The off label issue surfaces often in drug-and-device litigation, even where it should remain wholly submerged. Plaintiffs view off-label promotion as a way of altering the risk-benefit calculation, undermining preemption, and, of course, parading "bad conduct" in front of the jury. Strangely, the off-label attack occasionally is brought in cases where the plaintiff's use was on-label -- though judges are starting to shut that sort of thing down, if only on Rule 403 grounds.
Let's face it: off-label can flat-out sound bad. "Off-label" makes one think of "out-of-bounds." That negative connotation is especially virulent when a company witness agrees that off-label promotion is "wrong, illegal, unethical, causes halitosis" or whatever else the plaintiff lawyer lobs in at hour six of a deposition. It takes some doing to make juries - or even judges - understand what off-label really means.
The defense has a few things going for it. Doctors invariably testify that the option of off-label use is necessary. That is particularly true in oncology and pediatrics. Moreover, it is hard to see the harm from the sharing of truthful, non-misleading information about off-label use. To the latter point, the First Amendment should have a little something to say about whether the FDA or juries should be able to punish truthful speech. But we'd be kidding ourselves if we didn't acknowledge that the off-label issue is a mess. Companies are getting really, really good at training and monitoring sales representatives so as to minimize the risk of off-label promotion. Nevertheless, once aggressive plaintiff lawyers get their hands on thousands of sales call-notes, they'll come up with something at least vaguely malodorous.
Put aside our whining about how off-label issues can distort a product liability case; the treatment of off-label issues in this country amounts to bad policy. That is the gist of a recent article that is worth reading: Osborn, "Can I Tell You the Truth? A Comparative Perspective on Regulating Off-Label Scientific and Medical Information," Yale Journal of Health Policy, Law, and Ethics, Volume X, 299-56 (2010). (The article is available here.) Osborn argues that consumers are hurt by the unclear, draconian enforcement of the prohibition against off-label promotion. That crazy-quilt enforcement, whether by juries or AUSAs, ends up increasing the cost of drug development, inhibiting the adoption of effective new uses, and limiting the dissemination of scientifically valuable information. Osborn at 306.
Osborn does not address one policy ground we've seen urged in support of prohibiting off-label promotion -- that such promotion devalues the NDA process. The concern is that a company could do minimal research and get a drug approved for a narrow use, and then devote most of its marketing to an unapproved use. But most cases we've seen involve companies that were vigorously studying expanded uses and aiming to submit a supplemental NDA. In any event, it's not as if the government seems to care. It doesn't distinguish between the vast majority of conscientious companies versus those few that are gaming the system.
It's utterly unclear what off-label conduct will land one in the soup. Maybe that shouldn't be a surprise. After all, the ugly truth is that enforcement against off-label promotion rests on legally shaky grounds. The FDA and DOJ get there via sleight-of-hand, with the requirement that "labeling" (interpreted incredibly broadly) must provide "adequate directions for use," leading to the regulation-invented concept of an "intended use," which, if it lacks such directions (as it probably will for an off-label use), leads to a finding that the drug is "misbranded," leading to potential criminal exposure. Osborn at 309-10. Such "logic" is hardly compelling. But there it is.
From such an unclear foundation, we get unclear FDA rules. What's impermissible off-label promotion and what's permissible exchange of scientific information? Are sales reps doing something wrong merely by visiting doctors whose use would predominantly be off-label (eg, pediatricians)? Is it "consistent with" approved labeling to discuss a likely mechanism of action if that mechanism is not disclosed in the label? Osborn at 319.
An additional problem is that the FDA lacks transparency in its rulemaking and enforcement. The 2009 guidance on reprints is welcome, but it was much delayed and there are still more questions than answers. The result is rather like what Bentham called "dog-law": the dog gets whacked with the newspaper and has no idea why. There's no fair notice or predictability. In addition, FDA warning letters are paltry, one-off, perfunctory efforts. Compare them to SEC No Action letters, which discuss specific facts against a broad framework of laws, rules, and regulations. Osborn at 320-21. The FDA doesn't issue nearly enough guidances, whether or not they are explicitly identified as such. For example, the FDA asked for comments in the wake of the Thompson v. Western States Medical Center, 535 US 357 (2002) case, which held that the FDA's ban on advertising compound drugs violated commercial free speech rights. That was nice. There were many comments. And then? The "FDA failed to take action, publish its views, or otherwise seek to resolve the questions raised by Thompson." Osborn at 323.
Then the Department of Justice ups both the stakes and the confusion by suing companies under the False Statement Act even when the off-label promotion is not, in fact, false. The government also seems indifferent as to whether there is a causal link between the alleged off-label promotion and prescriptions. Osborn at 326. At the same time, "some arms of the government, such as the military, actively encourage off-label use by purchasing and providing drugs specifically intended for off-label use". Osborn at 304. But really now, who expects the government to be consistent?
Osborn also points out that the cases coming out of the US Attorney's offices in Boston and Philadelphia have been aggressive, "innovative," and devoid of "any apparent policy coordinating". Osborn at 323. Those cases might earn some agents credits and some AUSAs style points, but it's hardly the stuff of consistent policy and fair notice. What we have, according to Osborn, is "the government's de facto policy of limited rulemaking and broad enforcement." Osborn at 307.
To make matters worse, companies are under enormous pressure to kowtow to or settle with the FDA or the prosecutors when they challenge off-label statements. Companies have to live with the FDA every day, and the prospect of debarment following a successful prosecution -- a virtual corporate death sentence -- is too much to risk. Osborn at 327.
What this means is that there is a "paucity of federal judicial review". Id. At least if there was substantial case law people would have a better idea of what the rules are. Even in First Amendment jurisprudence the FDA's last minute safe-harbor two-step in the Washington Legal Foundation litigation muddied the issue of dissemination of peer-reviewed reprints regarding off-label uses -- which is apparently exactly what the FDA intended. Take a look at the Washington Legal Foundation "DDMAC watch" write-ups to see how the FDA treats the First Amendment like teenagers treat speed bumps in the mall parking lot.
Osborn gives some concrete examples where enforcement of the prohibition against off-label promotion has led to unclear results that probably have deprived some patients of drugs that would have helped them:
- Gilead Sciences Viread
- Cephalon's Provigil
- Genentech's Avastin
- Allergan's Botox
If you unfamiliar with any of these unhappy stories, Osborn does a nice job of summarizing them and why the government's enforcement likely did consumers more harm than good. Osborn at 332-39.
Osborn then discusses an "alternative model," the United Kingdom. Osborn at 340-49. Across the Atlantic there are fewer prosecutions, more government-industry collaboration, more self-regulation (including by competitors), and clearer rules. And nobody seems to suffer from any of it. Well, maybe plaintiff lawyers do. We haven't asked.
We know a lot of lawyers who stop reading law review articles halfway through. They find the first part, which analyzes the issue and provides heaps of nifty case cites, extremely useful. But they tend to ignore the second part, which typically offers a proposed solution. Here, Osborn's dissection of off-label enforcement - laying out how and why it is such a problem - is spot on. But his call for more self-regulation and a movement toward the British system will sound to some ears a wee bit unrealistic. We just can't see ourselves strolling into the Philadelphia Court of Common Pleas and pointing to the British example. And to be fair, that's not what Osborn is suggesting.
Indeed, Osborn makes some concrete, incremental suggestions that are eminently sensible and might make the American system of enforcement less of a lottery system:
- FDA should promptly issue clear rules on a number of the "hot"issues, such as consulting agreements, the internet, CME, and activities of Medical Science Liaisons;
- HHS should oversee most off-label investigations and only egregious cases should be referred to the DOJ;
- increased use of reasonable statutory civil penalties rather than waving the criminal hammer;
- giving the FDA more money to process supplemental NDAs for expanded indications; and
- Congress should clarify that the False Claims Act does not apply when there is no false statement.
Osborn at 353-55.
To this list we would add our wish that courts would confine the off-label issue to cases where it really applies and where a prescriber says that the promotion really made a difference. Granted, we're saying that out of self-interest. The policy benefit would be a nice bonus.