March 16 2016 ACC Philadelphia In House Counsel

March 16, 2016 ACC Philadelphia In House Counsel Conference A FREE FOR ALL? FREE SPEECH AND OFF-LABEL PROMOTION Navigating the Tensions Between FDA Enforcement and the First Amendment 2016 In House Counsel Conference

March 16, 2016 ACC Philadelphia In House Counsel Conference Presenters: Sean Wajert Erin Loucks Shook, Hardy & Bacon Managing Partner, Philadelphia swajert@shb. com Shook, Hardy & Bacon Associate, Philadelphia eloucks@shb. com Moderator: Andrea Small FMC Corporation Division Patent Counsel andrea. small@fmc. com

March 16, 2016 ACC Philadelphia In House Counsel Conference Overview • Pre-Amarin Landscape • The Sixties to Caronia • Amarin Pharma, Inc. v. FDA, S. D. N. Y. Aug. 7, 2015 • Vascepa® Background and FDA approval • Amarin’s Proactive Lawsuit and FDA Response • Caveats • Pacira Pharmaceuticals • Navigating the Post-Amarin World

March 16, 2016 ACC Philadelphia In House Counsel Conference Pre-Amarin Landscape FDA Long Held View: Off-label promotion by manufacturer is unlawful even if statements are truthful and non-misleading.

March 16, 2016 ACC Philadelphia In House Counsel Conference Pre-Amarin Landscape A pharmaceutical representative's promotion of an FDA-approved drug's off-label use is speech. “Speech in aid of pharmaceutical marketing. . . is a form of expression protected by the Free Speech Clause of the First Amendment. ” Sorrell v. IMS Health, Inc. , 131 S. Ct. 2653, 2659 (2011).

March 16, 2016 ACC Philadelphia In House Counsel Conference Pre-Amarin Landscape United States v. Caronia, 703 F. 3 d 149 (2 d Cir. 2012) • Vacated a conviction for conspiracy to sell misbranded drug. • To criminalize the simple promotion of a drug's off-label use by pharmaceutical manufacturers would run afoul of the First Amendment. • Off-label drug usage is not unlawful, and the FDA's drug approval process generally contemplates that approved drugs will be used in off-label ways. • So, it does not follow that prohibiting the truthful promotion of off-label drug usage would directly further the government's goals of preserving efficacy of FDA's drug approval process and reducing exposure to unsafe and ineffective drugs. • Not limited to a subset of truthful promotional speech, such as statements responding to doctors’ queries or statements by non-sales personnel.

March 16, 2016 ACC Philadelphia In House Counsel Conference Amarin – Background Amarin Pharma, Inc. v. FDA No. 1: 15 -cv-03588 (S. D. N. Y. Aug. 7, 2015) 2012 FDA Approval Vascepa®, an omega-3 fatty acid, approved as an adjunct to diet to reduce triglyceride levels in adults with severe hypertriglyceridemia

March 16, 2016 ACC Philadelphia In House Counsel Conference Amarin – Background SPA – Special Protocol Assessment • FDA declaration that uncompleted trial design, endpoints and analyses are acceptable for FDA approval. • Amarin believed it had satisfied all of FDA’s requirements to obtain approval of Vascepa® for persistently high triglycerides. • But FDA warned that any effort by Amarin to market Vascepa® for the proposed supplemental use could constitute misbranding under FDCA.

March 16, 2016 ACC Philadelphia In House Counsel Conference Amarin – Lawsuit May 2015 – Amarin Proactive Challenge to FDA • Claims the threat of prosecution for misbranding has a chilling effect on commercial speech protected by the First Amendment. • Seeks injunction prohibiting the FDA from bringing a misbranding action for Amarin’s truthful and non-misleading statements regarding Vascepa® directly to healthcare professionals—NOT in direct-to-consumer advertising: 1. disseminate study results; 2. report supportive but not conclusive research shows product may reduce the risk of coronary heart disease; 3. distribute reprints of peer-reviewed scientific publications relevant to the reduction of the risk of coronary heart disease. • With “contemporaneous disclosures” to ensure that the messages Amarin communicated to doctors concerning the use of Vascepa® in patients with persistently high triglycerides was not misleading.

March 16, 2016 ACC Philadelphia In House Counsel Conference Amarin – Lawsuit • FDA conceded: • It does not intend to object to proposed communications if made in truthful, non- misleading and balanced manner. • Contemporaneous disclosures regarding regulatory status, trial status and limitations of FDA approval would help to balance Amarin’s efficacy data related to off-label promotion. • But, FDA insisted: • That additional disclosures be made with proposed off-label promotion; • That Amarin could not make claims similar to qualified health claims of EPA- containing dietary supplements. • FDA also attempted to distinguish Caronia: • Caronia is fact-bound, turning on particular jury instructions given in trial. • Action was permitted when drug had been introduced into interstate commerce and had not been approved as safe and effective.

March 16, 2016 ACC Philadelphia In House Counsel Conference Amarin – Lawsuit Court Holdings: • Judge Paul A. Engelmayer rejected FDA’s interpretation of Caronia: the FDA may not bring such an action based on truthful promotional speech alone, consistent with the First Amendment. • Misbranding is not analogous to speech crimes of jury tampering, blackmail, or insider trading. • “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. ”

March 16, 2016 ACC Philadelphia In House Counsel Conference Amarin – Lawsuit Court Holdings (continued): Court evaluated and ruled on each of Amarin’s proposed off-label statements concerning Vascepa® along with FDA’s responses. • The “agreed-upon statements and disclosures” (e. g. , statements concerning the results of the key study; statements, along with the proposed contemporaneous disclosures) were “based on current information, truthful and non-misleading. ” • The “contested disclosures” such as “not-approved for” language. Judge eventually crafted, provided a revised disclosure. • Proposed cardiovascular disease claim, as revised during litigation, given its qualified phrasing and its acceptance elsewhere by the FDA, was presently truthful and non-misleading.

March 16, 2016 ACC Philadelphia In House Counsel Conference Amarin – Caveats • A manufacturer that leaves its sales force at liberty to communicate unscripted with doctors about offlabel 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. • 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. • Amarin bears the responsibility, going forward, of assuring that its communications to doctors regarding off-label use of Vascepa® remain truthful and non-misleading.

March 16, 2016 ACC Philadelphia In House Counsel Conference Post-Amarin Considerations Pacira Pharmaceuticals, et al. v. FDA , No. 1: 15 -cv-07055 (S. D. N. Y. Complaint filed 9/8/15) • Warning letter for alleged false and misleading promotion and misbranding its non-opioid pain drug, EXPAREL®, by promoting it for pain relief in surgeries other than those indicated. • Twists: • Whether the FDA is reading its own approved label correctly (FDA gave drug a broad approval, and can’t narrow the scope of that approval after the fact by threatening prosecution). • Whether its arguably new treatment of that label raises clarity and vagueness issues under the First Amendment (“regulation through warning letter” is unconstitutionally vague)

March 16, 2016 ACC Philadelphia In House Counsel Conference Post-Amarin Considerations Reed v. Town of Gilbert, 135 S. Ct. 2218 (2015) – Decided before Amarin • Town’s regulation of temporary advertising signs was unconstitutional because it discriminated on the basis of content between “ideological signs, ” “political signs, ” and “temporary directional signs. ” • “A law that is content based on its face is subject to strict scrutiny regardless of the government’s benign motive, content-neutral justification, or lack of animus toward the ideas contained in the regulated speech. ” Id. at 2228.

March 16, 2016 ACC Philadelphia In House Counsel Conference Post-Amarin Considerations Reed v. Town of Gilbert (continued) • Off-label use seems like a defined “topic. ” • Under Reed’s “topic”-based approach, the “commercial speech” test of Central Hudson Gas & Electric Corp. v. Public Service Commission, 447 U. S. 557 (1980), may not be needed. • See 135 S. Ct. at 2235 (Breyer, J. , concurring in the result) (Court has applied the heightened “strict scrutiny” standard even in cases where the less stringent “commercial speech” standard was thought traditionally appropriate. [citing Sorrell]).

March 16, 2016 ACC Philadelphia In House Counsel Conference Navigating the Waters • Evolving science must be considered when crafting off-label promotions. • Control sales force pitches. • The more information communicated the better – withholding truthful information from practitioners is not advised.

March 16, 2016 ACC Philadelphia In House Counsel Conference Navigating the Waters • Understand how Plaintiffs may use off-label promotions in products liability claims. • Violation of FDA regulations prohibiting off-label promotion cannot in and of itself be basis for state tort law action. • Buckman: No right of private action to enforce FDA regulations • Plaintiffs may allege off-label promotion as “evidence” to support traditional tort law claims

March 16, 2016 ACC Philadelphia In House Counsel Conference Navigating the Waters • Evidence that product “labeling” is defective/unreasonably dangerous (does not comply with federal law) • Evidence of manufacturer’s negligence/unreasonable conduct • Plaintiffs may seek to introduce FDA regulations on off-label promotion to show statutory violation, “per se negligence”

March 16, 2016 ACC Philadelphia In House Counsel Conference Questions?