First Amendment Suit: FDA Draws Line At Amarin's Heart Disease Claim

Amarin Pharmaceuticals Inc.’s bid for a court order to allow it to tell doctors about an unapproved use of its Rx fish oil drug Vascepa “is a frontal assault” on the new drug approval framework, FDA contends.

In a June 23 court filing opposing Amarin’s motion for a preliminary injunction against the agency, FDA says a decision in Amarin’s favor “has the potential to establish precedent that would return the country to the pre-1962 era when companies were not required to prove that their drugs were safe and effective for each of their intended uses.”

Amarin filed suit in May seeking a declaration that FDA’s regulations on off-label promotion are unconstitutional and it has a right to distribute truthful and non-misleading speech about Vascepa “even if that speech is off-label promotion” (Also see "Off-Label Litigation: Amarin Sues FDA In Bid To Promote Vascepa Fish Oil" - Pink Sheet, 7 May, 2015.).

FDA disagrees with Amarin’s argument that regulation of its communications violates its First Amendment right to free speech.

The agency says the only question before the court is whether the First Amendment permits the government to look at Amarin’s dissemination of information about unapproved uses “as evidence that Amarin intends a new use” for Vascepa (icosapent – a purified ethyl ester of eicosapentaenoic omega-3 fatty acid). “It unquestionably does: the evidentiary use of speech to prove intent is constitutional under the First Amendment.”

FDA sent Amarin a June 5 letter saying it would allow the company to distribute reprints of journal articles describing the results of a randomized, double-blind, placebo-controlled, 12-week study of icosapent in patients with persistently high triglyceride levels on statin background therapy, referred to as the “ANCHOR” trial (Also see "FDA “Approves” Amarin Vascepa Off-Label Campaign; Industry Groups Urge Court Not To Take The Bait" - Pink Sheet, 16 Jun, 2015.).

However, FDA bluntly rejects a separate argument made by Amarin that it should be permitted to make a cardiovascular health claim for its prescription product given that products marketed as dietary supplements can make the claim.

The agency notes its long history of analyzing omega-3 supplement claims, concluding there is no significant scientific agreement that omega-3 fatty acids reduce the risk of coronary heart disease.

On the other hand, though, FDA acknowledges that under Pearson v. Shalala and other court decisions, it does not currently object to the claim for supplements or conventional foods if certain conditions are met – applying enforcement discretion under its regulatory scheme for supplements.

“This low level of scientific evidence for qualified health claims resulting from Pearson and its progeny should not be extended to claims for drugs, which require substantial evidence of effectiveness to support approval of each approved use because dissemination of information with such a low level of scientific weight could undermine the important public health interest served by the premarket approval requirements for drugs,” FDA says,

The agency gives Amarin an option, though not one the firm likely will accept.

“If, however, you were to repackage and re-label your product as a dietary supplement … FDA would not object to your inclusion on that dietary supplement of the qualified health claim reference d above. Alternatively, if you wanted to distribute your product repackaged and relabeled as a dietary supplement, with a different claim, you could petition for a new qualified health claim.”

REDUCE-IT Trial Could Be Derailed

The agency says it does not object to most of Amarin’s proposed communications and those in dispute are the claim about reduced risk of heart disease and journal reprints and summaries of the ANCHOR trials results that are not disseminated as FDA described in its letter.

FDA approved Vascepa in 2012 for use as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia. In April, FDA issued a complete response letter declining to approve the drug for use by patients on statin therapy with very high triglyceride levels based on the results of Amarin’s ANCHOR trial.

FDA said the company had not provided evidence of a reduction in cardiovascular risk. The company is conducting a cardiovascular outcomes trial in patients with high triglyceride levels, REDUCE-IT – Reduction of Cardiovascular Events with EPA - Intervention Trial – the results of which are expected in 2018.

Amarin said it wants to be able to tell physicians about the results of the ANCHOR study right now and to provide peer-reviewed scientific publications “relevant to the potential effect of EPA on the reduction of the risk of coronary heart disease.”

FDA said dissemination of the heart disease claim in conjunction with the ANCHOR trial results would “perpetuate the unsubstantiated claim that Vascepa confers a clinical benefit by lowering triglyceride levels in patients with cardiovascular disease or risk.”

The agency is represented in the litigation by Preet Bharara, U.S. Attorney for the Southern District of New York. Accompanying Bharara’s 51-page memorandum is a 32-page declaration from Center for Drug Evaluation and Research Director Janet Woodcock describing the agency’s new drug approval requirements and the application of its policies on communication of unapproved uses to Amarin.

Woodcock said Amarin would have much less of an incentive to conduct the REDUCE-IT trial if the court authorizes it to make this claim.

“Although I understand that Amarin has stated that it intends to complete the REDUCE-IT trial, it is conceivable that Amarin might choose to forego the trial should it prevail in this lawsuit. Were that to happen, the medical and scientific community would be deprived of the robust scientific data promised by the REDUCE-IT trial regarding the safety and efficacy of Vascepa for the use related to cardiovascular disease,” Woodcock said.

Curtis Rosebraugh, director of the Office of Drug Evaluation II, also submitted a declaration describing the agency’s approval of Vascepa, Abbott Laboratories Inc.’s Trilipix (fenofibric acid), AbbVie Inc.’s Niaspan (niacin extended-release) and GlaxoSmithKline PLC’s Lovaza (omega-3-acid ethyl esters) and the cardiovascular outcomes trials relevant to those products’ labeling and approval.

Caronia Ruling Does Not Apply – FDA

Amarin cited the U.S. Second Circuit Court of Appeals’ 2012 ruling in U.S. v. Caronia in arguing its likelihood of success in the litigation. In that case the court ruled the government cannot prosecute pharmaceutical manufacturers or their representatives for speech promoting the lawful, off-label use of an approved drug.

“Caronia, however, did not decide whether it would be constitutionally permissible for the government to consider speech to be evidence of intended use,” FDA stated. “Instead, it involved the constitutionality of a ‘complete and criminal ban on off-label promotion.’”

“Moreover, unlike here, the Caronia court did not have the benefit of a government declaration demonstrating that the communications at issue might be misleading,” the agency said. “And – also unlike here – the Caronia court was not presented with any declarations explaining how the communications at issue would undermine the premarket approval regime and attendant public interest it furthers, and why various potential alternatives would fail to protect those interests.”

Woodcock said FDA examined alternative approaches, including those identified by the Second Circuit in Caronia, and found they were “impractical, ineffective, unrealistic, or based on inaccurate assumptions.”

The alternatives include an outright prohibition on the use of approved products for unapproved uses; setting ceilings or caps on the number of prescriptions for an unapproved use; limiting Medicare and Medicaid reimbursement to approved uses; prohibiting specific unapproved uses that are exceptionally concerning or developing tiers based on level of safety concerns; and allowing firms to promote an unapproved use as long as they disclose it is unapproved and include other warnings (Also see "FDA Reassessing Off-Label Policies To Address First Amendment Concerns" - Pink Sheet, 23 Apr, 2014.).

Amarin also asked the court to enjoin FDA from False Claims Act enforcement for its proposed communications. FDA said it is difficult to see how a false claim would arise if the indication cited is supported by a medical compendium and there is no other contention of falsity.

Besides, FDA said to bring an FCA action, the government must prove Amarin caused doctors to submit materially false claims to the government for payment of non-covered uses that were ineligible for payment and did so with knowledge of wrongdoing.

(Versions of this article also were published in “The Pink Sheet” DAILY and The RPM Report.)