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 misbranding 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 employees) 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 misbranding action. For the reasons that follow, the Court grants such relief.
Amarin is a biopharmaceutical company incorporated in Delaware and based in New Jersey. Compl. ¶ 24. It and four medical doctors resident in New York
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 Vascepa 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 Amarin's application for preliminary relief.
Before 1938, drug manufacturers could market drugs without premarket approval for safety or effectiveness.
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.
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).
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).
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 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.
The FDA itself has long recognized the benefits of using prescription drugs for off-label purposes. As early as 1982, the FDA stated that:
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."
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).
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 (citing 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
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 misbranded drugs into interstate commerce, and paid a $1 billion fine 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 pediatric 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 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 epilepticus.
More broadly, the 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. 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."
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.
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)(i); id. § 601.12(f)(4). Otherwise, the FDA generally does not require a manufacturer to seek preapproval of materials promoting a drug for an FDA-approved purpose.
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
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.
Later, the Court reviews Caronia in detail, see infra, pp. 224-29, because, unlike Amarin, and unlike much secondary commentary,
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.
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.
Vascepa was developed by Amarin to improve cardiovascular health. It is composed of pure eicosapentaenoic acid ("EPA"), an omega-3 fatty acid.
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 hypertriglyceridemia have increased risk of pancreatitis and cardiovascular disease. See Ketchum Decl., 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 ... hypertriglyceridemia"); 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 hypertriglyceridemia and, as discussed further below, the FDA has allowed a chemically similar 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.
The following recaps the relevant history 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.
Amarin's SPA agreement with the FDA regarding Vascepa for the second use was entered into on July 6, 2009. London Decl., 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.
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 Decl., 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 Decl. ¶ 71.
The ANCHOR study achieved each numeric objective that the SPA Agreement
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.
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 Decl., Ex. 109 ("10/16/13 Tr."); see also Ketchum Decl., Ex. 111 ("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)
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 Decl., Ex. K ("Sept. 11, 2014 FDA Appeal Denied Letter").
On April 27, 2015, the FDA issued its Complete Response Letter ("CRL"), a central document here. See London Decl., 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
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 analyses 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 Amarin'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.
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 Vascepa, 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
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 "demonstrat[ed] that Vascepa reduces triglyceride levels and has other favorable effects in adult patients with persistently high triglycerides." Id. ¶ 7. But, it alleged, because the FDA had refused to approve Vascepa for use in treating this patient population, "Amarin now finds itself in a bind":
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
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 Amarin 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 Caronia).
The Complaint sought protection for Amarin's speech both at a general and a statement specific level. 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 in 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-accurate 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
Id. ¶ 124.
The Complaint also sought a ruling that Amarin, free of the threat of a misbranding action, may provide doctors with:
Id. ¶ 124. The Court has appended Amarin'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:
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 Government 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).
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."). Amarin 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.
Before filing the Complaint, Amarin had not previewed to the FDA the communications
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 include [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:
Id. at 7. FDA Disclosure #2 thus expanded upon Amarin Disclosure #3; FDA Disclosures #1 and #3 were new.
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:
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 labeling. Id. at 9. The higher standard for drug labeling, the FDA stated, furthers the public interest, by:
Id. at 9-10.
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 out-lined 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. at 1. Amarin was seeking "to distribute its drug Vascepa under circumstances which could establish that Amarin intends an unapproved new use for Vascepa, i.e., 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 misbranding. Id. at 3.
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):
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):
Id. ¶ 31.
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.
Amarin argues that the FDA's threat to bring misbranding charges against it if it makes truthful statements promoting the off-label use of Vascepa is chilling it from engaging in, and preventing doctors from receiving, constitutionally protected speech. Amarin argues that under Caronia, a misbranding action cannot be brought against a manufacturer for conduct that consists solely of truthful and non-misleading speech. Amarin argues that either a preliminary injunction against enforcement action, or declaratory relief recognizing its First Amendment rights, is necessary to eliminate that chill.
In considering Amarin's application, the Court is guided by familiar standards. Amarin must establish that (1) it is likely to succeed on the merits, (2) it is likely to suffer irreparable harm absent preliminary relief, (3) the balance of equities tips in its favor, and (4) preliminary relief is in the
The parties' dispute centers on the first factor — the likelihood of success on the merits. The merits issue here — whether a misbranding action can be brought against Amarin for the speech it proposes, or whether the FDA's threat of such an action burdens protected speech — raises general and specific questions. At a general level, the parties disagree whether, under Caronia, a misbranding action can be brought against a manufacturer whose conduct consists solely of truthful and non-misleading speech to promote off-label use of an approved drug, and whether Caronia protects a manufacturer's proactive promotional speech. At a specific level, although the parties have narrowed their differences, they disagree about whether certain statements Amarin proposes to make are, in fact, truthful and non-misleading so as to be constitutionally protected.
The Court addresses the likelihood of success on the merits after first considering, and rejecting, the FDA's threshold argument that this case does not present a case or controversy. After considering the merits, the Court addresses the remaining preliminary relief factors.
At the threshold, a court "must be sure that there is a justiciable case or controversy under Article III." Holder v. Humanitarian Law Project, 561 U.S. 1, 15, 130 S.Ct. 2705, 177 L.Ed.2d 355 (2010). The plaintiff must show that "the `conflicting contentions of the parties ... present a real, substantial controversy between parties having adverse legal interests, a dispute definite and concrete, not hypothetical or abstract.'" Babbitt v. United Farm Workers Nat'l Union, 442 U.S. 289, 298, 99 S.Ct. 2301, 60 L.Ed.2d 895 (1979) (citation omitted). "One aspect of this limitation is the requirement that the plaintiff have standing to sue," Hedges v. Obama, 724 F.3d 170, 188 (2d Cir.2013), which requires a claim that:
Id. (quoting Rothstein v. UBS AG, 708 F.3d 82, 91 (2d Cir.2013)).
In the context of a pre-enforcement challenge on constitutional grounds, a plaintiff "must demonstrate a genuine threat that the alleged unconstitutional law is about to be enforced against him." Brache v. Westchester Cty., 658 F.2d 47, 51 (2d Cir.1981); see also Babbitt, 442 U.S. at 298, 99 S.Ct. 2301 (challenge proper when "plaintiff has alleged an intention to engage in a course of conduct arguably affected with a constitutional interest, but proscribed by a statute, and there exists a credible threat of prosecution thereunder"). In First Amendment cases, such challenges are assessed "under somewhat relaxed standing and ripeness rules." Nat'l Org. for Marriage, Inc. v. Walsh, 714 F.3d 682, 689 (2d Cir.2013). A plaintiff must still allege "something more than an abstract, subjective fear that his rights are chilled," but "a real and imminent fear of such chilling is enough." Id. Standing thus has been found where no enforcement
Amarin clearly has standing to challenge the FDA's threat to bring a misbranding action against it if it promotes Vascepa for an off-label use. "[S]tanding is to be determined as of the commencement of suit." Fenstermaker v. Obama, 354 Fed.Appx. 452, 455 n. 1 (2d Cir.2009) (summary order) (quoting Lujan v. Defenders of Wildlife, 504 U.S. 555, 571 n. 5, 112 S.Ct. 2130, 119 L.Ed.2d 351 (1992)); see also Comer v. Cisneros, 37 F.3d 775, 791 (2d Cir.1994). Here, 10 days before Amarin filed suit, the FDA had expressly threatened in the CRL to bring a misbranding action against it for promoting Vascepa off-label, i.e., if Amarin marketed Vascepa for persons with persistently high triglycerides without approval of that use. CRL, at 4. Particularly given the recent history of misbranding prosecutions against manufacturers based on the same legal theory, this threat gave Amarin a solid and real basis to fear such enforcement action. See Walsh, 714 F.3d at 689; see also Compl. ¶¶ 145-154 (alleging that FDA's threat to bring misbranding charges will, absent relief, chill Amarin from engaging in protected speech with doctors about off-label use of Vascepa); id. 163-64 (recounting history of prosecutions of off-label promotion, and FDA's public statement of intent to continue "to pursue aggressively" off-label promotion).
The FDA argues that the Woodcock Letter largely mooted this controversy, in that the FDA stated there that it did not object to Amarin's dissemination of certain information and would not base an enforcement action on such dissemination. FDA Br. 15-16. But although the Woodcock Letter removed some of Amarin's proposed communications to doctors as potential subjects of enforcement action, it left others in play.
Specifically, the FDA preserved the threat to bring misbranding charges against Amarin for its truthful speech regarding Vascepa in three sets of circumstances. The first is if Amarin distributed summaries and reprints of the ANCHOR study in a manner or format other than that specified by the FDA. Amarin, however, resists these limitations.
In sum, because Amarin did not accept the conditions set in the Woodcock Letter, that letter did not vitiate the CRL's threat of a misbranding action against Amarin or moot this controversy. See Doe v. U.S. Civil Serv. Comm'n, 483 F.Supp. 539, 555 (S.D.N.Y.1980) (rejecting defendants' claim of mootness "because their proposed settlement offer does not remove all `live issues' present in the case"); Doe v. Harris, 696 F.2d 109, 114 (D.C.Cir.1982) (similar). Fairly read, the Woodcock Letter sharpened for Amarin the circumstances under which the FDA reserved the right to bring a misbranding action. It thereby narrowed the range of communications with respect to which Amarin is exposed to the risk of such an action. But it did not eliminate that risk, by any means. Because Amarin faces a non-extinguished threat of a misbranding prosecution for speech it proposes to undertake as to Vascepa, there remains a live case or controversy.
Amarin makes two arguments — one broad, one narrow — why the FDA's threat to bring a misbranding action against it for truthful statements promoting the off-label use of Vascepa impermissibly burdens its First Amendment rights, such that its lawsuit seeking relief from this threat is substantially likely to prevail on the merits.
First, Amarin contends, the FDA is wrong to assert the authority to bring a misbranding action against a manufacturer based solely on truthful and non-misleading statements promoting an off-label use.
Second, more narrowly, Amarin contends, the specific statements it proposes to make about Vascepa are truthful and non-misleading, so as to be protected under Caronia. These statements, Amarin notes, all derive from the FDA-approved ANCHOR study or writings by (or approved by) the FDA. Amarin argues that the FDA is wrongly disputing that these statements are truthful and non-misleading.
The Court addresses these issues in turn.
In the CRL, the FDA first raised the prospect of a misbranding action against Amarin. But the CRL was unspecific as to the conduct on which the FDA might base such an action. The FDA stated only that that it might consider Vascepa misbranded if "it is marketed" for use by persons with persistently high triglycerides before the FDA had approved such use. From this, Amarin inferred that the FDA was threatening to bring a misbranding action based solely on truthful and non-misleading speech in which Amarin might engage that promoted this off-label use, e.g., statements reporting the results of the ANCHOR study.
In opposing preliminary relief, the FDA has now confirmed that Amarin's inference was correct. The FDA's brief, and its responses to the Court's questions at argument, clarify that the FDA is reserving the right to bring a misbranding action against Amarin where the only conduct on which that action would be based are truthful and non-misleading statements promoting this off-label use. In particular, the FDA took the position that, in such an action, it could establish the intent (mens rea) and act (actus reus) elements of misbranding as follows:
It is the FDA's position on the act requirement that raises First Amendment issues under Caronia. At argument, the Court questioned the FDA whether its position as to that requirement is consistent with Caronia; the Court stated that it, like Amarin, had read Caronia otherwise. The FDA responded that it views Caronia as a fact-bound decision that
The following exchange was indicative:
Tr. 54-55. Reinforcing the point, the FDA at argument likened misbranding actions based on the promotion of off-label use to other areas of law in which criminal liability can, consistent with the First Amendment, be based on speech alone. Tr. 57. Other crimes where "the speech is the act," the FDA stated, include jury tampering, insider trading, and blackmail. Id.; see also Tr. 83 ("There are cases in which it's just speech as is often the case when speech is an element of the crime").
In light of the parties' conflicting readings of Caronia and the FDA's position that it may bring a misbranding action against a manufacturer based solely on truthful and non-misleading speech evincing the intent to promote an off-label use, the Court has closely reviewed Caronia. The Court'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. A fair reading of that decision refutes the FDA's view that the Second Circuit's ruling was limited to the facts of Caronia's particular case. To be sure, the Circuit closely reviewed the record of Caronia's trial — in particular, the jury instructions and the government's closing argument. But the Circuit did so to isolate the acts upon which Caronia's conviction had rested — specifically to determine whether Caronia's speech had "served merely as `evidence of intent'" or whether Caronia had been "prosecuted for his speech." 703 F.3d at 160. The Circuit found the latter, holding that the record revealed that "the government did prosecute Caronia for his speech." Id. at 162. As the Circuit put the point: "[T]he proscribed conduct for which Caronia was prosecuted was precisely his speech in aid of pharmaceutical marketing." Id.
The issue, the Second Circuit stated, was whether, consistent with the First Amendment, a misbranding prosecution
The Second Circuit's thoroughgoing First Amendment analysis in Caronia, which led it to construe the FDCA's misbranding provisions so as not to reach truthful speech promoting offlabel use, further defeats the FDA's attempt to marginalize the holding in that case as fact-bound. The Circuit cast the issue as whether a misbranding prosecution that "identified [a defendant's] speech alone as the proscribed conduct" is constitutionally permissible. Id. And the Circuit's ensuing analysis underscored the categorical, rather than case-specific, nature of its holding that it is not.
The Second Circuit first noted that "`[s]peech in aid of pharmaceutical marketing... is a form of expression protected by the ... First Amendment,'" id. at 163 (quoting Sorrell v. IMS Health, Inc., ___ U.S. ___, 131 S.Ct. 2653, 2659, 180 L.Ed.2d 544 (2011)). It then applied to such speech truthfully promoting off-label drug use the four-prong test of Central Hudson, used to determine a restriction upon commercial speech violates the First Amendment. 703 F.3d at 164-69.
As to the first Central Hudson prong, the Second Circuit stated, promoting off-label drug use concerns "lawful activity" (off-label drug use) and "the promotion of off-label drug use is not in and of itself false or misleading." Id. at 165-66. As to the second prong, the Circuit stated, the Government's asserted interests — "preserving the effectiveness and integrity of the FDCA's drug approval process" and "reducing patient exposure to unsafe and ineffective drugs" — are substantial. Id. at 166. As to the third prong, which requires that a regulation directly and to a material degree advance the interest asserted, id. at 164, the Circuit found it not met. Construing the FDCA to prohibit truthful off-label promotion, the Circuit held, does not directly advance the asserted government interests — because off-label use of approved drugs is lawful, because the FDA's drug approval process itself contemplates such off-label use, and because "prohibiting the truthful promotion of off-label drug usage by a particular class of speakers" would not directly enhance "the FDA's approval process [or] reduc[e] patient exposure to unsafe and ineffective drugs." Id. at 166. On the contrary, penalizing truthful statements promoting an off-label use "`paternalistically' interferes with the ability of physicians and patients to receive potentially relevant treatment information." Id. (quoting Va. Bd. of Pharmacy v. Va. Citizens Consumer Council, Inc., 425 U.S. 748, 770, 96 S.Ct. 1817, 48 L.Ed.2d 346 (1976)). Finally, as to the fourth Central Hudson prong, which requires
This Court therefore rejects the FDA's reading of Caronia as a mere artifact of that case's particular facts and circumstances. By its explicit terms and its clearly-articulated reasoning, Caronia simply cannot be read as the proverbial "ticket good for one day only." See Smith v. Allwright, 321 U.S. 649, 669, 64 S.Ct. 757, 88 L.Ed. 987 (1944) (Roberts, J., dissenting). On the contrary, the Second Circuit, at the close of its Caronia analysis, presented its holding as a definitive one of statutory construction:
703 F.3d at 168-69 (emphasis added).
Therefore, insofar as Amarin seeks preliminary relief recognizing its First Amendment right to be free from a misbranding action based on truthful speech promoting the off-label use of an FDA-approved drug, Amarin has established a substantial likelihood of success on the merits on this point. Under Caronia, misbranding is unlike the crimes of jury tampering, blackmail, and insider trading to which the FDA has analogized, in which "the speech is the act." Tr. 83. Where 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.
The FDA makes three counterarguments. None is persuasive.
First, the FDA argues that that protecting truthful speech aimed at promoting off-label drug use is "a frontal assault ... on the framework for new drug approval that Congress created in 1962," FDA Br. 1, because allowing a manufacturer to promote such use "has to the potential to eviscerate [the] FDA drug approval regime." Tr. 41. The short answer is that the FDCA's drug-approval framework predates modem First Amendment law respecting commercial speech. The Supreme Court held in Central Hudson (1980) that the First Amendment gives qualified protection to commercial speech and in Sorrell (2011) that pharmaceutical marketing qualifies as such speech. It follows that the provisions of a 1962 statute that implicate such speech, such as the FDCA's misbranding provisions, today must be considered, and to the extent ambiguous construed, in light of contemporary
The Second Circuit's decision in Caronia reflected a careful Central Hudson analysis. And the Circuit, in Caronia, identified alternative, and less speech-restrictive, means for the FDA to achieve its objectives. The FDA's quarrel is, therefore, ultimately, with Caronia. Notably, however, despite a vigorous dissent to the effect that the panel majority had "call[ed] into question the very foundations of our century-old system of drug regulation," see 703 F.3d at 169 (Livingston, J., dissenting), the Government neither sought rehearing nor petitioned for certiorari in Caronia.
Second, the FDA, consistent with its guidance, urges the Court to limit the holding in Caronia to protect only certain types of truthful and non-misleading statements by manufacturers regarding off-label use. The FDA looks askance, for example, at statements made proactively to a doctor as opposed to those responding to a doctor's query; and at statements made to a doctor by a sales or marketing employee, as opposed to those by a scientist or physician. See, e.g., FDA Br. 17; Tr. 53-55, 62-65. As the FDA explains, the types of statements that it disfavors are, by nature, more likely to reflect a manufacturer's intent to promote off-label use of a drug as opposed to being mere responses to requests for information.
But Caronia did not turn on the intent element of misbranding. It turned on the actus reus requirement. And Caronia's holding was that the FDCA's misbranding provisions cannot constitutionally criminalize, and therefore do not reach, the act of truthful and non-misleading speech promoting off-label use. The Circuit did not limit that holding to a subset of truthful promotional speech, such as statements responding to doctors' queries or statements by non-sales personnel. Caronia instead construed the misbranding provisions not to reach any "truthful off-label promotion of FDA-approved prescription drugs." 703 F.3d at 168-69. And the reasons the Circuit gave in Caronia for that holding apply across-the-board to all truthful and non-misleading promotional speech. Indeed, the speech on which the Caronia prosecution itself was based involved the very types of statements promoting off-label use that the FDA most disfavors: proactive oral statements to a doctor by a manufacturer's sales representative. See id. at 155-56.
Third, the FDA notes that Caronia does not prohibit the Government from relying on truthful and non-misleading statements to establish, in a misbranding action, that the defendant intended to promote off-label use. See, e.g, FDA Br. 3, 23, 26 & n. 15; Tr. 52-54. But the proposition that speech can be admissible in evidence to prove intent or motive in a criminal case
The Government is of course correct that truthful speech can serve as evidence of intent. To illustrate, consider a misbranding prosecution of a manufacturer based on promotional actions other than truthful speech. The manufacturer's statements promoting off-label use might be admissible there, to shed light on the intent behind these actions or to present the scheme in full context. At argument, the Court posed a hypothetical in which a manufacturer paid doctors money or bought them resort vacations — allegedly to reward them for prescribing a drug for offlabel use. Amarin's counsel agreed that the manufacturer's truthful statements promoting off-label use could well be admissible to prove that its intent in paying the doctors had been to promote off-label (as opposed to, say, on-label) use. Tr. 11. Caronia does not limit the Government's ability to use promotional speech to establish intent in a misbranding action with a proper actus reus.
And, contrary to the FDA's concern, Caronia leaves room for prosecuting off-label marketing as misbranding. Two limits to Caronia's holding are worth highlighting. First, the First Amendment does not protect false or misleading commercial speech. Caronia's construction of the misbranding provisions so to exclude truthful promotion speech affords no protection to a manufacturer that uses false or misleading communications to promote an off-label use. Second, the First Amendment protects expression, not conduct. A manufacturer that engages in non-communicative activities to promote off-label use cannot use the First Amendment as a shield. Caronia holds protected, and out-side the reach of the FDCA's misbranding provisions, off-label promotion only where it wholly consists of truthful and non-misleading speech.
A final observation: 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. A manufacturer may also conclude that it is prudent to consult with the FDA before promoting off-label use. Reasonable minds may differ over whether a given statement is misleading in context; and
The Court turns next to the specific communications relating to Vascepa which Amarin seeks to make to doctors. As noted, Amarin proposes:
The Court evaluates these categories in turn.
At the outset, the Court notes that Vascepa's unusual and extensive regulatory history makes it realistic to determine, at this early stage, the truthfulness of Amarin's proposed statements regarding its off-label use.
With respect to the reprints of the 13 peer-reviewed scientific publications that address the effect of EPA (Vascepa's main component) on coronary heart disease, the FDA does not claim that these, viewed separately or together, are false or misleading. The FDA instead has described these as "the types of publications covered by the [FDA's] existing guidance" governing reprints of scientific publications. See Woodcock Letter, at 8. The FDA did caution Amarin not to accompany these reprints with misleading language, i.e., not to characterize an article as definitive or representative where this was not so, or to falsely imply that a study described in a reprint involved Vascepa. Id. But Amarin's proposed statements do not do so. The Court therefore holds, and the FDA does not dispute, that Amarin's dissemination of these reprints, under the circumstances proposed, would be neither false nor misleading.
The FDA does not claim that the summary of the ANCHOR study that Amarin appended to its Complaint as Exhibit B is false or misleading. The FDA has noted that summaries or excerpts of a study can be misleading if they omit material information or introduce bias. See Woodcock Letter, at 6. But, the FDA stated, Exhibit B "does not raise those types of concerns." Id.; see also FDA Br. 15.
The Court agrees. Exhibit B is an anodyne — and studiously neutral — overview of the ANCHOR study. It (1) defines — demographically, medically, and numerically — the patient and placebo groups, and (2) reports, statistically, by means of a chart, the outcomes of the 12-week study, including the extent to which Vascepa reduced triglyceride and other lipid parameters in the patient group relative to the placebo group. The Court therefore holds, and the FDA does not dispute, that Amarin's dissemination of this summary is neither false nor misleading.
In neither the Woodcock Letter nor its submissions in this litigation did the FDA object to Statement #2 and Statement #3 that Amarin proposes in its Complaint to make relating to the off-label use of Vascepa. To recap, these are:
The Court agrees that these statements are truthful and non-misleading. The Court understands that Amarin would accompany these statements by distributing the full text of Exhibit B.
The FDA also agreed to the substance of four of the five disclosures (#1, #3, #4, and #5) that Amarin proposed in its Complaint to give alongside its statements. To recap, these are:
See Woodcock Letter, at 7 & n. 15.
In addition, Amarin agreed to one of the three disclosures that the FDA proposed be given (in addition to Amarin's disclosures). This would be of:
See Ketchum Reply Decl. ¶ 12.
The parties disagree, however, as to two disclosures. The parties' positions as to each were sharpened over the course of briefing and argument.
Amarin's proposed Disclosure #2 initially read:
Compl. ¶ 124.
In the Woodcock Letter, the FDA took the position that this disclosure should be revised, to explain why the FDA had not approved Vascepa for this off-label purpose:
See Woodcock Letter, at 7.
Amarin, in its reply, proposed to revise its Disclosure #2 to add an introductory sentence and to revise the disclosure:
Ketchum Reply Decl. ¶ 22 (underlined text denotes Amarin's proposed additions). Amarin explained that its revision of the back end of the disclosure was necessary to capture accurately the FDA's basis for not approving Vascepa for the off-label use. The FDA's text, Amarin stated, had inaccurately implied that "the available evidence" had affirmatively established that reducing triglycerides with a drug does not reduce cardiovascular risk in the relevant population, whereas in fact, that proposition is unresolved (and is being assessed in the REDUCE-IT study). Id. ¶ 16. Amarin explained that its revision of the front of this disclosure was needed because the FDA's text "ma[de] no mention of the potential benefit for patients with persistently high triglycerides and low good cholesterol." Id. ¶ 19 (citing CRL, at 2).
At this early stage, the Court's judgment, based on its review of the parties' submissions, is that each party's proposal is less than optimal, but that a revised Disclosure #2, drawing upon both parties' final positions, achieves a truthful and non-misleading result.
As for the back end of the disclosure, the Court agrees with the FDA that an explanation for the FDA's decision not to approve Vascepa for off-label use is warranted, to give doctors a context in which to understand the agency's decision. Unexplained, the FDA's decision would be, potentially, a mystery. It might foster any number of unhelpful misconceptions. However, the Court agrees with Amarin that the FDA's proposed explanation has the potential to mislead, insofar as it implies that drug-induced triglyceride level reductions among patients with persistently high triglycerides have been affirmatively shown not to reduce the risk of cardiovascular events. In fact, as the parties agree, the studies to date on that point are simply not conclusive. Amarin's proposal to explain that there is "current uncertainty" regarding the cardiovascular benefits of such reductions is a fair and neutral statement of the present state of scientific knowledge and of the basis for the FDA's decision not to approve Vascepa to treat patients with persistently high triglycerides. The Court will, however, direct that the word "benefit" in Amarin's proposed text be replaced by the phrase "benefit, if any," so as to eliminate any risk that a doctor would assume that some benefit has been found.
As for the front end of the disclosure, for several reasons, the Court declines — at this stage — to give Amarin comfort with respect to the sentence it seeks synopsizing "[n]umerous national and international treatment guidelines and position statements." First, including this sentence adds a tenor of advocacy to the disclosure, which otherwise is neutral in tone. Second, the FDA, at argument, disputed — and the Court has not had occasion to resolve — whether that sentence is factually accurate. See Tr. 75-76 (arguing that this sentence was "based on outdated science"). Third, the sentence, which Amarin did not initially include Disclosure #2, is unnecessary to make the overall disclosure truthful and non-misleading. The addition of a sentence explaining the basis for the FDA's decision does not make it necessary to characterize worldwide treatment guidelines. The overall disclosure is fair and balanced without this sentence.
The Court, accordingly, holds that the following disclosure, drawing upon both parties' drafts, is, at present, truthful and non-misleading.
The parties are, of course, at liberty to pursue further refinements to this disclosure as this litigation moves forward.
The FDA's proposed Disclosure #3 initially read:
Woodcock Letter, at 7. In its reply, Amarin opposed this disclosure as unnecessary. See Ketchum Reply Decl. ¶ 25. However, Amarin urged that, if any disclosure along these lines was held necessary, the FDA's proposed disclosure be modified as follows.
Id. (the underlined text denotes Amarin's proposed additions).
This disclosure presents a close question. It is not clear that a disclosure along the lines proposed by the FDA is necessary to make Amarin's overall communications about Vascepa non-misleading. After all, doctors will already have been informed that the basis of the FDA's decision not to approve Vascepa for patients with persistently high triglycerides was the current uncertainty that reducing such triglycerides will yield a cardiovascular benefit. On the other hand, the disclosure drafted by the FDA is undisputedly accurate. And it gives doctors relevant information: The outcomes trials referred to in the FDA's disclosure are the very studies on which the FDA relied in not approving Vascepa's off-label use. The modifications Amarin urges are also factually accurate and add useful context.
At this stage, the Court's judgment is to err on the side of caution, meaning in favor of giving doctors more, not less, information. Because the FDA's disclosure, as modified by Amarin, is factually accurate and non-misleading, that disclosure will usefully guard against any misapprehension. The relief the Court grants — declaring that Amarin's package of proposed communications about Vascepa, as modified herein, is truthful and non-misleading, and therefore under Caronia cannot form the actus reus of a misbranding action —
The parties are, of course, at liberty to revisit this disclosure, too, as this litigation moves forward.
In the Complaint, Amarin proposed to make the following statement (the "coronary heart disease claim") to doctors in connection with Vascepa:
Compl. ¶ 124. Amarin noted that dietary supplement manufacturers are permitted to make this claim, verbatim, to consumers, on the packaging of dietary supplements that are chemically identical to Vascepa. Amarin Br. 8, 19-20.
In the Woodcock Letter, the FDA objected to Amarin's making this statement. Woodcock Letter, at 8-10. It explained that, although there is not "significant scientific agreement" on this point, the coronary heart disease claim is accurate and "supported by credible evidence," and therefore the FDA has permitted this claim to be made in connection with dietary supplements. See id. at 9. But, the FDA stated, the lower standard governing health statements on dietary supplements should not be extended to claims for drugs, "which require substantial evidence of effectiveness to support approval for each approved use." Id. (citing 21 U.S.C. § 355). And allowing claims "with such a low level of scientific weight could undermine the important public health interests served by the premarket approval requirements for drugs under the FDCA." Id. Accordingly, the FDA stated, allowing Amarin to make this statement in connection with Vascepa "would be potentially harmful to the public health, and [the] FDA would consider such conduct to be potentially misleading." Id. at 10 (emphasis added). The FDA also feared that this claim might lead a doctor to prescribe Vascepa instead of promoting healthy dietary and lifestyle changes or prescribing statin therapy. Id.
Before this Court, the FDA argues that use of the coronary heart disease claim in connection with Vascepa would be "potentially misleading," for three reasons. First, it "does not advise physicians to prescribe Vascepa as an adjunct in combination with statins"; a doctor could wrongly view Vascepa as a substitute for statin therapy. FDA Br. 32-33; Woodcock Decl. ¶ 37. Second, the claim may prompt doctors not to independently review the underlying medical research. FDA Br. 33. Third, the claim could lead doctors wrongly to conclude that the "[s]upportive but not conclusive research" includes the ANCHOR study itself. Id. In sum, the claim could "mislead physicians and cause them to conclude that Vascepa itself will provide a reduction in risk of coronary heart disease by lowering triglyceride levels in patients already on statin therapy who have or are at risk for cardiovascular disease." Id.; see also Woodcock Decl. ¶ 37.
In response, Amarin notes that the coronary heart disease claim is factually accurate, and acquiesced by the FDA in consumer-directed dietary supplement labeling. And, it argues, that claim, couched in nuanced language, would not mislead doctors. Ketchum Reply Decl. ¶ 29. A doctor could not read the statement to mean that "there is substantial evidence to support Vascepa's use to reduce the risk of coronary heart disease," as the claim states only that there is "supportive but not conclusive research" that consuming EPA and DHA-omega-3 fatty acids "may reduce the risk of coronary
Id. ¶ 31 (the underlined text denotes Amarin's proposed additions).
The Court's 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.
As to its truthfulness, the coronary heart disease claim is undisputedly an accurate account of the current state of scientific research. The FDA acknowledged so at argument, Tr. 49, and for this reason, it has permitted the same statement to be made directly to consumers. While the FDA notes that a higher standard for FDA approval governs health claims for drugs than for dietary supplements, the coronary heart disease claim does not refer to FDA approval or any regulatory standard. That claim is a representation of fact, and a textured one at that, as to the present state of scientific research as to a discrete proposition.
As to whether the claim is misleading if made in connection with Vascepa, the FDA has not so argued. It argues only that the claim is "potentially misleading," and whether it ever became misleading would "depend on [future] circumstances." Tr. 61.
As to the FDA's concern that a doctor might errantly conclude "that there is currently sufficient evidence to support a conclusion that drug-induced decreases in triglyceride levels lead to a reduction in the risk of cardiovascular events in patients on statin therapy," FDA Br. 23, Amarin's Statement #1 does not say that. And the disclosures that will accompany it refute that. They report that there is current uncertainty whether decreases in triglyceride levels reduce the risk of cardiovascular events, and, indeed, explain that that is why the FDA has not approved Vascepa to treat patients with persistently high triglycerides. Doctors can grasp that point. See Friedman, 13 F.Supp.2d at 67 ("Whether speech is `inherently misleading' depends on ... the `possibilities for deception,' ... whether `experience has proved that in fact that such advertising is subject to abuse,' ... and `the ability of the intended audience to evaluate the claims made.'") (internal citations omitted).
Finally, the FDA's concern that future events may one day make the coronary heart disease claim misleading cannot justify treating this presently true and non-misleading statement as if it were unprotected speech. "[A] governmental body seeking to sustain a restriction on commercial speech must demonstrate that the harms it recites are real and that its restriction will in fact alleviate them to a material degree"; "[t]his burden is not satisfied by mere speculation or conjecture." Edenfield v. Fane, 507 U.S. 761, 770-71, 113 S.Ct. 1792, 123 L.Ed.2d 543 (1993). The FDA cannot use the "rote invocation of the words `potentially misleading'" to discharge its burden. Ibanez v. Fla. Dep't of Business & Prof. Reg., Bd. of Accountancy, 512 U.S. 136, 146, 114 S.Ct. 2084, 129 L.Ed.2d 118 (1994). Of course, the FDA is at liberty to reassess the factual accuracy of this claim as circumstances change. If and when the FDA repudiates it, the Court would expect Amarin to respond accordingly.
The Court, therefore, holds that the coronary heart disease claim is presently truthful and non-misleading. Amarin may include that claim among its statements to doctors, without incurring liability for misbranding.
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.
The Court next addresses irreparable harm. "Where infringement of free speech is claimed, irreparable harm may normally be presumed." Am. Freedom Def. Initiative v. Metro. Transp. Auth., 880 F.Supp.2d 456, 465-66 (S.D.N.Y.2012) (citation omitted); see also N.Y. Magazine v. Metro. Transp. Auth., 136 F.3d 123, 127 (2d Cir.1998) ("The loss of First Amendment freedoms, for even minimal periods of time, unquestionable constitutes irreparable injury.") (internal quotation marks and citation omitted). And here, Amarin has established irreparable harm. Without relief, it has shown, its First Amendment rights will be chilled by the threat of a misbranding action. Amarin thus has "articulate[d] a `specific present objective harm or a threat of a specific future harm' [so as] to establish a cognizable claim based on the chilling of first amendment rights." Am. Postal Workers Union, AFL-CIO v. U.S. Postal Serv., 766 F.2d 715, 722 (2d Cir.1985) (quoting Laird v. Tatum, 408 U.S. 1, 14, 92 S.Ct. 2318, 33 L.Ed.2d 154 (1972)).
The remaining preliminary relief factors — the balance of equities and the public interest — here are intertwined. The Court "must balance the competing claims of injury and must consider the effect on each party of the granting or
Here, the equities, including the public interest, strongly favor granting Amarin relief. Doing so would eliminate the chill on Amarin's First Amendment rights. This serves the public interest, because "securing First Amendment rights is in the public interest," Walsh, 733 F.3d at 488, and "the Government does not have an interest" in the unconstitutional enforcement of a law, id. (quoting Am. Civil Liberties Union v. Ashcroft, 322 F.3d 240, 247 (3d Cir.2003)).
On the other side of the equation, the FDA fears that sanctioning Amarin's off-label promotion "would set a course toward undermining the drug approval process that Congress enacted in 1962 to cure serious public health problems that resulted from abuses under the prior regime." FDA Br. 49. But the Court's recognition that Amarin may engage in truthful and nonmisleading speech about the off-label use of Vascepa merely applies, to one drug, the construction of the misbranding statute adopted in Caronia. Had the FDA believed that Caronia gravely undermined the drug approval process, it should have sought review of that decision.
Finally, there is no basis to fear that promoting Vascepa for this off-label purpose would endanger the public health. Vascepa is a fish oil product. And it is already widely prescribed to treat patients with persistently high triglycerides. The FDA has acknowledged that it has no evidence that Vascepa is harmful — indeed, it volunteered that it would not object to Vascepa's being marketed as a dietary supplement. Tr. 46, 70-71.
The balance of equities and the public interest both thus overwhelmingly favor granting relief.
For the foregoing reasons, the Court grants Amarin's application for preliminary relief. Specifically the Court declares that:
The Clerk of Court is respectfully directed to terminate the motion pending at docket number 5.
An order will follow shortly as to next steps in this litigation.
SO ORDERED.
Bays H, Ballantyne C, Braeckman R, et al. Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies. Am J Cardiovasc Drugs. 2013;13:37-46.
Doi M, Nosaka K, Miyoshi T, et al. Early eicosapentaenoic acid treatment after percutaneous coronary intervention reduces acute inflammatory responses and ventricular arrhythmias in patients with acute myocardial infarction: a randomized, controlled study. Int J Cardiol. 2014:176(3):577-582.
Harris W. Are n-3 fatty acids still cardioprotective? Curr Opin Clin Nutr Metab Care. 2013;16(2):141-149.
Matsuzaki M, Yokoyama M, Saito Y, et al. Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease. Circ J. 2009;73:1283-1290.
Mozaffarian D, Lemaitre RN, King IB, et al. Plasma phospholipid long-chain omega-3 fatty acids and total and cause-specific mortality in older adults: the cardiovascular health study. Ann Intern Med. 2013;158(7):515-525.
Mozaffarian D, Wu JHY. Omega-3 Fatty Acids and Cardiovascular Disease. J Am Coll Cardiol. 2011;58(20):2047-2067.
Saito Y, Yokoyama M, Origasa H, et al. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis. 2008;200:135-140.
Takaki A, Umemoto S, Ono K, et al. Add-on therapy of EPA reduces oxidative stress and inhibits the progression of aortic stiffness in patients with coronary artery disease and statin therapy: a randomized controlled study. J Atheroscler Thromb. 2011;18:857-866.
Thies F, Garry JMC, Yaqoob P, et al. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomized controlled trial. Lancet. 2003;361:477-485.
Ueeda M, Doumei T, Takaya Y, et al. Serum n-3 polyunsaturated fatty acid levels correlate with the extent of coronary plaques and calcifications in patients with acute myocardial infarction. Circ J. 2008;72:1836-1843.
Vecka M, Dusejovska M, Stankova B, et al. N-3 polyunsaturated fatty acids in the treatment of atherogenic dyslipidemia. Neuroendocrinol Lett. 2012;33(Suppl. 2):87-92.
Wu JHY, Mozaffarian D. Omega-3 fatty acids, atherosclerosis progression and cardiovascular outcomes in recent trials: new pieces in a complex puzzle. Heart. 2014;100(7):530-533.
Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.
The effects of VASCEPA as add-on therapy to treatment with statins were evaluated in a randomized, placebo-controlled, double-blind, parallel-group study of 453 adult patients (226 on VASCEPA and 227 on placebo) with persistent high triglyceride levels (≥200 mg/dL and <500 mg/dL) despite statin therapy. All patients were receiving statin therapy (atorvastatin, rosuvastatin, or simvastatin) and were treated to LDL-C goal prior to randomization. Patients were randomized to either VASCEPA or placebo and treated for 12 weeks with statin co-therapy. The same statin at the same dose was continued throughout the study. The median baseline TG and LDL-C levels in these patients were 259 mg/dL and 83 mg/dL, respectively. The randomized population in this study was mostly Caucasian (96%) and male (61%). The mean age was 61 years and the mean body mass index was 35 kg/m
The changes in the major lipoprotein lipid parameters for the groups receiving VASCEPA plus statin or placebo plus statin are shown in the following table:
Vascepa 4 g/day + Statin Placebo + Statin Difference
N=226 N=227 (95% Confidence
Parameter Baseline % Change Baseline % Change Interval) p-value
TG (mg/dL) 265 -18 259 6 -22 (-27, -16) <0.0001
LDL-C (mg/dL) 82 2 84 9 -6 (-11, -2) <0.01
Non-HDL-C 128 -5 128 10 -14 (-17, -10) <0.0001
(mg/dL)
Apo B (mg/dL) 93 -2 91 7 -9 (-12, -6) <0.0001
VLDL-C 44 -12 42 15 -24 (-32, -17) <0.0001
(mg/dL)
TC (mg/dL) 167 -3 168 9 -12 (-15, -9) <0.0001
HDL-C (mg/dL) 37 -1 39 5 -5 (-7, -2) <0.01
% Change= Median Percent Change from Baseline
Difference= Median of [VASCEPA % Change — Placebo % Change] (Hodges-Lehmann Estimate)
p-values from Wilcoxon rank-sum test
VASCEPA significantly reduced TG, non-HDL-C, Apo B, VLDL-C, TC and HDL-C levels from baseline relative to placebo. The reduction in TG observed with VASCEPA was not associated with elevations in LDL-C relative to placebo.
The effect of VASCEPA on cardiovascular mortality and morbidity in patients with mixed dyslipidemia has not been determined.
