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A recent court decision enjoined the FDA from threatening prosecution against a drug manufacturer for off-label promotion of a prescription drug. Based on this and an earlier decision by an appellate court, it appears that the FDA can no longer prosecute a pharmaceutical manufacturer for a truthful and non-misleading off-label promotion to health care professionals, at least within the jurisdiction of the United States Court of Appeal for the Second Circuit, which covers Connecticut, New York and Vermont.

For this reason, the case, Amarin Pharma, Inc. v. FDA (Amarin), received a good deal of attention in the world of drug regulation. (Here is an excellent analysis by two attorneys who practice in the area of drug regulation.) First, we’ll take a look at the issue of off-label promotion. Then we’ll look at an issue that really didn’t engender much comment, but that I find fascinating: how the same substance can be subject to very different regulatory treatment, depending on whether it is sold as a dietary supplement or prescription drug.

Background: Initial approval of Vascepa and subsequent research

In 2012, the pharmaceutical manufacturer Amarin received FDA approval for a new drug, Vascepa, as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia (triglycerides ≥ 500mg/dL). Approval was based on a single phase 3 clinical trial.

Following that approval, Amarin designed a second single phase 3 clinical trial to look at the effect of Vascepa on triglyceride levels among statin-treated patients with persistently high triglycerides (≥ 200 and ≤ 500 mg/dL). Pursuant to an agreement with the FDA that, if it met certain conditions, Vascepa would obtain approval for this use, Amarin proceeded with an FDA-approved protocol. As a further condition of the agreement, it also began enrolling patients in a third trial to see if Vascepa actually reduced major cardiac events.

The second trial showed that Vascepa did decrease triglyceride levels, and Amarin thought it had fulfilled the agreement’s requirements for approval. However, the FDA convened an advisory panel and called into question the clinical validity of the reduction in triglycerides achieved in the second trial. That is, the FDA questioned whether that result would translate into an actual reduction in cardiac events. This was based on other research indicating, according to the FDA, that indeed it did not. This research did not include the third trial’s results, designed to answer this very question, because that trial won’t be completed until 2017.

The FDA rescinded its agreement, did not approve Vascepa’s use for patients with persistently high triglycerides, and notified Amarin that any effort to market Vascepa for this unapproved use could constitute misbranding under the Food, Drug, and Cosmetic Act (FDCA).

I’ll see you in court

What happened next gives one the impression that the FDA’s actions really frosted Amarin. Instead of waiting for the FDA to come after it for promoting off-label use, it hauled the FDA into court and asked the judge for a preliminary injunction preventing the agency from taking any action against the company for truthful, non-misleading promotion of Vascepa to health care professionals for patients with persistently high triglycerides. And it won.

By now you might be wondering: what, exactly, is in this Vascepa? It’s fish oil. Or, if you’re a stickler for details, it is, according to the FDA:

icosapent ethyl or ethyl-eicosapentaenoic acid (EPA). . . The drug substance, icosapent ethyl, is a long-chain, polyunsaturated omega-3 fatty acid ester derived from fish oil.

The recommended daily dose for treatment of severe hypertriglyceridemia is 4 grams daily.

Off-label prescribing is not per se illegal, although a physician can get into trouble if he falls below the standard of care. And, because the FDA doesn’t regulate doctors (the states do that), it can’t prevent it. Actually, the FDA doesn’t disapprove of what it sees as responsible off-label use. The FDA’s concern is with off-label promotion by pharmaceutical companies, and it has taken the position that such promotion violates the Food, Drug and Cosmetic Act, even though there is no such proscription in the Act itself. It does so by reasoning that off-label promotion amounts to “misbranding” the drug.

The FDA has backed off this absolute position in the last decade, and issued draft guidance on the circumstances under which truthful information about an off-label use can be distributed. This includes, for example, distribution of journal articles and medical texts that include information on unapproved uses. As with all draft guidance, it is not binding on the FDA or anyone else.

The court’s opinion has some interesting statistics on the ubiquity of off-label prescribing:

  • The most comprehensive study on off-label prescriptions in the United States, conducted in 2001, found that approximately 21% of prescriptions were for off-label purposes.
  • According to a 2000-2006 study, more than 90% of antidepressants prescribed to children and adolescents in an outpatient care setting were for off-label purposes.
  • Based on review of Veterans Affairs databases, more than 60% of prescriptions of antipsychotic drugs in 2007 were for off-label use.
  • A study of medication orders for 414 patients in 37 intensive care units across nation showed that more than 35% were for an off-label purpose and that 97% of patients received at least one off-label medication.

Not included was the fact that the vast majority of prescriptions for fish-oil drugs are off-label, including an estimated 75% of a competitor’s prescriptions.

In ruling on Amarin’s request for a preliminary injunction, the district court had to decide whether it was likely Amarin could ultimately succeed on the merits of its case. This, in turn, required the court to address whether the FDA could prevent Amarin from promoting off-label use of Vascepa for patients with persistently high triglycerides, even when the information was truthful and not misleading. Relying heavily on a decision of Second Circuit Court of Appeals, United States v. Coronia, the court held that the FDA could not constitutionally prevent Amarin from:

engag[ing] in truthful and non-misleading speech promoting the off-label use of Vascepa, i.e., to treat patients with persistently high triglycerides, and under Coronia, such speech may not form the basis of a prosecution for misbranding.

In Coronia, the government criminally prosecuted a drug rep for off-label promotion but the appellate court overturned his conviction. The Second Circuit first decided that:

‘[s]peech in aid of pharmaceutical marketing . . . is a form of expression protected by the . . . First Amendment’ . . . It then applied to such speech truthfully promoting off-label drug use the four-prong test of [the U.S. Supreme Court’s decision in] Central Hudson, used to determine a restriction upon commercial speech violates the First Amendment.

We won’t go through the entire Central Hudson analysis here, but it’s worth noting that while the court recognized that the FDA has a legitimate interest in protecting the integrity of the FDCA drug approval process, it had chosen means (a criminal prosecution) that was broader than necessary to achieve that goal, that off-label promotion is not per se illegal, and the FDA’s ban:

‘paternalistically’ interferes with the ability of physicians and patients to receive potentially relevant treatment information.

Although the FDA tried to distinguish Coronia, the district court didn’t buy it. If anything, the FDA’s position in Amarin was even weaker than in Coronia. It was threatening to go after Amarin for telling physicians the results of a clinical trial that the FDA itself had approved and whose results the FDA didn’t dispute. And, as the court pointed out, if the FDA didn’t like the Coronia decision, it should have sought rehearing or review by the U.S. Supreme Court. Now, it is stuck with the decision, like it or not.

At some point in this imbroglio, the FDA backed off a bit, and the parties tried to reach an agreement on what representations about off-label use of Vascepa could, and could not, make. (Actually, at the end, they weren’t that far apart.) Having decided the FDA could not constitutionally prohibit truthful promotion, the court proceeded to settle this dispute for them.

Which brings us to dietary supplements

As you may recall, unlike drugs, there is no pre-market approval of dietary supplements by the FDA. Supplement manufacturers are supposed to have evidence backing up their “structure and function” claims, but they don’t have to show their evidence to the FDA or the public. However, under the Nutrition Labeling and Education Act of 1990, dietary supplements can also make “qualified health claims” if the FDA:

determines based on the totality of the publicly available evidence (including evidence from well-designed studies conducted in a manner which is consistent with generally recognized scientific procedures and principles), that there is significant scientific agreement among experts qualified by scientific training and experience to evaluate such claims, that the claim is supported by such evidence.

Fish oil is sold as a dietary supplement and, like Vascepa, is promoted for its ability to reduce triglycerides. But the connection between high triglycerides and cardiovascular risk is not yet fully understood. (The full document is behind a paywall, but Scott Gavura helpfully provided me with some of its information on fish oil.)

Although the contribution of triglycerides to cardiovascular risk has been debated in the past, it now seems clear that elevated triglyceride levels are independently associated with cardiovascular risk, particularly coronary risk. It remains uncertain, however, whether this association is causal, such that hypertriglyceridemia, independent of associated lipoprotein, inflammatory and hemostatic abnormalities, causes atherosclerosis. It is also uncertain whether lowering triglyceride levels reduces risk.

This is the very concern that, according to the FDA, led it to renege on its agreement with Amarin.

Yet, the FDA permits fish oil dietary supplements to make the following “qualified health claim”:

Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease.

Which is, as noted above, true. But:

Active omega-3 fatty acids constitute only 30 to 50 percent of many fish oil supplements. In comparison, a commercial preparation (Lovaza in the United States and Omacor elsewhere) is 85 percent omega-3 fatty acids. In patients with severe hypertriglyceridemia, Lovaza (4 g/day) reduced triglyceride levels by 45 percent, but raised LDL-C levels by 31 percent. Another commercial preparation, Vascepa, is more than 95 percent icosapent-ethyl, the ethyl ester of EPA. Icosapent-ethyl (4 g/day) also reduced triglyceride levels by up to 45 percent, but did not significantly affect LDL-C levels. [References in original deleted.]

In fact, Amarin is using this difference between Vascepa and fish oil dietary supplements to promote its product. According to its website, you’d have to take 10 capsules of fish oil supplements a day to reduce triglycerides, and this could mean the supplement is actually more expensive than the prescription drugs. Plus, it says, low dose omega-3 fatty acids can raise “bad” cholesterol levels.

Amarin actually proposed to the FDA that it be allowed to make the same statement in its off-label promotion that the dietary supplement can make. Sounds reasonable.

The FDA said “no.” Why? Because, the statement:

would be potentially harmful to the public health, and [the FDA] would consider such conduct to be potentially misleading or potential evidence of intended use.

Further, according to the court, the FDA argued that the coronary heart disease claim could cause a physician to prescribe Vascepa in lieu of promoting health, dietary and lifestyle changes, or prescribing statin therapy.

However, the FDA stated that, if Amarin repackaged Vascepa as a dietary supplement, the FDA would not object to including the coronary heart disease claim, on certain conditions. That’s right. The company couldn’t promote it to doctors by making truthful coronary heart disease claims but selling it directly to consumers on that basis would be just fine.

In response, Amarin proposed adding the following information to the statement the dietary supplement manufacturers are allowed to use:

Vascepa should not be taken in place of a healthy diet and lifestyle or statin therapy.

The court agreed that, so qualified, Amarin could make this claim without exposing itself to liability for misbranding.

This result makes no sense whatsoever. True, it is an accurate reflection of the different statutory requirements for prescription drugs versus dietary supplements, and no one could find fault with the court for its decision permitting Amarin to make this qualified statement about Vascepa’s benefits. But, logically, it makes no sense. The law allows a claim to be made for a dietary supplement that cannot be made for a prescription drug, even though:

  • It’s essentially the same ingredient (derived from fish oil) although it is of pharmaceutical grade quality in Vascepa,
  • which can be taken at the same dose (it just takes more of the dietary supplement),
  • for the same purpose.

Yet, the prescription drug had to jump through all the hoops of a supplemental new drug approval, conduct a clinical trial, and, despite the favorable results, was denied approval. On the other hand, the dietary supplement companies, although they did have to meet the FDA’s standard for a qualified health claim, avoided all of this expense and didn’t have to go to court to protect their right to make this same statement to consumers without the further disclosure required of Amigen when promoting its product to doctors. And this is in spite of research showing that consumers don’t fully understand the level of evidence conveyed by a “qualified health claim.” (If you want to see how complicated the drug process actually was for Vascepa’s approved use, take a look at the FDA’s Approval Package for the drug.)

The side effects of Amarin

In addition to the salutary effect of providing an excellent example of why the regulation of dietary supplements should be reformed, what else does the Amarin decision portend? As one commentator noted, the Amarin case is different than the dozens of cases where pharmaceutical companies have paid billions of dollars in settling off-label promotion enforcement actions:

‘I don’t think it’s going to open the floodgates to irresponsible off-label promotion,’ said Dr. Daniel Carlat, a drug marketing expert and associate clinical professor of psychiatry at the Tufts University School of Medicine. ‘Companies are still going to have to be really cautious about what their sales reps say.’

Still, the case may raise questions about what constitutes truthful off-label marketing. Small clinical studies that are not well controlled that show a drug is effective for treating a particular condition or patient population may be held up as scientific data that is truthful and is not misleading. ‘That may be more likely to happen with a decision like this,’ Carlat said.

As a preventative against the FDA’s taking action, the court itself gave some sensible advice. It recommended that all manufacturers take advantage of the FDA’s guidance that a pharmaceutical manufacturer vet and script in advance statements about a drug’s off-label use. It warned that leaving drug reps “at liberty to converse unscripted with doctors about off-label use,” invites a misbranding action if false or misleading representations are made, adding that Caronia “leaves the FDA free to act against such lapses.”

After the decision, the parties jointly requested that the proceedings be stayed until October 30 to explore settlement of the matter. Even though a decision granting a preliminary injunction doesn’t preclude a finding in the FDA’s favor after a full adjudication on the merits, I think the FDA sees the handwriting on the wall.

Amarin has already inspired at least one other lawsuit. On September 8, pharmaceutical manufacturer Pacira filed a complaint in the U.S. District Court for the Southern District of New York seeking to prevent FDA from bringing an enforcement action against the company for what it claims is truthful and non-misleading speech concerning its product, Exparel.

Posted by Jann Bellamy

Jann J. Bellamy is a Florida attorney and lives in Tallahassee. She is one of the founders and Board members of the Society for Science-Based Medicine (SfSBM) dedicated to providing accurate information about CAM and advocating for state and federal laws that incorporate a science-based standard for all health care practitioners. She tracks state and federal bills that would allow pseudoscience in health care for the SfSBM website.  Her posts are archived here.