Drug minnow Amarin downs FDA in constitutional battle

Irish pharma firm wins major victory over FDA on off-label promotion of its drug Vascepa

In what was truly a case of David vs Goliath, Irish pharma minnow Amarin comprehensively saw off the might of the US drug regulator, the Food and Drugs Administration, in court.

At its heart, the case focused on whether Amarin was being deprived of its first amendment right to free speech in marketing off-label use of its one drug, Vascepa, a refined omega-3 fish oil drug that reduces harmful blood fats in people at risk of heart disease.

The FDA is responsible for certifying both the safety and efficacy of a drug before it can be marketed in the US. In short, without FDA approval, no drug or medical device can access what is by some distance the world’s largest market for pharma and medtech.

It has long taken the position that a drug manufacturer that makes or promotes an approved drug off-label – ie for uses not specifically approved by the regulator – violates the Federal Food, Drug and Cosmetic Act, the governing legislation, and can face criminal prosecution for “misbranding”.


Misbranding can also apply even where the drug is marketed for the condition approved, but at dosages not approved or to patient populations for which it is not specifically sanctioned. And it is not afraid to exercise its muscle when it feels companies have crossed the line.

Secondary uses

In recent years, as Judge

Paul Engelmayer

noted in his ruling, companies of the scale of GlaxoSmithKline, Abbott and Allergan have paid billions of dollars after being caught marketing their drugs for uses other than those for which they were specifically approved.

The problem is that while the FDA regulates the drug companies, it does not regulate doctors. They are free to prescribe off-label and the practice is widespread. A 2001 study published in the New England Journal of Medicine found that approximately 21 per cent of all prescriptions in the US were for off-label purposes.

And in certain areas, including anti-depressants for children and adolescents and antipsychotics among military veterans, off-label use has been found to account for the majority of prescriptions in a series of studies.

Amarin’s Vascepa was approved by the FDA for use in people with extreme levels of triglycerides – a patient population of roughly four million people in the US.

The Irish company had applied also to use the drug in treating people with lower, but still very high, levels of triglycerides – a group numbering closer to 35 million in the US. In doing so, it followed the FDA’s “special protocol assessment” – a written agreement setting out the design and size for clinical trials and the condition under which the FDA would approve the drug.

If the drug company follows the procedures set out in the protocol and meets the agreed benchmarks for efficacy, the FDA must approve the drug unless a “substantial scientific issue” affecting safety or effectiveness of the drug emerges after the trial has begun.

Amarin’s Anchor study met all its targets but, after some rival drugs using different approaches showed no impact on the risk of cardiovascular disease, the FDA advisory panel ruled against it.

It wants to wait instead for results, due in 2017 at the earliest, from another special protocol assessment trial studying the impact of the drug in heart disease for high-risk patients on statins – Reduce-IT.

The company has several times expressed concern that, at a cost of more than $100 million, loss-making Amarin may not be in a position to fund Reduce-IT to completion.

Although Amarin last week reported revenue growth of 40 per cent in its most recent quarter to $17.7 million, that still comes nowhere close to covering its costs.

With R&D spending of $12 million in the period and other general costs of $26 million, the company posted a pretax loss of $32 million in the three months to the end of June. So far this year, it has reported pretax losses of $63.65 million.

Truth of statements

Critically, the FDA refused to allow Amarin use information from the Anchor trial in promoting Vascepa, even though the FDA approved the shape of that trial and largely concedes that the statements are both truthful and non-misleading.

That information included the Anchor finding that the drug does lower triglyceride levels in people with persistently high triglyceride levels that are not responding either to diet or statins, as well as research findings that drugs such as Vascepa “may reduce the risk of coronary heart disease”.

The FDA warned any such statements could be considered misbranding.

Fearing it would be prosecuted over what it argued were true and non-misleading statement, Amarin sued the regulator in the New York second circuit court, accusing it of infringing its constitutional right to free speech.

The choice of court was based on a recently upheld appeal in the case of a salesman, Alfred Caronia, who was convicted of misbranding on the basis of statements made to a doctor.

He was cleared on the basis that the statements he made, in the words of Judge Engelmayer, “consisted solely of untruthful and non-misleading speech”.

Ironically, the Caronia case involved statements made about the narcolepsy drug Xyrem, which is now marketed by another Irish company, Jazz Pharmaceuticals, though the prosecution took place before it was acquired by Jazz.

Despite FDA argument that the two cases were different and that Amarin was engaged in a “frontal assault . . . on the framework for new drug approval that congress created in 1962”, Judge Engelmayer found in favour of Amarin in a ruling that is widely seen as fundamentally changing the rules governing off-label promotion.

Off-label promotion

Commenting on the outcome, lawyer

Jim Beck

of Reed Smith said: “As we’ve said before, at some point the FDA needs to give up its blunt, speech-based prohibition (which has been around since the early 1950s) and take a more sophisticated approach to off-label promotion and what the first amendment allows in the 21st century.

“With the first amendment handwriting now all over the wall, the FDA sorely needs a fallback plan.”