Megestrol Acetate

August 26, 2015 By Karl Thiel for BioSpace.com Amarin may be the last straw for FDA’s approach to regulating off-label promotion It might 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: Off-label promotion of drugs. It’s long been verboten, but the kinds of claims that companies can make and the information they can share may be about to change in a significant way. Enforcement on this issue has been costly. Civil and criminal penalties in 31 cases over the past 11 years total up to a little over $15 billion—a pretty stunning figure that involves, at some point or other, many of the world’s largest drug companies (and a not-insignificant number of smaller players). Settlements have ranged from the modest all the way up to GlaxoSmithKline ‘s record-breaking $3 billion settlement in 2012. Most of these cases allegedly involve bad actors doing illegal things, from doling out bribes and kickbacks to withholding data and presenting false or misleading information. (I say allegedly because virtually all settlements allow the perpetrators to admit no wrongdoing). But some, at least according to the companies involved, simply involved the presentation of truthful information on off-label uses of products. That may sound like a straightforward free speech issue, yet according to longstanding FDA doctrine, any presentation of information on a drug by a company or its representatives that doesn’t hew to the approved label constitutes “misbranding.” Doctors are of course free to prescribe drugs for alternative indications, but companies and sales reps generally can’t talk about it. Backlash Because of FDA’s authority, companies have long struggled to stay compliant—even if the record of legal settlements demonstrate that violations on some level happen with remarkable regularity. Several years ago, however, the industry started pushing back. Allergan broke new ground in 2009 by suing the FDA over its off-label promotion of Botox. The company was in a sticky situation because Botox is widely used off label, and its REMS (risk evaluation and mitigation strategy) required it to talk to doctors “in general terms” about the off-label use that was already happening. FDA said the company crossed the line, but Allergan said its speech was unfairly hampered. Ultimately, the company was forced to drop the suit as part of a $600 million settlement in 2010. 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. In this case, the claim was even narrower, saying that the FDA was limiting it from even talking about on-label claims. Again, it had to drop the suit as part of a $45 settlement in March 2013. Here’s where it gets more interesting. Just a few months before Par settled, the U.S. Federal Appeals Court for the second circuit court handed down the decision in United States v. Alfred Caronia . As I wrote at the time , FDA’s power to limit promotional speech had actually been legally contested since at least the 1990s, but Caronia represented the agency’s biggest defeat. 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. While a District court upheld this conviction, it was overturned in a 2-1 decision on appeal, on First Amendment grounds. What’s interesting is how the FDA reacted to the defeat. It decided not to seek either a rehearing or an appeal, simply letting the case stand...and then subsequently narrowing its interpretation of the decision. Most notably, it has 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 (e.g., a request for reimbursement of off-label use) falls afoul of the law. Fast Forward That gets us to the present. Just a couple weeks ago, Amarin prevailed in its own lawsuit against the FDA regarding Vascepa, its omega-3 fatty acid drug. Vascepa is approved to treat severe hypertriglyceridemia, but 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 effectively moved the goalposts and decided lowering triglycerides didn’t amount to 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 preemptively sued. While this was a motion for preliminary injunction, it’s notable that the judge discussed the merits of Amarin’s First Amendment claims and was very 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.” And this isn’t the only piece of new pressure on FDA: In July, the “ 21st Century Cures Act ” was passed by the U.S. House of Representatives by a 344-77 bipartisan vote and is currently working its way through the Senate. Among other things, this bill 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.” What Happens Next? At this point, it’s looking inevitable that the FDA will have to relax its standards, and its best strategy is to do so in a measured and thoughtful way—a process it has indeed already begun through some meetings with industry. So how might the 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 indeed spell trouble: In the past, company studies have occasionally found that widespread off-label uses of drugs were in fact dangerous. Without any incentive to do these kinds of studies, that kind of information might never be uncovered. However, that presumes that companies will be given a pretty free hand in the kind of information they share. That’s unlikely to be the case—or, at least, it’s in the FDA’s best interest to loosen the reins a bit before some blunt piece of legislation throws the floodgates open to promotional speech. All indications so far show that the FDA can maintain control. It simply must compromise and offer some clarity. For instance, a small clinical study supporting some off-label use may technically be truthful but its statistical power may render it irrelevant and therefore misleading. Companies, for their part, are likely to proceed with caution. Like the FDA, they may not want to risk a contradictory court opinion when things seem to be going their way. They also risk greater liability when drugs are used outside of FDA approved use, which should throw the brakes on more aggressive off-label promotion. Either way, I think the FDA’s days of pretending this simply didn’t happen are over with. - Karl Thiel Read the BioPharm Executive online newsletter August 26, 2015. Sign-up for the free monthly subscription to the BioPharm Executive .