benefit exists.  [(Id.  at 60.)] 

The court held that its own revision was “at present, truthful and non-misleading,” but 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 High-level Analysis and Holding Related to First Amendment Protection for 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 this court amplified Caronia’s central holding in Amarin’s as-applied challenge to FDA’s threat of prosecution for off-label promotion. 

At a high level, the court said that FDA “reserve[ed] the right” to prosecute Amarin for its truthful and non-misleading off-label promotion.  Id. at 44.  FDA’s argument was a refinement of its long-standing position that it would use Amarin’s speech as evidence of misbranding, and not prosecute the speech itself.  FDA, in its briefs as well as in its oral arguments stated that it could lawfully use speech to establish both 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.  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.  To bolster its point, FDA likened misbranding to other crimes where speech constitutes the act, such as jury tampering, blackmail, and insider trading.  Id. at 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. (emphasis in original). The court stated that, based on its reading of Caronia, misbranding is not like the analogous crimes of jury tampering, blackmail, or insider trading.  The court closed the door on FDA’s line of reason by stating, “[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 (emphasis in original).

FDA made three counter-arguments, none of which persuaded the court. First, FDA argues that Amarin’s proactive challenge constituted a “frontal assault” on FDA’s new drug approval process to which Congress gave effect in the 1962 amendments to the FDCA.  Id.  To this, the court simply stated that the 1962 amendments predate First Amendment jurisprudence protecting commercial speech (see Cent. Hudson Gas & Elec. Corp. v. Pub. Serv. Comm’n, 447 U.S. 557 (1980)) and finding that pharmaceutical speech qualifies for such protection (see Sorrell v. IMS Health, Inc., 131 S. Ct. 2653, 2672 (2011)).  Id.  The court went so far as to “ding” FDA for not seeking a rehearing or appeal of Caronia. 

Second, FDA argues that Caronia’s holding should only apply to certain types of truthful and non-misleading off-label promotion, consistent with FDA policy as expressed in its guidance documents.  For example, off-label promotion in the context of a solicited request for such information is permissible while the unsolicited provision of such information is not.  The court responded by stating that Caronia applies “across the board to all truthful and non-misleading promotional speech.”  Id. at 51 (emphasis in original). 

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 found this argument “beside the point” since Amarin’s lawsuit concerned only the situation in which FDA prosecuted Amarin for misbranding based on its truthful and non-misleading speech.  The court stated that the “construction [of the misbranding provision in the FDCA 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.

Conclusion

There are several points we would emphasize, as we read the court’s lengthy opinion in Amarin:

• Although the court reached the merits in this case, the opinion reflects a ruling only on Amarin’s motion for preliminary injunction.  However, it does provide a great deal of insight into the court’s thinking on the matter. 
• The government has a number of options at this point, one of which is to file an appeal, for which it has 60 days to do so.  We cannot predict whether the government will appeal, cut its losses and settle with Amarin, or continue to defend itself as the litigation progresses.  The government’s next move may have a significant impact on this ruling.
• While this ruling in Amarin, coupled with the Second Circuit’s decision in Caronia, appears to foreclose FDA from prosecuting a pharmaceutical manufacturer for truthful and non-misleading off-label promotion, it is important to note that this precedent has only been established in the Second Circuit to date and there is considerable uncertainty as to how sister Circuits would rule if faced with the same set of facts. 
• Finally, the limitation of First Amendment protection to truthful and non-misleading speech is not to be missed.  Indeed, the court gave very practical advice to manufacturers 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.  [(Amarin at 53.)]