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Will FDA Finally Stop Impinging on Free Speech?

Writer critiques agency’s approach to regulating off-label promotion

The off-label promotion of drugs may not be the kind of First Amendment right that gets a lot of attention during the presidential election cycle, but it has nevertheless cost the drug industry billions of dollars, according to BioSpace columnist Karl Thiel.

Civil and criminal penalties in 31 cases over the past 11 years have totaled a little over $15 billion, Thiel points out, and settlements have ranged from the modest all the way up to GlaxoSmithKline’s record-breaking $3 billion payout in 2012.

Most of these cases allegedly involved “bad actors” doing illegal things, such as doling out bribes and presenting false information. But some –– at least according to the companies involved –– simply involved the presentation of truthful information on off-label uses of products.

According to longstanding FDA doctrine, any presentation of information on a drug by a company or its representatives that doesn’t correspond to the approved labeling constitutes “misbranding,” Thiel says. Doctors are, of course, free to prescribe drugs for alternative indications, but companies and sales reps generally cannot talk about it.

Several years ago, the pharma industry started pushing back. Allergan broke new ground in 2009 by suing the FDA over its off-label promotion of Botox (onabotulinumtoxinA). The company was in a difficult situation because the drug is widely used off label, and its risk evaluation and mitigation strategy (REMS) required that its reps talk to doctors “in general terms” about the off-label use that was already happening. The FDA said the company crossed the line, but Allergan said its speech was unfairly hampered. In 2010, the company was forced to drop its suit as part of a $600 million settlement.

Par Pharma tried again in 2011, claiming in a lawsuit against the FDA that it had a constitutional right to “provide truthful information” about its appetite stimulant Megace ES (megestrol acetate). In that case, the claim was even narrower, saying that the FDA was limiting Par from even talking about on-label claims. Again, the company had to drop the suit as part of a $45 million settlement in 2013.

A few months before Par settled, the U.S. Court of Appeals for the Second Circuit handed down its decision in United States v. Alfred Caronia. The case involved a drug rep from Orphan Medical (now part of Jazz Pharma) who was convicted of misdemeanor conspiracy for presenting off-label information on the narcolepsy drug Xyrem (sodium oxibate). While a federal district court upheld the conviction, it was overturned in a 2-to-1 decision on appeal, on First Amendment grounds.

The FDA decided not to seek either a rehearing or an appeal, simply letting the case stand. It then suggested that Caronia has no bearing on prosecution under the False Claims Act. This has resulted in the confusing interpretation that while the promotional speech may be allowed, any conduct that results in a false claim, such as a request for reimbursement of off-label use, is illegal.

A few weeks ago, Thiel writes, Amarin prevailed in its own lawsuit against the FDA regarding Vascepa (icosapent ethyl), its omega-3 fatty acid drug. Vascepa is approved to treat severe hypertriglyceridemia, but it has also been shown to lower more moderately elevated triglycerides. Despite meeting the requirements of a special protocol assessment (SPA) for this population, the FDA decided that lowering triglycerides wasn’t clear enough evidence of improved health outcomes. That cost Amarin an expanded label, but the company still wanted to present its data to physicians. The FDA threatened it with legal action if it did, and Amarin pre-emptively sued.

Although this was a motion for a preliminary injunction, the judge discussed the merits of Amarin’s First Amendment claims and was specific about the meaning of Caronia. “The Court’s considered and firm view is that, under Caronia, the FDA may not bring such an action based on truthful promotional speech alone, consistent with the First Amendment.”

The FDA came under increased pressure in July, when the “21st Century Cures Act” was passed by the U.S. House of Representatives by a 344-to-77 vote. The bill is currently working its way through the Senate. Among other things, it requires the FDA to issue guidance “to clarify how drug and device manufacturers can permissibly disseminate truthful and non-misleading scientific and medical information about a drug or device that is not included in the approved labeling for the product.”

At this point, it seems inevitable that the FDA will have to relax its standards, Thiel writes. But how will the promotional landscape change?

Critics suggest that companies will no longer have the incentive to conduct trials on new indications when they can just promote them off-label, and that could spell trouble. In the past, company-sponsored studies have occasionally found that widespread off-label uses of drugs were in fact dangerous. Without any incentive to do these studies, that kind of information might never be uncovered, Thiel says.

In his opinion, it’s in the FDA’s best interest to be willing compromise and offer some clarity. For instance, a small clinical study supporting an off-label use may technically be truthful, but its statistical power may render it irrelevant and therefore misleading.

Source: BioSpace; August 26, 2015.

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