Thursday, May 15, 2008

Off-Label Use - Is The FDA Missing An Opportunity?

As we mentioned last week, we’re both going to be speaking on the same panel at the American Enterprise Institute’s conference next week about off-label use. That’s got us thinking – surprise, surprise – about off-label use.

So we’ve been reading a couple of things. One of them is the Justice Department’s recent amicus brief concerning off-label use and False Claims Act liability. Here’s a link to the brief.

Another thing we’ve been reviewing is some of the comments to the FDA’s proposal to loosen, just a bit, its restrictions on off-label promotion involving medical journal articles and medical textbooks. We blogged about that proposal shortly after it first came out. Now the comment period has closed (no, we didn’t comment – that would have to be paying work) and we were curious about what the interested parties were saying.

You can find and review all 96 comments here. When you click on this link, you’ll get a list of all the comments, and next to them are icons that take you to the comments themselves.

So what do we think? Well, we don’t claim to be experts in False Claims Act (“FCA”) litigation, and while reading the Department of Justice’s brief, we were pinching ourselves to remember that the Department both prosecutes these suits and is responsible for protecting the government’s money. So we can’t say that we’re really very surprised that the government took what to our uninitiated minds seems like a rather broad interpretation of the statute.

But we’re interested primarily in off-label use – and especially in the dissemination of truthful information about such uses, an activity that we believe is First Amendment protected. So we read the government’s brief with an eye towards whether a “false” claim can lie where all of the information that a manufacturer gave out to promote the use is truthful.

A lot of the DOJ's brief is about the off-label uses that the government pays for under certain circumstances. That’s because, for Medicare purposes, there are off-label uses – and then there are off-label uses. The government pays for off-label uses that are “supported” by citations in certain designated (and authoritative) medical compendia. 42 U.S.C. §1396r-8(k)(6). The DOJ goes through an extensive argument about whether the mere presence of a citation in those compendia qualifies as “support,” and if not, how much beyond a “mere” listing is needed to qualify as “support.” We suppose that reasonable minds may differ on that.

More important, to us is the fact that the government pays for some of the very same off-label uses that the FDA is simultaneously prohibiting manufacturers from promoting truthfully. That fact undercuts the constitutional validity of the FDA’s prohibition by putting the Agency at cross purposes with other agencies.

The DOJ’s brief doesn’t address, one way or the other, truthful promotion of off-label uses that are not “supported” by any of these compendia. That’s because the specific case in which it was filed (called Rost) involved an arguably “supported” use.

In its “support” argument, however, the DOJ doesn’t seem to be taking a position, one way or another, about truthful statements about off-label uses. Rather its argument is about whether there could ever be a false claim, because if an off-label use is “supported,” the government is supposed to pay for it, and thus it can’t be “false” (without more) to submit a claim for a “supported” off-label use.

How much more?

Even if an off-label use is “supported” within the meaning of the statute, it can be “false” for other reasons, the DOJ argues. We don’t care about kickbacks, unlicensed doctors, or non-existent patients. Beyond those examples, the government states, “a claim [for a supported off-label use] may be rendered false if a drug manufacturer falsified studies or engaged on other unlawful, fraudulent conduct in the promotion of a drug….” DOJ br. at 7. Well, falsifying studies is certainly not truthful activity, and there is no “or” between “unlawful” and “fraudulent,” so it seems like the government is limiting liability to promotional activity that is not only “unlawful” (such as truthful promotion of off-label use) but also “fraudulent.”

So far, so good.

But that’s as far as anything good goes.

Things then go rapidly downhill. The government asserts:

This court has held that illegal off-label marketing that results in the submission of impermissible claims for reimbursement states a claim under the FCA. … Proof of falsity could entail a showing that the provider sought payment from a federal health care program that was off-label and not covered by the program. It is not necessary also to show (or allege) an express falsehood from the defendant to the provider to satisfy the “falsity” element.

DOJ br. at 8 (emphasis added). Well, are we talking about falsehood or privity here?

The next paragraph starts out OK, “Defendants correctly observe that to state a claim … there must be a false record or statement.” Id. That’s good by itself, but it’s not by itself. After that, the rabbit goes into the hat:

[R]equiring a false statement to be made by the defendant drug company is contrary to the plain meaning of the FCA. Although [the FCA] requires the existence of a false statement, it does not require the false statement to be made by the defendant.

Id. at 8-9 (emphasis original). In other words, a manufacturer’s entirely truthful promotion of off-label use can still subject a manufacturer to liability if somebody else (usually a prescriber) then makes some false statement in connection with a claim. In a footnote, the DOJ clarifies that liability isn’t contingent on any control requirement – the other party’s false statement can occur without any “affirmative” direction by the manufacturer engaged in truthful promotion of off-label use. Id. at 10 n.8.

So, yes, it appears that the DOJ is taking the position that even a manufacturer’s entirely truthful promotion of off-label use is, without anything more on its (as opposed to somebody else’s) part, sufficient to subject it to liability under the FCA.

And there’s more – another footnote indicates that such liability extends even to promotion using medical journal articles and textbooks that the FDA has proposed should be allowed. See DOJ br. at 9-10 n. 7 (pointing out that the FDAMA safe harbor for such promotion has expired and that the FDA’s new guidance is non-binding).

We’ve learned that, with government amicus briefs, it’s very important to read the footnotes.

Thus, truth, apparently, is not a defense to the FCA.

Think about that – under the FCA, truth can be “false.”

Where have we heard that before?

So yes, not only is Big Brother watching, he’s ready and willing to sue.

So why do we care?

We care because, at least since the Supreme Court’s decision in Thompson v. Western States Medical Center, 535 U.S. 357 (2002), it’s been pretty clear that the FDA’s current regime, which relies upon prohibition of truthful speech to control promotion of off-label uses, is vulnerable to First Amendment constitutional challenge. If you’re interested in the detailed argument, it’s all set out here.

Anyway, that’s our premise.

We’re wondering where that challenge might come from and how it might look. We know that most major manufacturers would much rather cooperate with the FDA than raise constitutional challenges to its actions – especially First Amendment challenges that strike very close to the FDA’s institutional purpose (approval of regulated products). After all, FDA regulated manufacturers have to deal with the FDA on a regular basis.

These FCA cases, however, are for big bucks – many millions of dollars – and they can be brought by private individuals, who are statutorily authorized to sue on the government’s behalf. Well then, if: (1) a company’s facing huge potential liability, (2) it’s not litigating against the FDA directly, and (3) the facts about the truthfulness of the promotion are good enough, a direct First Amendment appellate challenge to the FDA’s prohibitory regime could well emerge from this type of litigation.

It’s the second part of this equation – the truthfulness of the promotion – that had us looking through the comments to the FDA’s proposed reprint practices guidance. As we discussed at length in our first post on this subject, the FDA’s proposal is loaded with caveats designed to ensure the truth and validity of the medical journal articles and published medical textbooks that it proposes to allow manufacturers to disseminate about off-label uses.

And, indeed, the extent of those restrictions are the subject of some of the industry’s critiques of the proposal. Generally speaking the industry groups, such as PhARMA, MDMA, and ADVAMED (the site’s not letting us link directly to all, so we’re won’t favor one over the other, you can find them all here), would like to broaden the categories of materials that can be used (right now it’s limited to “adequate and well-controlled clinical investigations”), would like to see the “safe harbor” language less equivocal, and don’t want anything that limits other, existing exceptions or impinges upon the First Amendment protection of truthful commercial and scientific speech.

In the middle are groups like the AMA, Sen. Grassley, and others, who offer varying degrees of support for FDA’s initiative, but urge the Agency to tighten up various aspects of it, such as ghostwriting and oversight.

At the other end are the trial lawyers and various consumer groups, whose comments oppose any change, and mostly consist of examples of what they see as industry overreaching and general misconduct. That’s par for the course for them.

A lot of their complaints, as well, have to do with “ghostwriting” of medical articles. That seems to be their hot topic du jour.

We (not surprisingly) don’t view ghostwriting as at all central to the FDA’s proposal. We’re much more concerned with ensuring the truthfulness of what’s actually written than we are with the identity of who actually puts pen to paper. As long as doctors get accurate information, we’re not going to spend much time on the byline.

We’re lawyers, and in our profession ghostwriting happens every day. Precedent remains precedent, even if most of a judge’s legal opinion was actually written by a law clerk. That’s ghostwriting. Nor are we offended that every word of this or that professor’s law review article isn’t actually penned by the professor, but instead by by law students or other research assistants working under the professor’s guidance. That’s the way things are in the law, and we don’t expect them to be different in medicine or other parts of the academic world.

To us, truth is truth and false is false, no matter who actually writes it.

But to the extent that the FDA thinks that ghostwriting tends to inject difficult to control biases into medical literature, or to obscure the actual source of the information from the reader, we wouldn’t be all that exercised if the Agency either chose to require disclosure of the practice, or even to prohibit it in articles to be disseminated under the proposed guidance.

In the greater scheme of things, ensuring the truthfulness and accuracy of the content of the articles and textbooks themselves is to us far more important than who’s listed or not listed as the author.

What we do see in looking over the comments is a possible lost opportunity for the FDA to use this limited guidance concerning published journal articles and textbooks to provide a “test drive” of a less speech-restrictive – and thus less constitutionally suspect – regime of dealing with off-label promotion.

Complaint #1 – off-label promotion generates too much off-label use that’s totally outside any regulatory control.

OK, then how about requiring some record keeping/monitoring as part of the guidance so that the FDA can see whether that’s true or not, and also use the information to formulate more tailored responses to particular situations? Let’s find out if this is true, and if it is whether there’s anything that should be done about it.

Complaint #2 – off-label promotion reduces the incentive to submit new uses for FDA approval.

That’s probably true, but it doesn’t have to be. Based upon the aforementioned record keeping and monitoring, we doubt it would be that hard for the FDA to come up with some formula (percentage off-label use, or dollar value of off-label use, something else, or some combination) under which it could require some off-label uses subject to the guidance to be submitted for approval by the manufacturer (or manufacturers, if there are generics involved). This leads us to….

Complaint #3 – the kinds of studies that the FDA requires for regulatory approval are just too expensive and time consuming to make any requirement to conduct them worthwhile.

That’s certainly what torpedoed the old FDAMA safe harbor - it wasn’t worth the candle to use it. But remember, the FDA’s proposed guidance is for articles and textbooks already describing “adequate and well controlled studies.” If we’ve got that kind of data at the front end, there’s less need for it at the back end.

There are plenty of cheaper ways than blinded, controlled studies for figuring out whether an off-label use is safe and effective. As Bone Screw veterans, we know that the FDA finally dealt with that product’s off-label use (which had become the medical standard of care, thereby ethically precluding studies that withheld treatment to control groups) by ordering a retrospective study. See 63 Fed. Reg. 40025 (FDA July 27, 1998). The Agency could employ the same administrative flexibility with off-label uses subject to the proposed guidance. After all, these aren’t new drugs, and the off-label uses are taking place anyway. It would seem to make sense to capture this clinical experience for labeling purposes if at all possible.

That kind of regime – allowing truthful speech, but accompanied by non-speech regulations – avoids the First Amendment problems inherent in the FDA’s current regime.

Remember, what’s under consideration (at least at this point) is not off-label promotion generally, but off-label promotion using published, peer reviewed materials, clearly labeled as involving unapproved uses.

After Western States, the likelihood isn’t great that someone complying with the proposed guidance could be constitutionally prosecuted for truthful off-label promotion. Even in the recent Caputo case (discussed here), where the facts were quite bad for the defendants, the court nevertheless gave the government a shot across the bow – warning prosecutors that lumping truthful off-label promotion together with false and fraudulent promotion raised serious constitutional questions. See United States v. Caputo, 517 F.3d 935, 938-40 (7th Cir. 2008).

Thus, even dropping the FDA’s proposed guidance altogether at this point would not prevent some brave soul from following it as a form of constitutionally protected commercial speech.

More fundamentally, we have to believe that one reason for the claimed industry “abuses” described in the comments opposing the FDA’s proposed guidance is the lack of any legal way, at present, to conduct off-label promotion. If the Agency were to provide industry with an avenue for off-label promotion, both legal and practical, that provided physicians with truthful information about off-label use, the industry would be foolish not to use it.

We know this industry – it is not foolish.

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