One Small Step for Amarin & One Giant Leap for Pharmaceutical Companies? - Only Time Will Tell

Friday's ruling in Amarin Pharma, Inc. v. United States Food & Drug Administration is a monumental event. It signals the dawn of a new era for prescription drug promotion.

For decades, drug companies have struggled with how to deliver information to physicians that inform prescribing decisions without running afoul of FDA's prohibition against off-label promotion.

The prohibition against off-label promotion runs counter to a world where doctors can, and do, lawfully prescribe approved drugs for either on-label or off-label uses. That a doctor's off-label use of drugs is lawful and permissible is a critical underpinning for the court's ruling here. So is its holding that FDA cannot ignore how commercial free speech law has evolved since the Drug Amendments of 1962 first required companies to demonstrate that a drug is both safe and effective for their intended uses.

It is a ruling that permits one company to share information about a new indication that FDA has, only recently, refused to approve. The FDA refusal occurred despite a successful clinical trial undertaken in consultation with FDA and conducted as FDA desired. FDA surprised Amarin by telling them they would need to await completion of the cardiovascular outcomes trial (despite having met the very milestone that FDA had set to qualify for an expanded indication of lowering triglycerides).

Currently the sole FDA-approved indication for Vascepa is as an adjunct to diet for patients with "very high" triglycerides (i.e., triglyceride levels above 500 mg/dL.) The expanded indication would have encompassed patients with "high" triglycerides (i.e., 200-499 mg/dL of blood).

Recent studies of other triglyceride-lowering medications fenofibrate and niacin, however, had failed to show any cardiovascular benefit. So on the same day that FDA rejected the expanded indication for Vascepa, it also rescinded approval of the requested indication (i.e., reducing triglyceride levels in patients with persistently high triglycerides) for fenofibrate and niacin products. (p. 26, n.46)

By agreement with FDA, a cardiovascular outcomes trial was halfway done when Amarin submitted its Supplemental New Drug Application (SNDA) for an expanded indication of lowering triglycerides in a new patient population. That the drug had in fact demonstrated potent triglyceride-lowering properties (in the study that FDA and Amarin had agreed upon) did not win the day. FDA ultimately said, no, actually we need that data on cardiovascular health outcomes completed first.

The good news is Judge Paul A. Engelmayer's thorough opinion reaffirms that yes, even prescription drug pharmaceutical companies enjoy First Amendment “free speech” protections. Those protections extend to unprompted truthful and non-misleading communications about what a drug can do, even if such statements are not directly included in the FDA-approved indications or, in fact, anywhere in the package insert.

There are, however, a few important caveats for what this decision means to prescription drug companies. These caveats are important as companies consider embarking on a wholesale revision of their current marketing policies:

1. Preliminary, not Permanent, Injunction – The Amarin decision is a "preliminary injunction" ruling. This means that the court has issued an order at the outset of a lawsuit that is only a "preliminary" ruling. The ruling will be revisited as the court determines whether a permanent injunction (against FDA off-label prohibitions and restrictions) is warranted.
2. New York Federal Court (Southern District) – The decision applies solely in the Southern District of New York, which is the jurisdiction where it was issued. Likewise, the United States v. Caronia decision (which came out of the U.S. Court of Appeals in the Second Circuit), did not trigger a monumental shift in how companies market their prescription drugs. The Caronia decision is only binding in New York, Connecticut and Vermont. (Therefore, the S.D.N.Y. court was obligated to follow Caronia, but had this lawsuit been filed elsewhere, the court could have chosen to follow or reject the Caronia 2-1 decision.)
3. Very Safe High Dose Fish Oil – The drug at issue is Vascepa^® (icosapent ethyl), which has an approved NDA for certain lipid-lowering claims. It is an FDA-approved product with pure eicosapentaenoic acid (EPA) as its active ingredient. Other drugs (fenofibrate, niacin and omega 3-acid ethyl esters) have approved NDAs for comparable claims, and EPA is also sold over-the-counter, although when offered over-the-counter, it is only available in lower dosages. The court remarked that FDA has acknowledged that it has no evidence that Vascepa is harmful, and that Vascepa could be sold as an over-the-counter dietary supplement if Amarin chose to do so. It is therefore not the type of product that contains extensive contraindications, precautions or warnings or a boxed warning. Indeed, the court concluded: "[T]here is no basis to fear that promoting Vascepa for this off-label purpose would endanger the public health." (p. 67). The particular safety profile of EPA was an important aspect of the court's analysis, which may have come out differently had a product with more safety concerns been at issue.
4. It is a Fact-Specific Ruling – The court painstakingly addressed in its 69-page opinion (plus two pages of exhibits) the various statements that Amarin proposed to make about its product and FDA's restrictions on how such statements could be made. Specifically, Amarin is now permitted to take three specific actions (but only with the detailed disclosures, many of which Amarin offered and that FDA or the court refined). The actions Amarin can now take are:
   • Reprints – Thirteen reprints may be disseminated even though they address the effect of EPA (the main component of Vascepa) on coronary heart disease (which is not one of Vascepa's approved uses). FDA acknowledged that these reprints may be disseminated under its existing guidance so long as they are not accompanied by misleading language. The court concluded that reprints must be accompanied by the disclosure statements that Amarin, or FDA, proposed (as modified by FDA or the court in this ruling). The court concludes that "Amarin's dissemination of these reprints, under the circumstances proposed, would be neither false nor misleading." (p. 55)
   • One Page ANCHOR Study Summary – A summary about the ANCHOR study can be proactively shared without awaiting an unsolicited request. That summary discusses the lowering of triglycerides in patients with "high" (but not "very high") triglycerides. The summary presents information in a neutral and objective manner. FDA agreed that the one-page statement (attached as an exhibit to the opinion) accurately summarizes the ANCHOR study (on lowering triglycerides in a new patient population) (even though FDA rejected adding that new indication). The summary includes a concluding comment that the effect of Vascepa on cardiovascular outcomes has not been determined.

The proactive dissemination of this study summary is an important "win" for Amarin because FDA had recently refused Amarin's request to expand its indication to include patients with "high" triglycerides. More importantly, FDA had also refused to include any of the ANCHOR data in the label.

• Dietary Supplement Claim – In addition, three promotional statements may be made. FDA determined two were acceptable "as is." Those statements discuss how the ANCHOR study of patients with 'high' triglyceride levels experienced a lowering of: (1) triglycerides; and (2) lowering of other markers such as non-HDL-C (non-"good cholesterol"), while not raising LDL-C ("bad cholesterol").

FDA accepted these two proposed statements from Amarin despite that the current label for Vascepa does not include an indication for use in patients with only "high" (not "very high") triglyceride levels. That approved marketing statement permits Amarin to address other endpoints in its study that enable Amarin to distinguish Vascepa from some competitor products that lower triglycerides, but also raise LDL-C ("bad cholesterol").

Most significantly, the decision permits Amarin to proceed with a statement (that those promoting dietary supplements already use), with a slight modification (underlined below) that Amarin proposed. (The court accepted the revised statement because FDA, in this litigation, expressed a concern that doctors might forego other useful treatment):

"Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease. Vascepa should not be taken in place of a healthy diet and lifestyle or statin therapy."

This is a significant ruling. Prescription drugs, unlike dietary supplements, usually cannot claim "potential" product efficacy. Rather, there must be “"substantial evidence" to prove that the expected benefits have already been shown. But the court noted that FDA had acknowledged at oral argument that it is undisputedly an accurate account of the current state of scientific research, and that the statement can be made directly to consumers (in the context of over-the-counter dietary supplements). In the court's view, taken in context with the other disclosure statements that Amarin will be making, the court determined that the statement is not misleading. (Meanwhile Amarin's cardiovascular outcomes study is ongoing).

Importantly, for each of the above actions, Amarin has agreed to make a set of detailed disclosures. FDA and Amarin reached agreement on the exact language for several of those specific disclosures during this litigation. For those disclosures where FDA and Amarin could not agree, the court inserted its own revisions (subject to further tweaking by the parties if they can both agree). Those disclosures must accompany each of the three proposed actions (i.e., dissemination of reprints, the one-page ANCHOR study summary and the three marketing statements).

As a result, the actions Amarin now may take, including the exact language of the specific disclosures that must accompany each of the above actions, all have the benefit of approval from FDA or the court. The disclosures include a statement that Amarin proposed: "Vascepa may not be eligible for reimbursement under government health care programs (Medicare/Medicaid) to reduce the risk of coronary heart disease or for treatment of statin-treated patients with mixed dyslipidemia and 'high' (>200mg/dL and < 500 mg/dL) triglyceride levels. We encourage you to check that for yourself." (p. 56)

What Happens Next?

What happens next is a wild card. The high levels of triglycerides were, and are still viewed, as a potential biomarker for cardiovascular risk. Congress, patient advocates and FDA have been focusing on biomarkers. The ability to inform about this information seems to have expanded. The Department of Justice and the Office of Inspector General of the Department of Health & Human Services have relied on the absolutist interpretation of off-label use as the cornerstone of their enforcement activities. Those actions must now be reevaluated.

Perhaps FDA will issue its long-promised new guidance to relax its off-label promotion restrictions. The court acknowledges that the 1998 Washington Legal Foundation vs. Henney case concluded when FDA adopted a less restrictive approach. (p. 17 fn. 34) Were FDA to relax its requirements, the issues in the Amarin case could potentially become moot and lead to the court's dismissal of the Amarin action as well. This could take some time, however, because FDA has yet to set a date for the hearings on this issue that it promised to hold this summer (which could serve as a precursor to such a guidance).

Meanwhile, the 21st Century Cures bill adds additional legislative pressure, to the judicial pressure now exerted, on FDA to loosen its off-label promotion restrictions. Further, FDA's actions in the case remain under scrutiny, because there is much more to occur in the Amarin lawsuit. FDA could file a motion for rehearing or appeal the decision. If FDA does not opt to take those steps, there will likely be a further work-up of the case so the court can determine whether a permanent injunction is warranted.

What Can Drug Companies Do Now?

Inevitably, emboldened by the Caronia and Amarin rulings, drug companies will want to take more aggressive action in disseminating truthful, non-misleading off-label information. Such an approach must, however, be undertaken with care. Indeed, the Amarin ruling acknowledges two limits that exist in the Caronia decision: 1) no First Amendment protection exists for false or misleading commercial speech; and 2) conduct plus speech is still subject to enforcement. As a result, the Amarin ruling states: "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." The court, therefore, suggests that companies consult with FDA before promoting off-label use because "[r]easonable minds may differ over whether a given statement is misleading in context; and developments in science or medicine may make a once-benign statement misleading." (p. 53)

The challenge, of course, is that had the court not held the FDA's feet to the fire in proceeding with the preliminary injunction motion hearing schedule (despite FDA's request for a delay of that hearing), the likelihood of prompt FDA response to any request for input remains low. FDA simply has not dedicated sufficient resources to offer predictable timeframes for responding to company requests for input on their proposed marketing messages.

Thus, Amarin here has won a victory for itself in obtaining both important concessions from FDA and, ultimately, court approval of a specific path to talk proactively about truthful, non-misleading information regarding its product beyond the confines of its label.

This win is also a win for drug companies. But unless companies undertake their own lawsuits or proactively seek FDA input (despite uncertain response times), proactive off-label marketing is still properly viewed as a high-risk endeavor. As it stands now, this opinion applies to the marketing of Vascepa in the Southern District of New York. It remains to be seen whether even the Court of Appeals for the Second Circuit (which encompasses New York, Connecticut and Vermont) will agree with this court's approach.

Conclusion

We may one day look back in disbelief at government prosecutions of off-label promotion ending in multi-billion dollar settlements. But while Judge Paul Engelmayer's ruling in Amarin restores new hope to pharmaceutical companies, the FDA off-label prohibitions and restrictions are not "off the table" just yet for the vast number of prescription drug companies, even though they too have important and valuable messages to share about their products.

Still, one company that has opted to challenge FDA in court has reaped the benefit of its preemptive strike and obtained valuable and prompt input from FDA. As a result, Amarin may proceed in the marketplace with discussion of its most recent successful clinical trial, which showed that Vascepa does reduce triglycerides and other blood markers (even while the current label states that the effect on cardiovascular mortality and morbidity has not been determined). They will do so with guidance from FDA (and, ultimately, the court) on a "path forward" for lawfully getting the word out about important new "off-label" updates for its drug. It was indeed a good day for Amarin – time will tell whether this signals the beginning of a new era for other companies who also want to share important, truthful and non-misleading information about their prescription drugs.