In a widely anticipated ruling on Friday, in the ongoing Amarin litigation against the United States Food and Drug Administration (FDA), Judge Engelmayer granted Amarin’s general and specific requests for relief, forcefully rejecting the Government’s assertion that the Second Circuit’s decision in United States v. Caronia, 703 F.3d 149 (2d Cir. 2012), does not preclude a misbranding action “where the acts to promote off-label use consist solely of truthful and non-misleading speech[.]” “The Court’s considered and firm view,” it held, “is that, under Caronia, the FDA may not bring such an action based on truthful promotional speech alone, consistent with the First Amendment.” Amarin thus rejects the limited interpretation of Caronia that the Government has been advancing for nearly three years. But the decision is more than just the “son of Caronia.”
Court Rejects FDA’s “Frontal Assault” Argument
Of major significance for FDA-regulated manufacturers, to an even greater extent than the Caroniadecision itself, Amarin addresses, and rejects, FDA’s frequently-articulated rationale that it must be allowed to regulate truthful, non-misleading off-label speech about drugs in order to protect the integrity of the drug approval process and thereby safeguard the public health. The Court acknowledged the Agency’s contention that permitting truthful off-label speech constitutes a “frontal assault . . . on the framework for new drug approval that Congress created in 1962,” but explained that the 1962 legislation creating the existing drug-approval scheme simply “predates modern First Amendment law respecting commercial speech.” The Court emphasized that the Federal Food, Drug and Cosmetic Act’s (FDCA) misbranding provisions “must be considered, and to the extent ambiguous construed, in light of contemporary First Amendment law, under which truthful and non-misleading commercial speech is constitutionally protected[.]” Moreover, the Court twice pointed to the Government’s own failure to seek further review of the Caronia holding, through rehearing or certiorari, as evidence that the Government’s rhetoric about the impact of that decision was overblown.
More specifically, while accepting FDA’s position on the need for the 1962 drug amendments to stem the tide of false and misleading drug promotion—even citing Congressman Waxman’s later published version of the legislative history—the Court nevertheless categorically rejected FDA’s assertion that adopting Amarin’s First Amendment position would eviscerate the new-drug approval process, with consequences to the public health. Indeed, in weighing the familiar factors bearing on eligibility for preliminary relief, the Court found that taking Amarin’s side on the First Amendment point advancedthe public interest, observing that “securing First Amendment rights is in the public interest[.]” Moreover, the Court took pains to describe FDA’s lack of authority to regulate physician prescribing practices, and the widespread nature and public health value of off-label use of prescription drugs in a variety of settings, including oncology and pediatrics.
Court Adopts Disclaimer Approach, Points to Infirmities in FDA’s Review of Vascepa®
Both thematically and in effect, the Court’s decision makes clear that the FDCA’s new-drug approval requirements and the First Amendment can be reconciled under a disclaimer-based regime that reflects the notion that patient care is advanced, rather than undermined, by accurate off-label information. In granting Amarin’s motion, the Court declared that (1) Amarin could promote its drug Vascepa® (icosapent ethyl) for the off-label indication of treating patients with persistently high triglycerides without that speech forming the basis of a misbranding prosecution, and (2) Amarin’s specific proposed statements (with accompanying contextual information as modified by the Court) were truthful and non-misleading. Notably, the Court authorized Amarin’s proposed use of a qualified coronary heart disease risk reduction statement, which FDA had concluded Amarin could not make for Vascepa based on the Agency’s conclusion that such a statement would be potentially misleading. The Court rejected the Agency’s position and rationale, concluding instead that the statement (accompanied with a disclaimer) is “undisputedly an accurate account of the current state of scientific research.” The Court also permitted Amarin’s proposed summary of a clinical trial designed to test the effectiveness of Vascepa in treating persistently high triglyceride levels, describing Amarin’s dissemination of the study and its results “as neither false nor misleading.”
Both the Agency’s highly unfavorable win-loss record in First Amendment cases and the facts of theAmarin case made FDA’s defeat at the district court level all but inevitable. The opinion notes numerous aspects of the company’s engagement with FDA that highlight the constitutional infirmities in FDA’s administration of its regulatory scheme with respect to Vascepa. In particular, the Court noted FDA’s decision to make approval of the supplemental indication contingent on a further clinical trial designed to generate data on a related endpoint—a point of interest to FDA but not necessary to vindicate the accuracy of the speech; the entitlement of dietary supplement manufacturers to make the same claim about cardiovascular risk reduction that FDA had concluded Amarin could not make for its drug version of a closely related fish oil-derived ingredient; and FDA’s rejection of the coronary heart disease risk reduction hypothesis for Vascepa based on data from outcome studies of other, unrelated lipid-lowering products. The Court also pointed to FDA’s failure to provide timely guidance on manufacturer communications about regulated products, despite its promise to do so within a year of its June 2014 response to the Medical Information Working Group’s 2011 and 2013 citizen petitions requesting action on off-label promotion-related issues. Moreover, the Court accepted FDA’s assertion that off-label use can sometimes cause harm, but emphasized the baselessness of any fear that encouraging the use of Vascepa in treating patients with persistently high (but not severely high) triglyceride levels “would endanger the public health.”
The decision did not answer all the open questions about communication of off-label information. Among other issues, the decision does not address (1) the proper interpretation of FDA’s regulations interpreting “intended use,” (2) the scope of FDA’s authority over “labeling,” and (3) the proper level of scrutiny—Central Hudson’s intermediate level of “heightened scrutiny” under Sorrell—afforded government restrictions on accurate speech concerning lawful activities. Nor does the opinion fully explicate the complex regulatory scheme that FDA has developed to provide manufacturers with limited, carefully controlled outlets for off-label speech (e.g., scientific exchange), or address the important Due Process deficiencies created by the ambiguity in FDA’s administration of the FDCA and its own implementing regulations.
Further Implications for Manufacturers
As a starting point, it is hard to see the government letting the decision stand if it remains committed to maintaining the current speech-restrictive regulatory scheme, and the district court’s opinion evinces a care and thoroughness that clearly assume the matter will be taken up on appeal. Even while the litigation continues, however, manufacturers could (cautiously) evaluate their existing policies and procedures in view of the Court’s analysis. The Court not only recognized manufacturers’ entitlement topromote off-label using truthful, non-misleading statements and materials, but also rejected FDA’s request to permit only company scientists’ responses to requests for off-label information, on the basis that proactive, promotional statements are “more likely to reflect a manufacturer’s intent to promote off-label[.]” Indeed, in rejecting FDA’s request, the Court pointed out that the “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.”
As a result, there is a sound rationale not only in the underlying First Amendment decisional law but also in the Amarin decision itself to conclude that sales representatives may lawfully engage in truthful, non-misleading promotion of an off-label use of an approved product. Although the Amarin decision itself is but a single district court decision in one judicial circuit, it reflects a compelling application of the principles explicated in Caronia. And both decisions are fully consistent with decades of case law both repeatedly excoriating FDA for overstepping constitutional limitations in regulating manufacturer speech and emphasizing the First Amendment rule that the Government is prohibited, as an absolute matter, from restricting truthful, non-misleading speech concerning lawful activities.
The decision has significant potential implications for ongoing regulatory proceedings. Despite a string of losses in First Amendment cases over the past three decades in multiple program areas, the Agency’s day-to-day actions and communications with regulated entities have consistently reflected hostility to speech rights. For manufacturers willing to bring proposed promotional materials to FDA for prior comment or otherwise engaged in correspondence with FDA over the permissibility of their speech (e.g., in response to enforcement correspondence), the decision in Amarin further buttresses arguments supporting a freer promotion using unlabeled clinical data. It will likely be necessary to advance the First Amendment point in the context of supervisory review, however, because of continued resistance to the notion of constitutional limitations on FDA’s authority over manufacturer speech at the program level.
The decision also strengthens the hands of those manufacturers willing to bring their own First Amendment challenges. In rejecting FDA’s attempt to moot the dispute, the Court pointed to boilerplate language from a complete response letter stating that Vascepa “may be considered to be misbranded under the [FDCA] if it is marketed with this change before approval of this supplemental application.” The Court indicated that “the FDA had expressly threatened . . . to bring a misbranding action against it [Amarin] for promoting Vascepa off-label, i.e., if Amarin marketed Vascepa for persons with persistently high triglycerides without approval of that use.” Vague references to the possibility of misbranding liability are common in FDA correspondence, and the Court’s emphasis on such language in finding a justiciable controversy should, in appropriate cases, alleviate manufacturer concerns about lack of standing or the failure of a complaint to present a ripe controversy.
Implications for FDA
FDA must decide whether to continue to defend the constitutionality of the current regulatory regime or adapt its regulatory scheme to constitutional norms. In rethinking its public health role in view of evolving societal expectations and firmly established First Amendment limitations, FDA will have to consider whether, contrary to many of its assumptions over the years, patient care can be enhanced by less regulation of manufacturer communications to physicians, payors and even patients. FDA has a continued opportunity to clarify its regulatory scheme while also better aligning its rules with constitutional limitations by responding more fully to the two citizen petitions the Agency granted last year. See Citizen Petition Response here.
FDA’s task will not be easy, but it is essential. Senior officials within FDA doubtless have been following developments in the First Amendment case law carefully, but lack of consensus among career personnel and with HHS has precluded the Agency from taking firm steps to respond to industry requests for clarity and reform. The Amarin decision should encourage the development of that consensus. To be sure, FDA’s history of extricating itself from First Amendment disputes without major program modifications may embolden those inside and outside the Agency who are resistant to change, and the Amarin litigation has not yet concluded. But the decisions in both Caronia and Amarinpoint to the importance of immediate change. If FDA cannot implement common-sense regulatory reform in response to the courts’ continued application of well-established First Amendment principles to manufacturer speech about off-label uses, then Congress may have no real choice but to modify the Agency’s statutory authority. The alternative is continued judicial involvement in the review of proposed manufacturer promotional claims and erosion of FDA’s role as the world’s premiere regulator of medical products.