FDA Settles Amarin First Amendment Challenge

Amarin Pharma and the FDA recently announced a widely expected settlement of First Amendment litigation over restrictions on the company's promotion of its Vascepa product.

Readers may recall that this was one of several recent challenges to the FDA's attempt to restrict off-label promotion of prescription products, even if that speech is truthful and not misleading. Several trends have combined to undercut this overreach by FDA. A pharmaceutical representative's promotion of an FDA-approved drug's off-label use is speech. And “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).  Then, in United States v. Caronia, 703 F.3d 149 (2d Cir. 2012), the court vacated a conviction for conspiracy to sell a misbranded drug, recognizing that 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 stated goals of preserving the efficacy of FDA's drug approval process and reducing patient exposure to unsafe and ineffective drugs. This ruling was not limited to a subset of truthful promotional speech, such as statements responding to doctors’ queries or statements by non-sales personnel.
 

In Amarin Pharma, Inc. v. FDA, No. 1:15-cv-03588 (S.D.N.Y. Aug. 7, 2015), the issues surrounded proposed statements by the company concerning its Vascepa®, an omega-3 fatty acid, approved in 2012 as an adjunct to diet to reduce triglyceride levels in adults with severe hypertriglyceridemia. The FDA had entered into an SPA (Special Protocol Assessment) with the company for an expanded use. Amarin believed it had satisfied all of FDA’s requirements to obtain approval of Vascepa® for persistently high triglycerides pursuant to the SPA.  But FDA warned that any effort by Amarin to market Vascepa® for the proposed supplemental use could constitute misbranding under FDCA.

The company sued, arguing that the threat of prosecution for misbranding has a chilling effect on commercial speech protected by the First Amendment. It sought an 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.  Specifically the company wanted to affirm its right to disseminate study results; report supportive but not conclusive research shows that their product may reduce the risk of coronary heart disease; and distribute reprints of peer-reviewed scientific publications relevant to the reduction of the risk of coronary heart disease.  The company was willing to do this along 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.  The FDA did not agree, and attempted to distinguish Caronia as fact-bound, turning on the particular jury instructions given in that trial.

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.”  

The court then 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 were handled through a court-crafted, revised disclosure. The proposed cardiovascular disease claim, as revised during litigation, given its qualified phrasing and its acceptance elsewhere by the FDA, was found by the court to be presently truthful and non-misleading.

The court did mention some caveats: A manufacturer that leaves its sales force at liberty to communicate 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. 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. So, said the court, Amarin bears the responsibility, going forward, of assuring that its communications to doctors regarding off-label use of Vascepa® remain truthful and non-misleading.

Rather than appeal, the government worked towards a settlement.  Under its terms, the FDA agrees to be bound by the court's conclusion that Amarin may engage in truthful and nonmisleading speech promoting the off-label use of the drug.  The company committed t ensure that it stays current on evolving science and updates its promotional statements accordingly.  The settlement agreement also provides for a procedure by which the FDA will give advance review to as many as two promotional communications annually for off-label uses of Vascepa, along with a timetable and process for resolving any concerns that the FDA may have about those new communications.

 

A copy of the settlement here.

 

 

Stay in Amarin Extended

The court recently extended its stay of the proceedings in Amarin Pharma Inc.'s suit against the FDA challenging threatened agency action concerning the alleged promotion of drugs for off-label uses See Amarin Pharma, Inc. v. FDA, No. 15-cv-3588 (S.D.N.Y.,  order 10/30/15).  The stay to December 17th is reportedly to give the parties more time to engage in settlement discussions. This one remains a case to watch for those in the pharma practice area.

First Amendment doctrine, and its relationship to the FDCA, has changed dramatically since the FDCA and many of its implementing regulations were adopted.  And one may question whether the FDA has kept up with these changes.

Earlier this Summer, the district court granted a motion for preliminary injunction in favor of Amarin, reaching the merits of Amarin’s First Amendment claims.  The case concerned Vascepa , an omega-3 fatty acid obtained from fish oil. Vascepa was approved to reduce triglyceride levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia. Amarin was seeking a new indication pursuant to a Special Protocol Assessment (“SPA”) agreement with FDA, for patients with “persistently high” triglycerides (≥ 200 and ≤ 500 mg/dL).  While Amarin believed it had satisfied all of FDA’s requirements to obtain the new approval, FDA disagreed and rescinded the SPA. FDA went further to warn Amarin that any effort by Amarin to market Vascepa for the proposed supplemental use could constitute "misbranding" under the Federal Food, Drug, and Cosmetic Act.

Amarin filed a civil complaint against FDA, claiming that this threat of prosecution for misbranding had a chilling effect on its commercial speech.  Amarin proposed to engage in truthful, non-misleading speech about Vascepa directly with healthcare professionals, such as disseminating study results and reprints of peer-reviewed scientific publications. The company also proposed to make "contemporaneous disclosures” to ensure that the messages were not at all misleading.

The court noted that in contrast to FDA’s long-standing position that off-label promotion of drug products can constitute criminal misbranding, off-label use is not illegal and may even be the standard of care in some circumstances.  The company relied on the Second Circuit's First Amendment decision in Caronia, but the FDA argued Caronia was a narrow, fact-bound decision, turning on particular jury instructions given at the sales rep's  trial. At the least, it ought to be construed in harmony with FDA regulations distingusihing between directed off-label speech and requests by the practicioner for information. The court rejected FDA’s interpretation, finding the FDA may not bring such an action based on truthful promotional speech alone. “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.”

With this rule in mind, the court evaluated and ruled on each of Amarin’s proposed off-label statements concerning Vascepa along with FDA’s responses.  This included the “agreed-upon statements and disclosures,” which were found to be “based on current information, truthful and non-misleading.”  And then the additional “contested disclosures” (such as “not-approved for” use language). The court eventually crafted a revised hybrid disclosure on that.  The court also said the proposed cardiovascular disease claim, as revised during litigation, given its qualified phrasing and its acceptance in other contexts by the FDA, was presently truthful and non-misleading.

 

The court offered a few important caveats: 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.

And the dynamic nature of science and medicine is such that knowledge is ever-advancing. A statement that is fair and balanced today may become incomplete in the future as new studies are done or new data is acquired.

Again, one to keep an eye on.
 

 

PhRMA Responds to FDA Letter in First Amendment Dispute

The Pharmaceutical Research and Manufacturers of America last week submitted an amicus brief relating to the FDA's response to a drug company's suit challenging limits on truthful communications about off-label uses of a drug. See Amarin Pharma, Inc. v. FDA,  No. 15-cv-03588 (S.D.N.Y)(amicus brief filed 6/11/15).

Readers will recall that the case involves FDA interpretations that potentially make a drug manufacturer criminally and civilly liable for providing truthful and non-misleading scientific and medical information to well-trained health care professionals regarding unapproved uses of FDA-approved drugs or data that are not contained in the FDA approved labeling for such medicines. (Our friends over at the Drug and Device Law Blog have covered this issue extensively.)

PhRMA said in the amicus brief filed June 11th in the U.S. District Court for the Southern District of New York that FDA's recent maneuver -- a regulatory letter to the plaintiff, Amarin Pharma  --did not “cure the constitutional defects in FDA's content-based restrictions on protected speech.” In the letter, the FDA said it now all of a sudden doesn't object to many of the "off-label statements" the company might consider making about its cholesterol treatment drug.  So, the agency wouldn't necessarily consider the dissemination of some of that information to be false or misleading.

Because doctors routinely lawfully prescribe FDA-approved drugs for unapproved uses, informed patient care relies upon doctors having access to accurate, comprehensive, and current information about such uses. Biopharmaceutical manufacturers are an important source of this knowledge, said the brief. Amarin has a First Amendment right to provide such truthful and non-misleading  information. Doctors have a First Amendment right to receive it. And patients have a strong health-related interest in an affirmation of those rights. 

FDA’s recent made-for-litigation “regulatory letter” to Amarin does not cure the constitutional defects in FDA’s content-based restrictions on protected speech. The brief argued that instead FDA exacerbates and reinforces them in a footnote which reiterates in broad strokes the Agency’s 
longstanding position that the FDCA and FDA’s implementing regulations prohibit manufacturers from speaking to healthcare professionals about unapproved uses. Beyond that, the letter purports to be an exercise of enforcement discretion, relies on “draft” guidance documents that FDA itself contends do not bind the Agency, and contains significant caveats that preserve the Government’s option to pursue criminal and civil enforcement based on manufacturers’ protected speech.

For example, “under these circumstances,” FDA stated in the letter, it does not intend to object to the proposed communications “if made in the manner and to the extent described below.” FDA thus seeks to create a one-off discretionary exception, applicable to this case and nowhere else -- precisely the type of case-by-case determination regarding the legality of speech that the First Amendment forbids. Moreover, the letter relies exclusively on guidance documents that FDA itself contends are non-binding. Even if they would be deemed binding, many of the guidance documents cited in FDA’s letter remain in “draft” form.  PhRMA and others have submitted comments to FDA objecting to many aspects of these draft guidance documents, because, among other things, they continue to censor and burden protected speech based on both its content and the identity of the speaker.

The brief points out that FDA’s letter is not the first instance of a discretionary modification of ostensibly nonbinding guidance infringing on First Amendment rights. When manufacturers have
challenged FDA’s approach to speech about unapproved uses in Court, FDA has previously made ad hoc statements backing off of certain of those policies as a matter of enforcement discretion and with carefully vague caveats. FDA should not be permitted, argued the amicus, to avoid judicial scrutiny of its published regulations restricting protected speech on the basis of such non-final and potentially nonbinding “guidance” and such revocable assertions of enforcement discretion. 

Certainly one to watch.

PhRMA Submits Amicus Brief on First Amendment Issues

The Pharmaceutical Research and Manufacturers of America recently submitted an amicus brief urging a federal court to dismiss a whistleblower's False Claims Act suit because the off-label claims in the case violate the defendants' free speech rights. See U.S. ex rel. Solis v. Millennium Pharmaceuticals Inc. et al., No. 2:09-cv-03010 (E.D. Cal. Brief August 15, 2014). The Pharmaceutical Research and Manufacturers of America (“PhRMA”) is a voluntary, nonprofit association representing the nation’s leading research-based pharmaceutical and biotechnology companies.

Readers know that physicians may lawfully prescribe FDA-approved drugs to treat any condition or disease, including unapproved uses, based on their independent medical judgment. See Buckman Co. v. Plaintiffs’ Legal Comm., 531 U.S. 341, 350 (2001). Indeed, many unapproved uses are integral to the practice of medicine, and reflect the standard of patient care. E.g., Joseph W. Cranston et al., Report of the Council on Scientific Affairs: Unlabeled Indications of Food and Drug Administration-Approved Drugs, 32 Drug Info. J. 1049, 1050 (1998). The case here involved a qui tam False Claims Act (FCA) suit against defendants. This case raises serious First Amendment concerns, said amicus, because relator’s and the United States’ construction of the FCA would impose liability on manufacturers for engaging in truthful speech about “off-label” uses of their drugs, i.e., particular uses of an FDA-approved medication that the FDA has not yet approved. The First Amendment unquestionably protects such truthful and non-misleading speech. E.g., Sorrell v. IMS Health Inc., 131 S. Ct. 2653, 2659 (2011).  The prevalence of unapproved—but fully legal—uses of many FDA-approved prescription medicines to treat patients makes it critical that healthcare professionals have access to accurate, comprehensive, and current information about such uses. 

Notably, pointed out amicus, neither relator nor the government alleged that the speech at issue here—relaying reprinted articles about unapproved uses of the drug Integrilin from peer-reviewed journals, and summarizing the results of clinical trials—was false or misleading. Relator and the United States did not even agree on why the FCA proscribes this speech, or how this speech somehow causes others to submit false claims. But their interpretations of the FCA shared a critical flaw according to the Brief: both threaten core First Amendment rights and should be rejected under principles of constitutional avoidance. See Edward J. DeBartolo Corp. v. Fla. Gulf Coast Bldg. & Const. Trades Council, 485 U.S. 568, 575 (1988).

These constitutional concerns seem well-founded: “Speech in aid of pharmaceutical marketing . . . is a form of expression protected by the Free Speech Clause of the First Amendment.” Sorrell, 131 S. Ct. at 2659. Interpreting the FDCA to punish manufacturers for truthfully speaking about unapproved uses impermissibly restricts speech based on its content and the identity of the speaker, and thus triggers heightened scrutiny. These First Amendment concerns apply with particular force to the speech that relator targeted here. The Complaint alleged that the manufacturer merely distributed reprints of medical studies published in reputable independent journals like Cardiology, the American Heart Journal, and the American Journal of Cardiology, and sent letters accurately relaying summaries of clinical trials.  There was no question that the authors of the reprints, the studies’ investigators, physicians, or anyone other than manufacturers can speak about the reprints and trial results as much as they wish. Indeed, everyone but manufacturers apparently can talk to physicians about prescribing Integrilin for unapproved uses without penalty. Relator even conceded that the manufacturer can distribute reprints promoting unapproved uses so long as physicians request such information.

Physicians who received the reprints or other information from the manufacturer in this case received precisely the type of educational information that a trained physician would wish to receive about his patients. Physicians were not only free to disregard these reprints; their Hippocratic Oath obligated them to use their own, independent medical judgment as to whether a given prescription was warranted. And after those physicians prescribed the FDA-approved drug for an unapproved use, hospitals then made additional, independent determinations whether the prescriptions were reimbursable. Only after that did hospitals submit claims to the government.

A good summary of the issues from defense perspective.