The question concerning what drug makers should be allowed to convey about unapproved uses for their medicines has been widely debated ever since a federal appeals court three years ago overturned the criminal conviction of a sales rep for promoting so-called off-label uses of a drug. The court ruled his actions constituted protected speech, after determining that the information that had been conveyed was truthful and not misleading.

Since then, the pharmaceutical industry has been lobbying the FDA to revise its guidelines, because the decision only applied to three states covered by one particular judicial district. For their part, agency officials have promised guidance is forthcoming and were about to hold a public meeting this summer to, presumably, clarify their thinking about balancing free speech and guarding public health.

Now, though, a new court ruling may force the FDA to rethink its approach.

Preliminary Opinion
Last month, a federal court judge issued a preliminary opinion in case that may strengthen the position taken by drug makers and their supporters. The opinion allows a small company called Amarin to convey off-label information—primarily, peer-reviewed medical studies—to physicians about a drug, so long as that information is truthful and misleading.

The opinion came in response to an unusual lawsuit that Amarin filed in May that claimed the FDA was inhibiting its First Amendment rights to distribute information about Vascepa, a prescription fish oil pill that was approved to treat people with very high triglycerides, a type of fat in the blood that can lead to heart disease.

As you might imagine, there was some history here. Amarin made this move after the FDA rejected its request this past spring to market Vascepa for people with high triglyceride levels. Why? The clash originated with what is known in regulatory parlance over a Special Protocol Agreement between the drug maker and the agency.

In this instance, the SPA hinged on a clinical trial that Amarin conducted to win approval to promote Vascepa for combating high triglyceride levels. It is worth noting that this market is about 10 times the size of the market for people with very high triglyceride levels. And two years ago, some Wall Street analysts were estimating Vascepa could easily become a $1 billion seller.

This SPA was, essentially, a blueprint the FDA agreed to follow toward approving Vascepa for this wider patient population. But the agency later took the rare step of rescinding the agreement when other high-profile clinical data subsequently emerged and raised questions about the extent to which lowering triglyceride levels can be translated into reducing cardiovascular risk.

The regulatory change at heart incensed Amarin, because the drug maker believed it had satisfied all of the FDA requirements to obtain approval of Vascepa for persistently high triglycerides, as spelled out in the SPA. Notably, the ANCHOR trial met its primary endpoint, which was to demonstrate statistically significant reductions in triglyceride levels with Vascepa compared to a placebo.

Fighting Back
The drug maker fought back by arguing in its lawsuit that it should be able, nonetheless, to distribute the clinical trial information and other peer-reviewed data to physicians without fear that its sales people could be accused of violating the law. Notably, Amarin won still wider attention to its cause by hiring famed constitutional attorney Floyd Abrams.

“Many doctors who, consistent with clinical guidelines, treat patients with persistently high triglycerides with drug therapy know the clinical profile of other drugs, but do not know similar information about Vascepa,” Amarin argued in its lawsuit. “These doctors need complete information about their treatment options to make fully-informed decisions about what is best for their patients.”

This argument is, of course, predicated on the knowledge that off-label prescribing happens every day. Physicians are free to prescribe any drug for any particular clinical purpose, even when that drug is not actually approved by the FDA for that use. But the widespread understanding that off-label prescribing is a regular occurrence often prompted the pharmaceutical industry to cross-regulatory and legal lines.

Many drug makers, in fact, have been fined huge sums for off-label marketing over the past decade. The list of violators is a virtual who’s who of the global pharmaceutical industry—Pfizer; Bristol-Myers Squibb; Eli Lilly; AstraZeneca; Johnson & Johnson; Novartis; Amgen; GlaxoSmithKline; Abbott Laboratories; Allergan and Schering-Plough, which was acquired by Merck. And this is a partial list.

Consequently, the pharmaceutical industry has suffered a collective black eye as a barrage of settlements involving nearly every big drug maker—and many mid-sized and smaller ones—have regularly been announced by U.S. authorities. As far as FDA officials are concerned, the only thing standing between improper marketing and patient harm is the law that restricts off-label marketing.

Free Speech
As far as Amarin is concerned, its own goal is simple, but fundamental—drug makers should have the right to convey what it describes as “carefully circumscribed, truthful, and scientifically-accurate statements” about the clinical trial and related information. The drug maker had also maintained it would include disclaimers about risks and the limitations that emerged from trial data.
“It’s important the FDA does not have the power to stifle speech,” Mr. Abrams told The Wall Street Journal. “And FDA is effectively stifling speech.”

And U.S. District Court Judge Paul Engelmayer agreed. His opinion is significant because, as the FDA Law blog noted, he “appears to foreclose FDA from prosecuting a pharmaceutical manufacturer for truthful and non-misleading off-label promotion.” In effect, the FDA would have a much harder time making a case that a drug maker misbranded a medicine by distributing accurate clinical trial data, for instance.

Before we continue, there are some caveats. First, the ruling is preliminary—Amarin won an injunction that prevents the FDA from charging it with misbranding Vascepa, assuming sales reps distribute trial data. For now, the case continues, and the FDA could appeal, cut its losses and settle the case, or continue to litigate.

Moreover, this only applies to three states covered by the second judicial circuit—New York, Vermont and Connecticut. So the pharmaceutical industry and its backers may be heartened by the opinion, but the likelihood that drug makers will suddenly instruct their reps to distribute off-label information around the country is rather unlikely. Rather, this is a classic wait-and-see situation.

Meanwhile, drug makers will have to contemplate a key portion of the opinion—how to vet truthful and non-misleading information. Amarin has a head start in this regard, because the drug maker had a fair amount of data to support its claims, starting with its own Anchor trial that demonstrated Vascepa lowered high triglyceride levels.

Interestingly, the FDA sanctioned much of the information that the drug maker hoped to convey to physicians. We know this because the agency said so in a letter filed in court in June in response to the lawsuit. The FDA “does not have concerns with much of the information you proposed to communicate” and “would not consider the dissemination of most of that information to be false or misleading.”

The agency, in fact, implied the litigation might have been avoided if only Amarin had discussed the issue and reviewed the materials with the agency before filing its lawsuit. To some, this was seen as a pre-emptive move by the FDA to blunt the impact of the lawsuit. More tellingly, still others noted this suggested an emerging blueprint for drug makers to follow haggling over distribution of off-label information.

In effect, the FDA seemed to be saying that Amarin should have simply have approached agency officials with its plan and the specific information to be disseminated. In his opinion in the Amarin case, Mr. Engelmayer implied the same sort of thinking. This is hardly surprising, however, since the FDA, effectively, opened the door itself to the same notion with its June letter.

“Although the FDA cannot require a manufacturer to choreograph its truthful promotional speech to conform to the agency’s specifications, there is practical wisdom to much of the FDA guidance, including that a manufacturer vet and script in advance its statements about a drug’s off-label use,” he wrote. “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,” he concluded.

On the surface, this makes perfect sense. After all, why should any drug maker risk litigation and fines or have a sales rep face a criminal case if there is an opportunity to review such information with the agency before providing it to physicians? Using this logic, the pharmaceutical industry could, theoretically, create an opportunity to proceed with off-label marketing without fear of prosecution.

Seeking FDA Input
Not surprisingly, experts say it would behoove drug makers to seek FDA input before proceeding with any such marketing. But there is an important caveat here—this is only a suggestion. There is nothing to say that a drug maker has to seek FDA input or receive an FDA blessing before disseminating off-label information. While it may be prudent to do so, the Engelmayer opinion did not really articulate who has the legal burden for determining whether information is truthful and not misleading.

Even if a drug maker does sit down with agency officials to review materials to distribute to physicians, what happens if there is disagreement over what is considered truthful or, still more likely, misleading information? Will FDA officials be willing to loosen their grip on judging such things? And what would be the rules for the agency to follow in trying to walk this regulatory tightrope?
A drug maker may very well back down in the face of disagreement, but the Amarin case suggests the pharmaceutical industry may now, instead, feel emboldened to forge ahead. Obviously, this approach could lead to an enforcement action and litigation, and a court would then have to become the arbiter for determining truthful and not misleading information.

But federal courts are not always viewed as the best venues for deciding such things. A key question is the extent to which individual judges or appeals panels should make scientific judgments about the veracity of clinical trial data. Again, we are in the early stages of sorting out the implications of the Amarin case, but this line of thinking suggests there could be case-by-case decisions and a lack of uniformity.

In effect, we would be left with an imperfect and patchwork mechanism for determining whether a drug maker is distributing information to physicians that is, potentially, harmful to patients. And here is another thought to consider: unless the FDA obtains an injunction while litigation is under way, a drug maker could continue to distribute the information until a case is finally resolved.

This not only gives a drug maker a possible free hand during this process, but for a time, some may see this as a situation where the fox is guarding the chicken coop. Think about it, while a drug maker and FDA battle in court, questions remain about whether some information given physicians is misleading. This scenario may not happen very often, but could lead to one instance too many for some patients.

“This is a really important question and the Amarin decision does not give a clear answer to the problem. And we still have to see how the FDA decides to proceed [with the case],” says Patti Zettler, an associate professor at the Georgia State University College of Law who is also a former associate chief counsel in the FDA Office of Chief Counsel.

She suggests that, while there’s no official statement from the FDA, drug makers may consider pushing the boundaries about what the FDA believes is truthful and non-misleading speech.  And this could make the FDA more hesitant about taking enforcement actions against drug makers.

But whether a sea change in pharmaceutical marketing is just around the corner is still unclear. Another expert notes that the Amarin case was unique and, most important, set a high hurdle for determining truthful and non-misleading information, given that the drug maker had a lot of quality data at its disposal.

The FDA, meanwhile, still says a new guidance is forthcoming, although another a year or two may pass before there is any clarity. In the interim, the value of the Amarin opinion will likely depend on the specific circumstances confronting drug makers. Looked at another way, the floodgates for off-label marketing probably have not opened, just yet. 

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Ed Silverman pilots the Pharmalot blog that tracks the pharmaceutical industry. His coverage includes research and development, marketing, pricing, regulation, deals, litigation and legislation. Before joining Stat, an offshoot of The Boston Globe, Mr. Silverman had run Pharmalot for eight years and worked at The Wall Street Journal, The Star-Ledger of New Jersey, New York Newsday and Investor’s Business Daily, among other publications. A New York City native, he received a B.A. in accounting from Binghamton University and a M.A. in journalism from New York University.