Amarin Pharma, Inc. v. United States Food & Drug Administration (119 F. Supp. 3d 196, 2015)

OPINION & ORDER

PAUL A. ENGELMAYER, District Judge:

In United States v. Caronia, 703 F.3d 149 (2d Cir.2012), the Court of Appeals for the Second Circuit vacated a pharmaceutical sales representative’s conviction for conspiring to introduce a misbranded drug into interstate commerce, in violation of 21 U.S.C. §§ 331(a) and 333(a)(1). The conviction was based" on Caronia’s having promoted a drug for “off-label use,” that is, a use other than the one approved by the U.S. Food and Drug Administration (the “FDA”). Caronia’s conduct to promote the off-label use, however, had consisted solely of truthful and non-misleading speech. The Second Circuit held that, to avoid infringing the First Amendment, the misbranding provisions of the Federal Food, Drug and Cosmetic Act (the “FDCA”) must be construed “as not prohibiting and criminalizing the truthful off-label promotion of FDA-approved prescription drugs” where the off-label use itself is lawful. 703 F.3d at 168.

This case grows out of the decision in Caronia and involves the same misbrand-ing provisions. Plaintiff Amarin Pharma, Inc. (“Amarin”) manufactures a triglyceride-lowering drug, Vascepa. The FDA has approved Vascepa for one use, but doctors have widely, and lawfully, prescribed it for another. Amarin wishes to make truthful statements to doctors relating to Vascepa’s off-label use. The specific statements Amarin seeks to make are derived largely from an FDA-approved study of Vascepa’s off-label use, and from writings by the FDA itself on that subject. Amarin therefore contends, and the FDA largely but not wholly concedes, that the statements Amarin seeks to make are truthful and non-misleading. However, the FDA, recognizing that Amarin’s purpose in making these statements would be to.promote an unapproved use of Vascepa, has threatened to bring misbranding charges against Amarin (and, presumably, its émployees) if it does so.

In this action, Amarin claims that the FDA’s threat of a misbranding' action is chilling it from engaging in constitutionally protected truthful speech. Amarin seeks preliminary relief to ensure its ability to engage in truthful and - non-misleading speech free from the threat of a misbrand-ing action. For the reasons that follow, the Court grants such relief.

I. Background

Amarin is a biopharmaceutieal company, incorporated in Delaware and based in New Jersey. Compl. ¶24. It and four medical doctors resident in New York (collectively, “Amarin”) bring this suit against the FDA, two officials with responsibility over the FDA (Dr. Stephen Ostroff and Sylvia Matthews Burwell), and the United States (collectively, the “FDA”). The FDA is the federal agency responsible for approving, disapproving, and otherwise regulating food, drugs, .medical devices, and biologies under the FDCA. Id. ¶25.

In this background section, the Court first reviews the statutory and regulatory framework under the FDCA governing the sale and marketing of drugs, the provisions relevant to the off-label promotion of drugs, and the FDA’s response to date to the Caronia decision addressing the interplay between these provisions and the First Amendment. The Court then reviews the FDA’s evaluation of Vaseepa and the basis for its decision to not approve it for -the off-label use at issue here. The Court then reviews this lawsuit and Ama-rin’s application for preliminary relief,

A. The Statutory and Regulatory Framework

1, Briéf History of the FDCA

Before 1938, drug manufacturers could market drugs without premarket approval for safety or effectiveness. In .1938, a year after more than 100 Americans died after ingesting a toxic drug (elixir sulfani-lamide), Congress enacted the FDCA.

As originally enacted, the FDC A required drugs to be approved for safety, but not for effectiveness, before their introduction into the market. See Drug Industry Act- of .1962, S.Rep. No. 87-1744, at 37 (1962), reprinted in 1962 U.S.C.C.A.N. 2884 (reprinted at London Decl., Ex. Z-4, at 8). As a result, even where the evidence did not support a manufacturer’s therapeutic claims, the FDA still approved of drugs for general distribution as long as they were shown to be “safe under conditions proposed for their use in the labeling.” Id.

This regulatory regime led to a profusion of drug advertising that had “a deliberate’intent to mislead.” Id.; see also The Drug Industry Antitrust Act of 1962: Hearings before the Antitrust Subcomm. of the H. Comm, on the Judiciary, 87th Cong.. 67 (reprinted at London Decl.,' Ex. AA-1, at 4) (“[T]he physician is bombarded with seductive, advertising which fails to tell the truth, the whole truth, and nothing but the truth. This often leads him into prescribing a new drug without adequate warning or information about its possible side effects and, indeed, without any solid clinical evidence that the drug is effective or is even as safe as the advertisers claim.”); Waxman, A History, 58 Food & Drug L.J. at 301-02.

In response to rampant false and misleading advertising of drugs, Congress amended the FDCA by enacting the Drug Amendments of 1962. These require manufacturers to demonstrate that their drugs are both safe and effective for their intended uses before they are approved for distribution. Pub.L. No. 87-781, 76 Stat. 780 (1962) (“Kefauver-Harris Amendments”); 21 U.S.C. § 355(a), (d). Specifically, the FDCA, as amended, provides that: “No person' shall introduce or deliver for introduction into interstate commerce any new drug,” without the FDA’s approval of a “new drug application,” which must demonstrate the drug’s safety and efficacy through a series of pre-clinical and clinical trials, and must indicate the proposed labeling for the drug. 21 U.S.C. § 355. FDA approval is therefore necessary before a manufacturer can distribute a drug.

2. Thé Prescription and Use of Approved Drugs for Off-Label Purposes

Significant here, however, the FDA does not regulate ’doctors. After a drug has-been approved by the FDA, a doctor may lawfully prescribe it for both FDA-approved and non-FDA approved (“off-label”) uses. See Caronia, 703 F.3d at 153 (citing Buckman Co. v. Plaintiffs’ Legal Comm., 531 U.S. 341, 350, 121 S.Ct. 1012, 148 L.Ed.2d 854 (2001); Weaver v. Reagen, 886 F.2d 194, 198 (8th Cir.1989); John E. Osborn, Can I Tell You the Truth? A Comparative Perspective on Regulating Off-Label Scientific and Medical Information, 10 Yale J. Health Pol’y L. & Ethics 299, 303 (2010) (“Physicians may prescribe FDA-approved drugs ... for any therapeutic use that is appropriate in their medical judgment.”)).

The prescription of FDA-approved drugs for off-label purposes is widespread. The most comprehensive study on off-label prescriptions in the United States, conducted in 2001, found that approximately 21% of prescriptions were for off-label purposes. See Randall S. Stafford, Regulating Off-Label Drug Use: Rethinking the Role of the FDA, 358 N. Engl. J. Med. 1427, 1427 (2008). In certain fields, off-label prescription is the norm rather than the exception. See Euni Lee et al., Off-label prescribing patterns of antidepressants in children and adolescents, 21 Pharmacoepidemiology &.Drug Safety 137 (2012) (in 2000-2006 study, more than 90% of antidepressants prescribed to children and adolescents in an outpatient care setting were for off-label purposes); Douglas L. Leslie et al., Off-label me of antipsychotic medication in the department of Veterans Affairs health system, 60 Psychiatric Servs. 1175 (2009) (based on review of Veterans Affairs databases, more than 60% of prescriptions of antipsychotic drugs in 2007 were for off-label use); see also Ishaq Lat et al., Off-label medication use in adult Critical care patients, 26 J. Critical Care 89, 91 (2010) (study of medication orders for 414 patients in 37 intensive care units across nation showed that more than 35% were for an off-label purpose and that 97% of patients received at least one off-label medication).

And the therapeutic — indeed,, sometimes life-saving — value of off-label uses of FDA approved drugs has been widely recognized. = ■

In the area of oncology, for example, doctors commonly prescribe drugs for off-label purposes. For a doctor treating a cancer patient, the option of waiting years for possible FDA approval of a new use for an existing drug will often be untenable, and drugs approved by the FDA to treat one type of cancer have proven effective in combatting others, including by reducing tumors or enhancing the effectiveness of chemotherapy. In 2009, in recognition that certain drugs may be a cancer patient’s “last hope,” Medicare expanded its coverage of cancer treatment drugs to include drugs not FDA-approved for' that purpose. For example, Medicare today covers Gemzar, a drug that the FDÁ has approved to treat only four types of cancer, to treat a dozen other cancers, including advanced cervical cancer.

In’other areas of medicine, too, there are numerous examples in which drugs have been successfully prescribed to treat conditions other than those for which the FDA approved them.

A doctor’s off-label prescription also may involve using a drug for an approved condition but at an unapproved dosage or directed to an unapproved patient population. For example, many drugs that the FDA has approved for use by adults have not been approved for pediatric use, in some instances because of the challenges presented by testing drugs on infants and children. As a result, the labels on these drugs lack instructions as to pediatric doses. Pediatricians, however, commonly prescribe such drugs to children; this off-label usage has proven effective in treating children for, among other things, severe emotional and behavioral disorders, respiratory and allergic diseases, and pain.

The FDA itself has long recognized the benefits of using prescription drugs for off-label purposes. As early as, 1982, the FDA stated that:

Once a product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling. Such “unapproved” or, more precisely, “unlabeled” uses may be appropriate and rational in certain circumstances, and may, in fact, reflect approaches to drug therapy that have been extensively reported in medi- • cal literature.

U.S. Food and Drug Admin., FDA Drug Bulletin, 12 FDA Drug Bull. 1, 5 (1982). And in 2009, the FDA acknowledged that: “[O]ff-label uses or treatment regimens may be important and may even constitute a medically recognized standard of care.” Court decisions in the area have similarly recognized this point. See, e.g., Caronia, 703 F.3d at 153; Wash. Legal Found, v. Friedman, 13 F.Supp.2d 51, 56-58 (D.D.C. 1998) [hereinafter “Friedman”], amended, 36 F.Supp.2d 16 (D.D.C.1999), appeal dismissed, judgment vacated in part sub nom., Wash. Legal Found, v. Henney, 202 F.3d 331 (D.C.Cir.2000).

3. The FDA’s Prohibition on the Promotion of Drugs for Off-Label Use

Notwithstanding the potential benefits of off-label use of approved drugs, the FDA has long taken the position that a drug manufacturer who markets or promotes an approved drug for an unapproved use violates the FDCA. This position reflects an application of, rather than an explicit prohibition within, the FDCA; as the Second Circuit observed in Caronia: “The FDCA and its accompanying regulations do not expressly prohibit the ‘promotion’ or ‘marketing’ of drugs for off-label use.” 703 F.3d at 154.

Specifically, the FDA’s position is that a manufacturer who markets or promotes an offlabel drug risks criminal liability for “misbranding” under 21 U.S.C. § 331(a), which prohibits “[t]he introduction or delivery for introduction into interstate commerce of any food, drug, device, tobacco product, or cosmetic that is adulterated or misbranded.” Misbranding carries a term of up to one year imprisonment and a fine of up to $1,000 per occurrence, see 21 U.S.C. § 333(a)(1), but if the defendant either acted with “the intent to defraud or mislead” or is a repeat offender, a term of up to three years imprisonment and a fine of up to $10,000 is authorized, see id § 333(a)(2).

Under the statute, a drug is misbranded if its labeling does not contain “adequate directions for use.” Id. § 352(f). The FDA has defined “adequate directions for use” as “directions under which the lay[person] can use a drug safely.and for the purposes for which it is intended.” 21 C.F.R. § 201.5. It has defined “intended use” as “the objective intent of the persons legally responsible for the labeling of drugs”; “intended use” may be demonstrated by “oral or written statements by such persons or their representatives” and “the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised.” Id. § 201.128.

Among the materials that may serve as proof of a manufacturer’s intended use are promotional statements by the company or its representatives. See id. § 201.5. “Off-label promotional statements could thus presumably constitute evidence of an intended use of a drug that the FDA has not approved.” Caronia, 703 F.3d at 155 (cit: ing 21 C.F.R. § 201.5). FDA regulations state that a manufacturer that wishes to market or promote an approved drug for a new use (whether a new condition, dosage, or population) must submit.a “supplemental new drug application”; the drug must undergo new clinical trials to demonstrate its safety and effectiveness for the new use. 21 C.F.R. § 314.70; Friedman, 13 F.Supp.2d at 55. Until the FDA has approved the new use, the manufacturer may not promote the drug for that use. 21 C.F.R. § 314.70.

On the basis of these provisions, in recent years, federal prosecutors, in conjunction with the FDA, have actively pursued criminal misbranding charges against pharmaceutical companies and their sales representatives based on their promotion of approved drugs for non-approved purposes.

For example, in 2012, GlaxoSmithKline LLC (“GSK”) pled guilty in the District of Massachusetts to introducing two mis-branded drugs into interstate commerce, and paid a $1 billion fíne and forfeiture. One misbranding charge was based on GSK’s promotion of the drug Paxil for treating depression in patients under age 18; the FDA had not approved Paxil for pediatiic use. The other was based on GSK’s promotion of the drug Wellbutrin for weight loss, and to treat sexual dysfunction, substance addictions, and attention deficit hyperactivity disorder; the FDA had approved the drug only to treat major depressive disorder. In 2012, Abbott Laboratories Inc. (“Abbott Labs”) pled guilty in the Western District of Vir-

ginia to misbranding the drug Depakote, and paid a $500 million fine. The FDA had approved Depakote only for epileptic seizures, bipolar mania, and the prevention of migraines, but Abbott Labs had promoted it for other uses, including treating schizophrenia. And in 2010, Allergan Inc. (“Allergan”) pled guilty in the Northern District of Georgia to misbranding based on its off-label promotion of the therapeutic version of Botox, and paid a $375 million fíne. The FDA had approved Botox to treat crossed eyes, involuntary eyelid and neck muscle contraction, excessive underarm sweating, and adult upper-limb spasticity, but Allergan had promoted it for headache, pain, spasticity, and juvenile cerebral palsy. See also Caronia, 703 F.3d at 154 (listing examples of enforcement action); Kurtzberg Deck, Exs. 1-3 (same).

In instances where a manufacturer’s statements promoting a drug’s off-label use are untrue or misleading or may promote unsafe usage, the FDA has explained, such misbranding actions further public safety. There are many examples in which prescriptions of an approved drug for off-label use has caused harm. For example, Gabitril, a drug approved to treat partial seizures, was prescribed off-label to treat psychiatric conditions, but caused patients to suffer seizures and status epilep-ticus. And the off-label use of quinine for nocturnal leg cramps caused adverse reactions, including thrombocytopenia and gastrointestinal bleeding.

More broadly, the FDA has stated, its goal in pursuing misbranding charges against manufacturers based on the óff-label promotion of drugs is to encourage use of the FDA’s drug review and approval process. Such prosecutions, the FDA has stated, deter manufacturers from evading the FDA’s review process for additional uses of approved drugs.- For example, in announcing the settlement with Allergan regarding Botox, the FDA stated: “The FDA approval process ensures that pharmaceutical companies market their medications for uses that are proven to be safe and effective, and this case demonstrates that companies that fail to comply with these rules face criminal prosecution and stiff penalties.” And in describing its settlement with Abbott Labs regarding Depakote, the FDA stated that the settlement reflected the agency’s commitment to “hold[ing] pharmaceutical companies accountable for marketing practices that undermine the drug approval process.”

In addition to facing criminal exposure for misbranding, a drug manufacturer who promotes a drug for off-label use may face civil suit under the False Claims Act (“FCA”), 31 U.S.C. § -3729 et seq., on the theory that the company, in the course of its off-label promotion/caused false claims to be submitted to-government health care programs for non-covered and non-FDA-approved uses.’ In recent years, the Government has brought FCA claims on this theory, often in conjunction with criminal prosecutions' under the FDCA for mis-branding.

4. The FDA’s Regulations as to Manufacturers’ Marketing Materials and Responses to Inquiries Regarding Off-Label Usage

A final set of relevant FDA regulations are those relating to a manufacturer’s marketing materials. When a manufacturer applies for approval to market a new drug, it must submit to. the FDA “specimens of mailing pieces and any other labeling or advertising devised for promotion of the drug product at the time of initial dissemination of the labeling and at the time of. initial publication of the advertisement for a prescription drug product.” 21 C.F.R. § 314.81(B)(3)©; id. § 601.12(f)(4). Otherwise, the FDA generally does not require a manufacturer to seek preappro-val of materials- promoting a drug for an FDA-approved purpose.

The FDA does, however, encourage manufacturers to request advisory comments before a drug’s launch, with respect to promotional materials aimed at healthcare professionals. Such materials may include-sales or visual aids, advertisements in medical journals, and product websites. The FDA’s Office of Prescription Drug Promotion (the “OPDP”) reviews such materials to ensure, inter alia, that they are not false or misleading; it provides written comments on proposed materials, reviews complaints of alleged violations, and initiates enforcement actions as to materials it finds false or misleading. The OPDP also operates a “Bad Ad” program that receives reports of alleged violations of the FDA’s restrictions on promotion, including reports of-promotion of-a drug for .an unapproved use.

The FDA also has issued draft guidance as to how manufacturers should respond to unsolicited requests for off-label information about prescription drugs. ■'

If a- person makes a private unsolicited request for off-label information, the' manufacturer should disseminate information only to that person and tailored to answer only the requester’s specific question. The information disseminated must be truthful, non-misleading, accurate, and balanced. The FDA further recommends that responses to questions or requests for information about off-label usage be referred to ;the manufacturer’s medical or scientific representative or department, and that sales and marketing, personnel have.no input on the content of the manufacturer’s response. Manufacturers are required to maintain records of all such requests for information and of the information that was provided in response.

If a person makes a public unsolicited request for off-label information (for example, on an Internet forum), the FDA requires that the manufacturer'provide only its contact information, and not include any off-label information, even if it is truthful and non-misleading. The FDA advises the manufacturer to state that the question raised pertains to an unapproved use and that the individual can contact the manufacturer’s medical/scientifíc representative or medical affairs department with the specific unsolicited request to obtain more information.

5. The Decision in Caronia and the FDA’s Regulatory Response

Before Caronia, only limited First Amendment challenges to the FDA’s policies with respect to the off-label promotion of approved drugs had reached the courts, and none had challenged the FDA’s application of the misbranding provisions to truthful and non-misleading promotional statements.

Most notable of these First Amendment challenges was the 1998 decision in Friedman, supra. The plaintiff there, a public interest group, sought to enjoin as facially unconstitutional FDA policies (expressed in guidance documents) that had restricted manufacturers from distributing textbook excerpts and article reprints from medical and scientific journals to the extent they (1) addressed off-label uses of FDA-approved drugs and (2) were truthful and non-misleading. The district court rejected the FDA’s argument that these communications proposed an illegal transaction and thus were unprotected. 13 F.Supp.2d at 62-65; see Wash. Legal Found. v. Henney, 202 F.3d 331, 334 (D,C.Cir.2000). It-held that the communications were commercial speech and that the FDA’s restrictions were unconstitutional under the test for commercial speech of Central Hudson Gas & Electric Corp. v. Public Service Commission of New York, 447 U.S. 557, 100 S.Ct. 2343, 65 L.Ed.2d 341 (1980). Although recognizing .that the FDA’s policies advanced a substantial government interest in requiring manufacturers to submit supplemental applications for new drug uses, 13 F.Supp.2d at 70-73, the court held the FDA’s restrictions on such speech were more extensive than necessary, and thus breached the First Amendment, id., at 65-69, 72-74. It enjoined the FDA from prohibiting manufacturers from distributing the reprints and excerpts “regardless of whether such [materials] include[ ] a significant or exclusive focus” on off-label uses. Id. at 74-75. However, while the case was on appeal, the FDA adopted a much narrower construction of its guidance documents. This mooted the controversy and caused the injunction to be lifted.

The Second Circuit’s 2012 decision in Caronia addressed, for the first time, the interplay between the FDCA’s misbrand-ing provisions and the First Amendment. A drug manufacturer’s sales representative, Caronia, was caught on tape touting to doctors the drug Xyrem, which the FDA had approved to treat narcoleptic patients, for unapproved uses. Caronia was charged and convicted of conspiracy to misbrand based on his truthful statements regarding those off-label uses. Vacating the conviction, the Second Circuit held that a manufacturer’s speech promoting off-label use is constitutionally protected commercial speech, and that the First Amendment places limits on a misbrand-ing prosecution to the extent it is based on the truthful promotion of FDA-approved drugs for off-label use. Applying the principle of constitutional avoidance, the Circuit held that the FDCA’s misbranding provisions could not be construed “to criminalize the simple promotion of a drug’s off-label use by pharmaceutical manufacturers and their representatives because such a construction — and a conviction obtained under [this] application of the FDCA — would run afoul of the First Amendment.” 703 F.3d at 162. Thus, the Circuit held, “[t]he government cannot prosecute pharmaceutical manufacturers and their representatives under the FDCA for speech promoting the lawful, off-label use of an FDA-approved drug.” Id. at 169.

Later, the Court reviews Caronia in detail, see infra, pp. 224-29, because, unlike Amarin, and unlike much secondary commentary, the FDA reads that decision narrowly, and as turning on the particular circumstances of Caronia’s trial. The FDA thereby reads Caronia to preserve for the Government the ability to bring a misbranding action against a manufacturer or its representative where the conduct at issue consists solely of truthful and non-misleading speech promoting an off-label use of an approved drug. This reading of Caronia is reflected in the position the FDA has taken in this case.

In February 2014, the FDA responded to Caronia by issuing updated draft guidance as to the dissemination of scientific or medical journal articles. The FDA authorized manufacturers to distribute such articles relating to unapproved uses of drugs, under certain conditions. When a manufacturer distributes journal articles that include information on off-label uses of its drug, the FDA stated, it will not use the fact of such distribution as evidence of the manufacturer’s intent that the drug be used for an unapproved use, provided that the manufacturer makes certain disclosures with the articles. But, the FDA has stated, if a sales representative characterizes an article to suggest that a drug is safe or effective for an unapproved use, the agency may use such speech as evidence that the manufacturer intended to promote that use.

Separately, in June 2014, the FDA agreed, in response to a citizen petition, to conduct a “comprehensive review [of its] regulatory regime governing communications about medical products,” with the intent to issue, within a year, new guidance regarding such issues. As of this decision, no such guidance has issued. During this litigation, the FDA told Amarin that “new guidance will be forthcoming,” but at argument on July 7, 2015, the FDA declined to state what the status or timetable is with respect to such guidance. Tr. 73-74.

B. History of the FDA’s Review of Vascepa

1. Overview

Vascepa was developed by Amarin to improve cardiovascular health. It is composed of pure eicosapentaenoic acid (“EPA”), an omega-3 fatty acid. Amarin has sought FDA approval for two separate uses of Vascepa.

First, on September 25, 2011, Amarin sought, and on July 26, 2012, received, FDA approval to market Vascepa for treating adult patients with triglyceride levels above 500 mg/dL of blood (“severe hypertriglyceridemia,” or “very high triglycerides”). Persons with severe hyper-triglyceridemia have increased risk of pan-creatitis and cardiováscular disease. See Ketchum Deck, Ex. 1 (“FDA Approval Letter”), at 1 (approving new drug application for use of Vascepa “as an adjunct to diet to reduce triglyceride ... levels in adult patients with severe ... hypertrigly-ceridemia”); Ketchum Decl., Ex. 2 (“FDA-approved label for Vascepa”); see also Woodcock Letter, at 1-2. The FDA approved Vascepa based on a showing that Vascepa was effective in reducing very high triglyceride levels. FDA Approval Letter, at 1.

Second, Amarin has sought approval to market Vascepa for patients with triglyceride levels between 200 and 499 mg/dL of blood and who are already on statin' therapy (“persistently high triglycerides”). This second use is the off-label use at issue in this case. It is undisputed that Vascepa is effective in reducing such triglyceride levels, as reflected in an FDA-approved study (the “ANCHOR study”) of this point and as confirmed by ■ the FDA in correspondence with Amarin. It is also undisputed that Vascepa is safe, insofar as it is safely used for persons with severe hyper-triglyceridemia and, as discussed further below, the FDA has allowed a chemically similár dietary supplement to be sold to the public. The FDA, however, has denied Amarin’s application for approval of this second use because recent scientific studies have left it unclear whether reducing the triglyceride levels of persons with persistently high triglycerides reduces cardiovascular risk.

2. Clinical Trials of Vascepa for Patients with Persistently High Triglycerides

The following recaps the relevant histo-' ry of the FDA’s review of Vascepa for the second use — for patients with -persistently high triglyceride levels.

While completing the study that led to FDA approval of Vascepa for the treatment of patients with very high triglycerides -(the “MARINE” study), Amarin sought to examine the effect of Vascepa , in treating persistently high triglyceride levels. It did so pursuant to the FDA’s, “special protocol assessment,” or “SPA,” program. An SPA agreement is a written agreement that a manufacturer may enter into with the FDA, which sets out the design and size parameters for clinical trials of a new drug, and the conditions under which the -FDA would approve the drug. For the manufacturer, such an agreement minimizes development risk by providing regulatory predictability: Provided that the manufacturer follows the procedure set in the SPA agreement and the drug proves meets the benchmarks for effectiveness set in the agreement, the FDA must approve the drug. The FDA can rescind an SPA agreement only if “a substantial scientific issue essential to determining the safety or effectiveness of the drug has been identified after the testing has begun.”

Amarin’s SPA agreement with the FDA regarding Vascepa for the .second use was entered into on July 6, 2009. London Deck, Ex. B (“ANCHOR SPA Agreement”). The agreement set out the design of a clinical trial (the “ANCHOR study”) to test whether Vascepa was effective at lowering triglycerides in patients with persistently high triglyceride levels. ANCHOR SPA Agreement, at 1. The ANCHOR study was also designed to test the numerical effect of Vascepa on other lipid, lipoprotein, and inflammatory parameters relevant to cardiovascular health, such as non-HDL cholesterol. Id. Amarin also agreed to undertake a separate clinical study, aimed at testing whether Vascepa was effective in helping prevent major cardiovascular events in high-risk patients, including those with persistently high triglyceride levels. This study was called “REDUCE-IT.” The FDA required that Amarin enroll at least 50% of planned patients in the REDUCE-IT study before it would accept for review Amarin’s application for approval of Vascepa for patients with persistently high triglycerides under the ANCHOR SPA Agreement. This requirement was designed to ensure that the clinical study aimed at testing Vascepa’s effect on cardiovascular risk reduction was well underway before the FDA decided whether to approve the use of Vascepa in treating such patients.

Consistent with this, on August 5, 2011, while the ANCHOR test was ongoing, Amarin entered into another SPA agreement with the FDA, this one keyed to the REDUCE-IT study. See London Deck, Ex. E (“REDUCE-IT SPA Agreement”). The REDUCE-IT study is ongoing. It is expected to be completed by the end of 2017, with results to be available in 2018. Ketchum Deck ¶ 71.

The ANCHOR study achieved each numeric objective that the SPA Agreement had set: The results showed that Vascepa produced a statistically significant decrease in triglyceride levels in persons with persistently high triglycerides, as well as in other lipid, lipoprotein, and inflammatory biomarkers. Id. ,¶62; Christie M. Ballantyne et al., Efficacy and Safety of Eicosapentaenoic Acid Ethyl Ester (AMR101) Therapy in Statin-Treated Patients with Persistent High Triglycerides from the ANCHOR Study), 110 Am. J. of Cardiology 984, 985, 987 (2012) (reprinted in Ketchum Decl., Ex. 5).

On February 21, 2013, Amarin submitted a supplemental new drug application to the FDA, based on the ANCHOR trial results and the ANCHOR SPA Agreement. London Deck, Ex. H, at 1 (“Feb. 21, 2013 Amarin SNDA Letter”). Because Amarin had met all requirements for approval set out in the ANCHOR SPA Agreement, Amarin anticipated that the FDA would approve Vascepa for the additional use that Amarin sought, ie., by patients with persistently high triglycerides. Ketchum Deck ¶ 79.

However, on October 16, 2013, the FDA convened a public Advisory Committee regarding Vascepa to determine if reductions in triglyceride levels, as demonstrated in the ANCHOR study results, would reduce cardiovascular risk. Ketchum Deck, Ex. 109 (“10/16/13 Tr.”); see also Ketchum Deck, Ex. Ill (“FDA SPA Rescind Agreement Letter”). The FDA noted that three different clinical trials (the ACCORD-Lipid, AIM-HIGH, and HPS2-THRIVE studies) involving other manufacturers’ triglyceride-reducing drugs (which each used either fenofibrates or niacin) had found that the reduction of triglyceride levels, in patients with persistently high triglycerides had had no impact on the risk of cardiovascular events. Id. at 1. The FDA Advisory Committee concluded that although Amarin had satisfied the terms of the ANCHOR SPA Agreement and that Vascepa had reduced triglyceride levels in patients with persistently high triglycerides, there was “substantial uncertainty” whether reducing triglyceride levels would significantly , reduce the risk for cardiovascular events in such patients. Id. at 2.

On October 29, 2013, the FDA rescinded the ANCHOR SPA Agreement, finding that a “substantial scientific issue” had arisen as- to whether the - reduction of triglyceride levels alone established an effective reduction in overall cardiovascular risk in patients with persistently high triglyceride levels. Id. Amarin appealed the decision through three successive levels of FDA review. See London Decl., Ex. G (“April 22, 2014 FDA Appeal Denied Letter”); London Deck, Ex. K (“Sept. 11, 2014 FDA Appeal Denied Letter”).

3. The FDA’s April 27, 2015 Complete Response Letter

On April 27, 2015, the FDA issued its Complete Response Letter (“CRL”), a central document here. See London Deck, Ex. M. The FDA there acknowledged that the ANCHOR study had been carried out consistent with its specifications. It also acknowledged that Vascepa had significantly reduced triglyceride levels in patients with persistently high such levels, and had met the statistical “endpoints,” or goals, set in the ANCHOR study. The FDA noted that the “primary endpoint” of that study had been the percentage change in triglyceride levels during a 12-week period of usage by such statin-treated patients. It recognized that the patients in the study who had used Vascepa experienced a 21.5% “treatment difference” over those who had used a placebo (mineral oil), controlling for all other variables. Id. at 1.

However, the FDA refused to approve Amarin’s proposed new use for Vascepa to lower triglyceride levels among such patients. It explained that the “clinical rationale,” or premise, of the ANCHOR study had been that reducing triglyceride levels in that population would reduce the risk of cardiovascular events. But, the FDA stated, the results of the clinical trials involving other drugs that had also reduced triglyceride levels had yielded “insufficient data to support a drug-induced change in serum [triglycerides] as a surrogate for reducing [cardiovascular] risk in this population.” Id. at 2. These trials “failed to demonstrate any additional benefit” of such drugs, and although some later analy-ses had suggested that patients with high triglycerides may benefit from using such drugs, “this remains to be confirmed.” Id. The FDA added: “Given the current level of uncertainty regarding the benefits of drug-induced changes in lipid/lipoprotein parameters on [cardiovascular] risk among statin-treated patients with residually high [triglycerides], you will need to provide evidence that Vascepa reduces the risk of major adverse [cardiovascular] events in patients at high risk for cardiovascular disease.... We anticipate that the final results from the REDUCE-IT trial could be submitted to satisfy this deficiency.” Id. at 2. Accordingly, the FDA stated, before it would approve Vascepa for use in patients with persistently high triglycerides, Amarin would need to supply evidence, such as from the ongoing REDUCE-IT study, that the drug reduces the risk of cardiovascular events. Id.

The FDA also refused to approve Ama-rin’s request to include the ANCHOR results in the Vascepa label. It “reserve[d] comment until .the application is otherwise adequate.” Id.

In the penultimate sentence of the CRL, the FDA stated: “This product [Vascepa] may be considered to be misbranded under the [FDCA] if it is marketed with this change before approval of this supplemental application.” Id. at 4. The CRL did not elaborate on this point.

C. This Litigation

1. The Complaint

On May 7, 2015, 10 days after receiving the CRL, Amarin and the doctor plaintiffs filed the Complaint. Dkt. 1 (“Compl.”). It brought an as-applied First Amendment challenge to FDA regulations that prohibit Amarin “from making completely truthful and non-misleading statements about its product to sophisticated healthcare professionals,” including the doctor plaintiffs. Compl. ¶ 1.

Specifically, the Complaint alleged that Amarin wishes to make truthful statements to healthcare professionals (hereinafter, “doctors”) regarding Vasce-pa, including that the ANCHOR study demonstrates that Vascepa significantly reduces triglyceride levels in patients with persistently high triglyceride levels. But, it alleged, Amarin is inhibited from doing so by the FDA’s threat, articulated in the CRL, to bring a misbranding action based on-such off-label promotion.

The Complaint alleged that doctors desire and may act on this information: “[D]octors across America” commonly prescribe drugs to treat “patients at risk for cardiovascular disease and who have persistently high triglyceride levels in their blood (i.e., high despite statin therapy) to lower those patients’ triglycerides and/or non-HDL cholesterol.” Id. ¶2. Prescribing such drugs “is a medically-accepted practice supported by numerous national and international cardiovascular treatment guidelines and position statements”; doctors do so “because, in their medical judgment, drug therapy is the best course of treatment for these patients.” Id. (footnote citing treatment guidelines and position statements omitted). Moreover, doctors prescribe such drugs “even though there is not yet definitive clinical evidence affirmatively demonstrating that lowering triglyceride levels and/or non-HDL cholesterol levels in such patients ultimately reduces cardiovascular risk.” Id. ¶ 6. Such doctors, the Complaint alleged, “need truthful and non-misleading information about these drugs to make informed decisions about what is best for their patients,” but the “[FDA]’s current regime for regulating the flow of ‘off-label’ information to doctors about prescription drugs ... severely restricts medical professionals’ access to information from the source most knowledgeable about the drugs: the drug manufacturers — in this case, Amarin.” Id. ¶ 3.

As to Vascepa specifically, the Complaint stated, the FDA does not dispute that an FDA-approved “double-blind, placebo-controlled trial” — the ANCHOR study — had “demonstrated] that Vascepa reduces triglyceride levels and has other favorable effects in adult patients with persistently high triglycerides.” Id. ¶ 7. But, it allegéd, because the FDA had refused to approve Vascepa for use in treating this patient population, “Amarin now finds itself in a bind”: ■

Using pharmaceuticals like Vascepa in the treatment of patients with persistently high, triglycerides is commonplace in medical practice. However, because FDA has refused to approve Vascepa for patients with persistently high triglycerides, Amarin may not communicate truthful and non-misleading information about Vascepa to healthcare professionals such as the Doctor Plaintiffs without fear of criminal prosecution and civil liability. -That is because FDA regulations forbid promotion of drugs for unapproved or “off-label” uses, even if such promotion is entirely truthful and presented in a non-misleading manner— FDA’s treatment of Vascepa therefore operates to keep doctors, such as the Doctor Plaintiffs, and consequently their patients, in the dark about all of the options for drug therapy they are legally empowered to prescribe to treat persistently high triglyceride levels.”

Id. ¶¶ 8-9.

Separately, the Complaint alleged, the .FDA’s restrictions on off-label promotion of Vascepa harm Amarin because the FDA had — until recently — “permitted manufacturers of other triglyceride-lowering drugs, such as fenofibrates, niacin, and another omega-3 fatty acid-based drug, to market their drugs for treatment of persistently high triglycerides.” Id. ¶ 9. Amarin, however, is prohibited from communicating to doctors information about Vascepa, a “treatment alternative.” Id. Further, the. Complaint alleged, the FDA’s ban on off-label promotion of Vascepa prevented it from making the same “qualified health claim” that the FDA, for more than a decade, has allowed manufacturers of dietary supplements containing a chemically identical omega-3 fatty acid to make to consumers: “Supportive but not conclusive research shows that consumption of ÉPA and DHA omega-3 fatty acids may reduce the risk of coronary artery disease.” Id. ¶ Í1. ’ This, the Complaint alleged, has led doctors “to advise their patients to take omega-3 dietary supplements instead of pharmaceuticals like Vascepa,” Id. ¶ 116.

The Complaint therefore sought relief recognizing that the “FDA’s prohibitions on ‘offlabel’ promotion, as applied to truthful and .non-misleading speech Amarin wishes to make,” are unconstitutional under the. First Amendment, and that Ama-rin may engage in truthful and non-misleading speech to doctors about Vascepa free from the risk of criminal prosecution even if such speech constitutes off-label promotion. Id. ¶ 14. Such, a holding, the Complaint stated, “falls squarely within Second Circuit precedent.” Id. (citing Ca-ronia).

The Complaint sought protection for Amarin’s speech both at a general and a statement'specificlevel. As to the former, Amarin sought relief confirming that, free from the threat of a misbranding action, it may engage in truthful and non-misleading speech with doctors intended to promote Vascepa for off-label use, and that its right to engage iri such speech includes the right to initiate discussions on that subject and to engage in a dialogue with doctors about it. See, e.g., CompL ¶¶ 17, 19. As to the latter, Amarin sought a ruling permitting it to make to doctors, free from the threat of such an action, specific “carefully-circumscribed, truthful, and scientifically-ac-eurate statements,” Id. ¶ 15, each drawn from either the ANCHOR study, the CRL letter, or other FDA-approved language. The three specific statements for which Amarin sought such comfort were:

Statement' # 1: “Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease.”

•Statement #%: “The ANCHOR study demonstrates that Vascepa lowers triglyceride levels in patients with high triglyceride levels not controlled by diet and statin therapy.”

•Statement #S: “In the ANCHOR study, .Vascepa 4g/day significantly reduced TG [triglycerides], non-HDL-C [non-high density lipoprotein cholesterol or non~“good cholesterol”], Apo B [Apóiipoproteiñ B], VLDLC [very-low-density lipoprotein cholesterol], TC [total cholesterol] and HDL-C [high density lipoprotein cholesterol or “good cholésterol”] levels from baseline relative to placebo in patients with high (>200 mg/dL and <500 mg/dL) triglyceride levels not controlled by diet and statin therapy. The reduction in TG [triglycerides] observed with Vascepa was not associated with elevations in LDL-C [low-density lipoprotein cholesterol or “bad cholesterol”] relative to placebo.”

Id. ¶ 124.

The Complaint also sought a ruling that Amarin, free of the threat of a misbrand-ing action, may provide doctors with:

13 specifically identified peer-reviewed scientific publications relating to the potential effect of EPA on the reduction of the risk of coronary heart disease, see id., Ex. A (listing these publications), and

written summary of the ANCHOR study; including a chart reporting efficacy data from that study, see id., Ex. B (containing this summary).

Id. ¶ 124. The Court has appended Ama-rin’s Exhibits A and B to this decision.

Finally, to assure that its statements were not misleading, Amarin proposed to contemporaneously make the following five disclosures to doctors:

Amarin Disclosure # 1: “FDA has not approved Vascepa to reduce the risk of coronary heart disease.”

Amarán Disclosure # 2: “FDA has not approved Vascepa for the treatment of statin-treated patients with mixed dys-lipidemia and high (> 200 mg/dL and < 500 mg/dL) triglyceride levels.”

Amann Disclosure # 3: “The effect of Vascepa on the risk of cardiovascular mortality and morbidity has not been determined.”

Amann Disclosure # I: “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

• Amann Disclosure # 5: “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.”

Id. Without such relief, the Complaint alleged, Amarin and its employees have a “real” fear of criminal prosecution if they engage in truthful off-label promotion of Vascepa, including•,because the Govern-' ment has announced its intent “ ‘to pursue aggressively’ alleged incidents of ‘off-label’ promotion.” Id. ¶¶ 164-66 (reviewing prosecutions, enforcement actions, and FDA statements regarding off-label promotion).

2. Amarin’s Motion for Preliminary Relief

On May 22, 2015, Amarin moved for preliminary relief, tracking that sought in the Complaint. It sought an injunction that would prohibit the FDA from bringing a misbranding action against Amarin for its truthful and non-misleading statements to doctors regarding Vascepa, including the statements !set out in the Complaint. See Dkt. 5 (motion); Dkt. 13 (supporting brief) (“Amarin Br.”). Ama-rin later confirmed that, as an alternative to an injunction blocking enforcement action, effective relief could take the form of a declaration to the effect that the communications it intended were' protected against a misbranding action. Tr. 14-15.

Amarin moved primarily under the First Amendment, but alternatively, under the due process clause, on the ground that the FDA’s regulations as to misbranding were vague and did not “fairly notify Amarin of what off-label promotion is permitted and what is forbidden.” Amarin Br. 3^4. Amarin separately sought protection from civil claims under the FCA, on the premise that the Government might seek to hold Amarin liable if doctors submitted false claims securing reimbursement in connection with Vascepa prescriptions.

3. The FDA’s Response— the Woodcock Letter

Before filing the Complaint, Amarin had not previewed to the FDA the communications about Yascepa that it sought to make. In a June 5, 2015 letter by Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, the FDA set out its position. See Dkt. 24, Ex. A (“Woodcock Letter”). The Woodcock Letter narrowed the parties’ dispute as to some of Amarin’s proposed communications, including by noting that some “fall within the scope” of existing FDA guidance allowing manufacturers to disseminate to doctors “truthful and non-misleading scientific or medical publications on unapproved new uses.” Id. at 5. The Woodcock Letter further attempted to moot the dispute altogether by proposing defined conditions under which Amarin could communicate certain of the information in question to doctors, and under which the FDA would then agree not to bring a misbranding action. Id. at 1. The Woodcock Letter added that the FDA was “engaged in a comprehensive review of its regulations and guidance documents regarding manufacturers’ dissemination of information regarding their medical products, and new guidance will be forthcoming.” Id. at 5-6.

The Woodcock Letter set out the conditions on which the FDA would acquiesce to certain statements Amarin proposed to make. See id. at 6 (if Amarin made its statements “in the manner and to the extent described,” FDA would not “object to Amarin’s proposed communications.”). The letter clustered these statements as follows:

a. Distribution of results of the ANCHOR study: As to Amarin’s desire to give doctors the ANCHOR study’s results, the FDA stated, it would not object to Amarin’s giving truthful and non-misleading summaries. The FDA stated that it “would not necessarily have agreed to in-elude [the summary Amarin attached to its Complaint as Exhibit B] in its entirety in FDA-approved labeling if the indication had been approved.” Id. But, the FDA stated, it would not consider that summary false or misleading, or as evidence of intended off-label promotion, “as long as the distribution of Exhibit B is accompanied with” five specified disclosures “and is disseminated in the manner summarized below.” Id.

Two of the five disclosures upon which the FDA insisted were Amarin’s Disclosures # 1 and # 3. The other three the FDA sought were:

•FDA Disclosure # 1: “Any potential financial or affiliation biases between the firm and those who conducted the ANCHOR study.”

•FDA Disclosure #2: “Vascepa is not approved for the treatment of statin-treated patients with mixed dyslipide-mia and high (> 200 mg/dL and < 500 mg/dL) triglyceride levels. 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”; and

• FDA Disclosure # 3: “Recent cardiovascular outcome trials (ACCORD-Lipid, AIM-HIGH, and HPS2-THRIVE) each failed to demonstrate incremental cardiovascular benefit of adding a second lipid-altering drug (fenofibrate or formulations of niacin), despite reducing triglyceride levels, among statin-treated patients with well-controlled low-density lipoprotein-cholesterol.”

Id. at 7. FDA Disclosure # 2 thus expanded upon Amarin Disclosure # 3; FDA Disclosures # 1 and # 3 were new. The FDA also asked that, “[t]o further protect against misleading the audience,” Amarin provide copies of the current FDA-approved labeling and, when distributing a summary of the ANCHOR study, a reprint of a particular journal article. Id. And it asked that Amarin distribute “such information in educational or scientific settings, and not including such information with or attached to promotional or marketing materials,” and “by persons with the appropriate background or training to accurately communicate this scientific information.” Id. (emphasis added).

Finally, to the extent Amarin chose to provide a summary different from its Exhibit B, the FDA stated that would not find it false or misleading on the conditions that:

the summary remains factual, does not omit material information, and does not otherwise introduce bias. In particular, the communication could be misleading if it implied or suggested that the ANCHOR study supports the conclusion that lowering triglyceride levels lowers the risk of [cardiovascular disease] in patients already treated with statins or that available evidence establishes that there is a clinical benefit in lowering [triglyceride] levels for patients with high [triglyceride] levels. We also believe that to avoid being misleading any summary would show not only the differences between Vascepa and the mineral oil placebo, but also the changes from baseline to endpoint in each of the treatment groups, as you have done in Exhibit B.

Id. at 6-7.

b. Distribution of additional reprints:

Amarin, the FDA noted, sought to distribute 13 scientific publications regarding “the potential effect of EPA on the reduction of the risk of coronary heart disease.” Id. at 8 (citing Compl., Ex. A). The FDA stated that such publications were covered by its existing guidance, and that it would not object to their distribution as long as they were accompanied with the same disclosures and were disseminated in the same manner as the ANCHOR study summary. Id.-

c. Coronary heart disease claim: In its Statement # 1, Amarin sought to make, to doctors, the same claim regarding coronary heart disease that the FDA has permitted food and dietary supplement manufacturers to make directly to consumers on the labels of chemically similar omega-3 fatty acids. Woodcock Letter, at 8. The FDA, however, objected to Amarin’s making that statement in connection with Vascepa. Doing, so “would be potentially harmful to the public health, and [the] FDA would consider such conduct to be potentially misleading or potential evidence of intended use.” Id. at 10 (emphasis added). The coronary heart disease claim, the FDA stated, could cause a physician to prescribe Vascepa in lieu of promoting healthy dietary and lifestyle changes or prescribing statin therapy. Id. However, the FDA stated, if Amarin repackaged Vascepa as a dietary supplement, the FDA would not object to including the coronary heart disease claim, on certain conditions. Id. The FDA distinguished the context of dietary supplements because a lesser showing is required for health claims on supplement labeling products than on drug labéling. Id. at 9. The higher standard for drug labeling, the FDA stated, furthers the public interest, by:

(1) creating incentives to develop robust scientific data regarding the safety and efficacy of a drug for a particular use; (2) requiring review of those data before the marketing of the product for that use to prevent harm to patients, and to ensure that healthcare providers have a sound basis for making treatment decisions before the use is widespread; (3) providing for the review of safety and efficacy data by an independent body to ensure that claims are appropriate supported; (4) requiring the development of labeling that provides information necessary for- the safe and effective use of the product; and (5) preventing firms from misleadingly marketing their products.

Id. at 9-10.

4. The FDA’s Opposition to Preliminary Relief

On June 23, 2015, the FDA filed its brief opposing preliminary relief. Dkt. 51 (“FDA Br.”).' It first argued that, if that Amarin accepted the conditions that the FDA had set out in the Woodcock Letter, the controversy would be moot. So long as Amarin took “the reasonable steps outlined in the Letter” regarding the substance and manner of distribution of the ANCHOR summary study and associated reprints, the FDA stated, these would not be bases for an enforcement action. Id. at' 15. And if Amarin also agreed not to make the coronary heart disease claim, the FDA stated, there would no longer be a “credible threat of prosecution.” Id. at 16-17.

If Amarin did not modify the statements it proposed to make to doctors, however, the FDA opposed granting preliminary relief. Amarin’s plan to make proactive statements to doctors regarding an off-label use of Vascepa, the FDA stated, was, a “frontal assault ... on the framework for new drug approval that Congress created in 1962,” Id. af 1. Amarin was seeking “to distribute its drug Vascepa under circumstances which could establish that Amarin intends an unapproved new use for Vascepa, ie., a use for which FDA has not determined the drug is safe and effective.” Id. And, , the FDA argued, were it to bring a misbranding claim against Amarin based on its promotional statements, this would not “prohibit speech.” Id. at 2. Caronia, the FDA explained, did not block the FDA from using speech as evidence of a manufacturer’s intent in a prosecution for mis-branding. Id. at 3.

5. Amarin’s Reply

On June 30, 2015, Amarin replied. Dkt. 67 (“Amarin Reply Br.”). Amarin declined the FDA’s proposal to moot the controversy. Although it agreed to some disclosures urged by the FDA, Amarin declined to adopt others, or to accept the FDA’s limits on the manner by which Amarin distributed summaries and reprints and communicated with doctors. See Ketchum Reply Decl. ¶¶ 12-13. Amarin asserted the right to “engage in a full and truthful dialogue with healthcare professionals” aimed at promoting the off-label use of Vascepa, Amarin Reply Br, at 2 (citing Compl. ¶ 93). The FDA’s threat to bring a misbranding prosecution based on its truthful and non-misleading statements to doctors, Amarin stated, was an attempt to “refight old, lost battles.” Id. at 3.

As -to specific statements regarding Vascepa, Amarin accepted FDA Disclosure # 1, but resisted FDA Disclosures # 2 and # 3 because these “convey a one-sided and misleading view of the -evidence.” Ketchum Reply Decl. ¶ 13. If' the Court determined that additional disclosures along these lines were necessary, Amarin argued, their text should be modified as follows (the underlined text denotes Amarin’s proposed additions):

•FDA Disclosure #2: Numerous national and international treatment guidelines and position statements recommend drug therapy as an adjunct to healthy dietary and lifestyle changes and statin therapy for patients at risk for cardiovascular disease and who have persistently high triglyceride levels in their blood (i.e., high despite statin therapy) to lower those patients’ triglycerides and/or non-HDL cholesterol. 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 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.

•FDA Disclosure #3: Recent cardiovascular outcomes trials (ACCORDLi-pid, AIM-HIGH, and HPS2-THRIVE), while not designed to test the effect of lowering triglyceride levels in patients vAth high triglyceride levels after statin therapy, each failed to demonstrate incremental cardiovascular benefit of adding a second lipid-altering drug (fenofibrate or formulations of niacin), despite raising high-density lipoprotein cholesterol and reducing triglyceride levels, among sta-tin-treated patients with well-controlled low-density lipoproteincholesterol.

Id. ¶¶ 22, 25.

Finally, as to the coronary heart disease claim drawn from the dietary supplement labeling, Amarin argued that it should be permitted to use the same text. It argued that, if any change were held necessary to make the claim non-misleading, it consist of adding a sentence (underlined below):

“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. ”

7<7¶31.

6. Argument

On July 7,2015, the Court heard lengthy argument on Amarin’s application for preliminary relief. See Dkt. 70 (“Tr.”). The argument highlighted -the parties’ disagreement as to' the FDA’s latitude, after Caronia, to bring misbranding actions based on truthful statements promoting the off-label use of FDA-approved drugs. Argument also focused on the specific statements Amarin has proposed to make to doctors about Vascepa. ' The Court draws upon these arguments as relevant in the ensuing discussion.

II, Discussion

A. Overview

Amarin argues that the FDA’s threat to bring misbranding charges against it if it makes truthful statements promoting the off-label use of Vascep